Conventional and novel stem cell based therapies for androgenic alopecia
Dodanim Talavera-Adame,1 Daniella Newman,2 Nathan Newman1
1American Advanced Medical Corp. (Private Practice), Beverly Hills, CA,
2Western University of Health Sciences, Pomona, CA, USA
Abstract
The prevalence of androgenic alopecia (AGA) increases with age and it affects both men and women. Patients diagnosed with AGA may experience decreased quality of life, depression, and feel self-conscious. There are a variety of therapeutic options ranging from prescription drugs to non-prescription medications. Currently, AGA involves an annual global market revenue of US$4 billion and a growth rate of 1.8%, indicating a growing consumer market. Although natural and synthetic ingredients can promote hair growth and, therefore, be useful to treat AGA, some of them have important adverse effects and unknown mechanisms of action that limit their use and benefits. Biologic factors that include signaling from stem cells, dermal papilla cells, and platelet-rich plasma are some of the current therapeutic agents being studied for hair restoration with milder side effects. However, most of the mechanisms exerted by these factors in hair restoration are still being researched. In this review, we analyze the therapeutic agents that have been used for AGA and emphasize the potential of new therapies based on advances in stem cell technologies and regenerative medicine.
Introduction
The prevalence of androgenic alopecia (AGA) increases with age, and is estimated to affect about 80% of Caucasian men.1 Female AGA, also known as female pattern hair loss, affects 32% of women in the ninth decade of life.2 The consumer market for products that promote hair growth has been increasing dramatically.3 These products promote hair regeneration based on the knowledge about the hair follicle (HF) cycle.4,5 However, in most cases, the mechanisms of action of these products are not well characterized and the results are variable or with undesirable side effects.6 At present, only two treatments for AGA have been approved by the US Food and Drug Administration (FDA): Minoxidil and Finasteride.7–10Although these medications have proved to be effective in some cases, their use is limited by their side effects.11,12 With the emergence of stem cells (SCs), many mechanisms that lead to tissue regeneration have been discovered.13 Hair regeneration has become one of the targets for SC technologies to restore the hair in AGA.14 Several SC factors such as peptides exert essential signals to promote hair regrowth.15,16 Some of these signals stimulate differentiation of SCs to keratinocytes which are important for HF growth.17 Other signals can stimulate dermal papilla cells (DPCs) that promote SC proliferation in the HF.18,19 In this review, we describe HF characteristics and discuss different therapies used currently for AGA and possible novel agents for hair regeneration. These therapies include FDA-approved medications, non-prescription physical or chemical agents, natural ingredients, small molecules, biologic factors, and signals derived from SCs.
HF and SC niche
The HF undergoes biologic changes from an actively growing stage (anagen) to a quiescent stage (telogen) with an intermediate remodeling stage (catagen).4 HFSCs are located in the bulge region of the follicle and they interact with mesenchymal SCs (MSCs) located in the dermal papilla (DP).18 These signal exchanges promote activation of some cellular pathways that are essential for DPC growth, function, and survival, such as the activation of Wnt signaling pathway.19–21 Other signals, such as those from endothelial cells (ECs) located at the DP, are also essential for HF maintenance.22 EC dysfunction that impairs adequate blood supply may limits or inhibits hair growth.22 For instance, Minoxidil, a synthetic agent, is able to promote hair growth by increasing blood flow and the production of prostaglandin E2 (PGE2).7 It has been shown that proteins that belong to the transforming growth factor (TGF) superfamily, such as bone morphogenetic proteins (BMPs), also exert signals to maintain the capacity of DPCs to induce HF growing in vivo and in vitro.23 These BMPs may be released by several cells that compose the follicle, including ECs.24–26 ECs may provide signals for BMP receptor activation in DPCs similar to those signals that promote survival of MSCs in human embryoid bodies composed of multipotent cells.24,25 DPCs have been derived from pluripotent SCs in an attempt to study their potential for hair regeneration in vitro and in vivo.27 Together, dermal blood vessels and DPCs orchestrate a suitable microenvironment for the growth and survival of HFSCs.28,29 Interestingly, the expression of Forkhead box C1 regulates the quiescence of HFSCs located in the bulge region (Figure 1).30 HFSCs are quiescent during mid-anagen and maintain this stage until the next hair cycle.29,30 However, during early anagen stage, these cells undergo a short proliferative phase in which they self-renew and produce new hair.30 Therefore, the bulge region constitutes a SC niche that makes multiple signals toward quiescence or proliferation stages.30–34 It is known that fibroblasts and adipocyte signals are able to inhibit the proliferation of HFSCs.34 Additionally, BMP6 and fibroblast growth factor 18 (FGF18) from bulge cells exert inhibitory effects on HFSC proliferation.34 Dihydrotestosterone (DHT) also inhibits HF growth.35 Agents that reduce DHT, such as Finasteride, promote hair regrowth by inhibiting Type II 5a-reductase.8,14,36 In contrast to these inhibitory effects, DPCs located at the base of the HF provide activation signals (Figure 1).18,34 The crosstalk between DPCs and HFSCs leads to inhibition of inhibitory effects with the resultant cell proliferation toward hair regeneration (anagen).30,31,37 With the self-renewal of HFSCs, the outer root sheath (ORS) forms, and signals from DPCs to the bulge cells diminish in a way that the bulge cells start again with their quiescent stage.4,34As mentioned earlier, Forkhead box C1 transcription factor has an important role in maintaining the threshold for HFSC activation.30 The knockdown of these factors in bulge cells reduces the cells’ threshold for proliferation, and the anagen cycle starts more frequently due to promotion of HFSC proliferation in shorter periods of time.30
Laser therapy
Light amplification by stimulated emission of radiation (LASER) generates electromagnetic radiation which is uniform in polarization, phase, and wavelength.45 Low-level laser therapy (LLLT), also called “cold laser” therapy, since it utilizes lower power densities than those needed to produce heating of tissue. Transdermal LLLT has been used for therapeutic purposes via photobiomodulation.46,47 Several clinical conditions, such as rheumatoid arthritis, mucositis, pain, and other inflammatory diseases, have been treated with these laser devices.48–50 LLLT promotes cell proliferation by stimulating cellular production of adenosine triphosphate and creating a shift in overall cell redox potential toward greater intracellular oxidation.51 The redox state of the cell regulates activation of signaling pathways that ultimately promotes high transcription factor activity and gene expression of factors associated with the cell cycle.52 Physical agents such as lasers have been also used to prevent hair loss in a wavelength range in the red and near infrared (600–1,070 nm).5,47,51,53 Laser therapy emits light that penetrates the scalp and promotes hair growth by increasing the blood flow.54 This increase gives rise to EC proliferation and migration due to upregulation of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase.55,56 In addition, the laser energy itself stimulates metabolism in catagen or telogen follicles, resulting in the production of anagen hair.53,54A specific effect of LLLT has been demonstrated to promote proliferation of HFSCs, forcing the hair to start the anagen phase.57
Biologic agents that promote hair growth and their mechanisms of action
SC signaling
Recently, it has been found that SCs release factors that can promote hair growth.16 These factors and their mechanisms of action have been summarized in Table 3. These factors, known as “secretomes”, are able to promote skin regeneration, wound healing, and immunologic modulation, among other effects.58,59 Some of these factors, such as epidermal growth factor (EGF), basic fibroblast growth factor, hepatocyte growth factor (HGF) and HGF activator, VEGF, insulin-like growth factor (IGF), TGF-ß, and platelet-derived growth factor (PDGF), are able to provide signals that promote hair growth.15,60–64 As mentioned before, DPCs provide signals to HFSCs located in the bulge that proliferate and migrate either to the DP or to the epidermis to repopulate the basal layer (Figure 1).32,65 Enhancement in growth factor expression (except for EGF) has been reported when the adipose SCs are cultured in hypoxic conditions.15 Also, SCs increase their self-renewal capacity under these conditions.66–68 Low oxygen concentrations (1%–5%) increase the level of expression of SC factors that include VEGF, basic fibroblast growth factor, IGF binding protein 1 (IGFBP-1), IGF binding protein 2 (IGFBP-2), macrophage colony-stimulating factor (M-CSF), M-CSF receptor (M-CSFR), and PDGF receptor ß (PDGFR-ß).15,69,70 While these groups of factors promote HF growth in intact skin, another group of factors, such as M-CSF, M-CSFR, and interleukin-6, are involved in wound-induced hair neogenesis.71 HGF and HGF activator stimulate DPCs to promote proliferation of epithelial follicular cells.61 Epidermal growth factor promotes cellular migration via the activation of Wnt/ß-catenin signaling.60 VEGF promotes hair growth and increases the follicle size mainly by perifollicular angiogenesis.72 Blocking VEGF activity by neutralizing antibodies reduced the size and growth of the HF.72 PDGF and its receptor (PDGFR-a) are essential for follicular development by promoting upregulation of genes involved in HF differentiation and regulating the anagen phase in HFs.64,73 They are also expressed in neonatal skin cells that surround the HF.73 Monoclonal antibodies to PDGFR-a (APA5) produced failure in hair germ induction, supporting that PDGFR-a and its ligand have an essential role in hair differentiation and development.73 IGF-1 promotes proliferation, survival, and migration of HF cells.69,74 In addition, IGF binding proteins (IGFBPs) also promote hair growth and hair cell survival by regulating IGF-1 effects and its interaction with extracellular matrix proteins in the HF.70 Higher levels of IGF-1 and IGFBPs in beard DPCs suggest that IGF-1 levels are associated with androgens.74 Furthermore, DPCs from non-balding scalps showed significantly higher levels of IGF-1 and IGFBP-6, in contrast to DPCs from balding scalps.74
Table 3
Stem cell factors and small molecules that promote hair growth and their mechanisms of action
| Factor | Mechanism of action |
|---|---|
| HGF and HGF activator61 | Factor secreted by DPC that promotes proliferation of epithelial follicular cells |
| EGF60 | Promotes growth and migration of follicle ORS cells by activation of Wnt/ß-catenin signaling |
| bFGF62 | Promotes the development of hair follicle |
| IL-693 | Involved in WIHN through STAT3 activation |
| VEGF72 | Promotes perifollicular angiogenesis |
| TGF-ß63 | Stimulates the signaling pathways that regulate hair cycle |
| IGF-169 | Promotes proliferation, survival, and migration of hair follicle cells |
| IGFBP-1 to -670 | Regulates IGF-1 effects and its interaction with extracellular matrix proteins at the hair follicle level |
| BMP23 | Maintains DPC phenotype which is crucial for stimulation of hair follicle stem cell |
| BMPR1a23 | Maintains the proper identity of DPCs that is essential for specific DPC function |
| M-CSF71 | Involved in wound-induced hair regrowth |
| M-CSFR71 | Involved in wound-induced hair regrowth |
| PDGF and PDGFR-ß/-a64 | Upregulates the genes involved in hair follicle differentiation. Induction and regulation of anagen phase. PDGF and its receptors are essential for follicular development |
| Wnt3a97 | Involved in hair follicle development through ß-catenin signaling |
| PGE279,80 | Stimulates anagen phase in hair follicles |
| PGF2a and analogs79,80 | Promotes transition from telogen to anagen phase of the hair cycle |
| BIO98 | GSK-3 inhibitor |
| PGE2 or inhibition of PGD2 or PGD2 receptor D2/GPR4477 | Promotes follicle regeneration |
| Iron and l-lysine95 | Under investigation |
Abbreviations: bFGF, basic fibroblast growth factor; BIO, (2’Z,3’E)-6-bromoindirubin-3′-oxime; BMP, bone morphogenetic protein; DPCs, dermal papilla cells; EGF, epidermal growth factor; GSK-3, glycogen synthase kinase-3; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor 1; IGFBP-1, insulin-like growth factor-binding protein 1; IL-6, interleukin-6; M-CSF, microphage colony-stimulating factor; M-CSFR, microphage colony-stimulating factor receptor; ORS, outer root sheath; PDGF, platelet-derived growth factor; PDGFR-a, platelet-derived growth factor receptor alpha; PDGFR-ß, platelet-derived growth factor receptor beta; PGD2, prostaglandin D2; PGE2, prostaglandin E2; TGF-ß1, transforming growth factor ß1; VEGF, vascular endothelial growth factor; WIHN, wound-induced hair neogenesis; Wnt3a, wingless-type MMTV integration site family, member 3A.
Small molecules
Small molecules with low molecular weight (<900 Da) and the size of 10-9 m are organic compounds that are able to regulate some biologic processes.75 Some small molecules have been tested for their role in hair growth.76 Synthetic, non-peptidyl small molecules that act as agonists of the hedgehog pathway have the ability to promote follicular cycling in adult mouse skin.76 PGE2 and prostaglandin D2 (PGD2) have also been associated with the hair cycle (Table 3).77 PGD2 is elevated in the scalp of balding men and inhibits hair lengthening via GPR44 receptor.78 Also, it is known that PGE2 and PGF2a promote hair growth, while PGD2 inhibits this process.77,79 Prostaglandin analogs of PGF2a have been used originally to decrease ocular pressure in glaucoma with parallel effects in the growth of eyelashes, which suggests a specific effect in HF activation.80 PGD2 receptors are located in the upper and lower ORS region and in the DP, suggesting that these prostaglandins play an important role in hair cycle.81 Molecules such as quercetin are able to inhibit PGD2 and, in this way, promote hair growth.82–84 Antagonists of PGD2 receptor (formally named chemoattractant receptor-homologous expressed in Th2 cells) such as setipiprant have been used to treat allergic diseases such as asthma, but they also have beneficial effects in AGA.85–87 Another small molecule l-ascorbic acid 2-phosphate promotes proliferation of ORS keratinocytes through the secretion of IGF-1 from DPCs via phosphatidylinositol 3-kinase.88 Recently, it has been described that small-molecule inhibitors of Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway promote hair regrowth in humans.89 Janus kinase inhibitors are currently approved by the FDA for the treatment of some specific diseases such as psoriasis and other autoimmune-mediated diseases.90–94 Also, another group of small molecules such as iron and the amino acid l-Lysine are essential for hair growth (Table 3).95
Cellular therapy
The multipotent SCs in the bulge region of the HF receive signals from DPCs in order to proliferate and survive.27,28,65,84,96 It has been shown that Wnt/ß-catenin signaling is essential for the growth and maintenance of DPCs.19,97 These cells can be isolated and cultured in vitro with media supplemented with 10% fetal bovine serum and FGF-2.37,98 However, they lose versican expression that correlates with decrease in follicle-inducing activity in culture.98 Versican is the most abundant component of HF extracellular matrix.99 Inhibition of glycogen synthase kinase-3 by (2’Z,3’E)-6-bromoindirubin-3′-oxime (BIO) promotes hair growth in mouse vibrissa follicles in culture by activation of Wnt signaling.98 Therefore, the increase of Wnt signaling in DPCs apparently is one of the main factors that promote hair growth.19 DPCs have been also generated from human embryonic SCs that induced HF formation after murine transplantation.27
Platelet-rich plasma
Platelets are anucleate cells generated by fragmentation of megakaryocytes in the bone marrow.100 These cells are actively involved in the hemostatic process after releasing biologically active molecules (cytokines).100–102 Because of the platelets’ higher capacity to produce and release these factors, autologous platelet-rich plasma (PRP) has been used to treat chronic wounds.103 Therefore, PRP can be used as autologous therapy for regenerative purposes, for example, chondrogenic differentiation, wound healing, fat grafting, AGA, alopecia areata, facial scars, and dermal volume augmentation.101,104–108 PRP contains human platelets in a small volume that is five to seven times higher than in normal blood and it has been proven to be beneficial to treat AGA.10,105,109–111 The factors released by these platelets after their activation, such as PDGFs (PDGFaa, PDGFbb, PDGFab), TGF-ß1, TGF-ß2, EGF, VEGF, and FGF, promote proliferation of DPCs and, therefore, may be beneficial for AGA treatment.109,112–114 Clinical experiments indicate that patients with AGA treated with autologous PRP show improved hair count and thickness.109
In search of novel therapies
In this paper, we reviewed and discussed the use of therapeutic agents for hair regeneration and the knowledge to promote the development of new therapies for AGA based on the advances in regenerative medicine. The HF is a complex structure that grows when adequate signaling is provided to the HFSCs. These cells are located in the follicle bulge and receive signals from MSCs located in the dermis that are called DPCs. The secretory phenotype of DPCs is determined by local and circulatory signals or hormones. Recent discoveries have demonstrated that SCs in culture are able to activate DPCs and HFSCs and, in this way, promote hair growth. The study of these cellular signals can provide the necessary knowledge for developing more effective therapeutic agents for the treatment of AGA with minimal side effects. Therefore, advancements in the field of regenerative medicine may generate novel therapeutic alternatives. However, further research and clinical studies are needed to evaluate their efficacy.
Disclosure
The authors report no conflicts of interest in this work.
References
|
Blumeyer A, Tosti A, Messenger A, et al; European Dermatology Forum (EDF). Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. J Dtsch Dermatol Ges. 2011;9(Suppl 6):S1–S57. |
||
|
Ramos PM, Miot HA. Female pattern hair loss : a clinical and pathophysiological review. An Bras Dermatol. 2015;90(4):529–543. |
||
|
Otberg N, Finner AM, Shapiro J. Androgenetic alopecia. Endocrinolo Metab Clin North Am. 2007;36(2):379–398. |
||
|
Plikus MV, Chuong CM. Complex hair cycle domain patterns and regenerative hair waves in living rodents. J Invest Dermatol. 2008;128(5):1071–1080. |
||
|
McElwee KJ, Shapiro JS. Promising therapies for treating and/or preventing androgenic alopecia. Skin Therapy Lett. 2012;17(6):1–4. |
||
|
Perez-Mora N, Velasco C, Bermüdez F. Oral finasteride presents with sexual-unrelated withdrawal in long-term treated androgenic alopecia in men. Skinmed. 2015;13(3):179–183. |
||
|
Gupta AK, Charrette A. Topical minoxidil: systematic review and meta-analysis of its efficacy in androgenetic alopecia. Skinmed. 2015;13(3):185–189. |
||
|
Shapiro J, Kaufman KD. Use of finasteride in the treatment of men with androgenetic alopecia (male pattern hair loss). J Investig Dermatol Symp Proc. 2003;8(1):20–23. |
||
|
Rossi A, Anzalone A, Fortuna MC, et al. Multi-therapies in androgenetic alopecia: review and clinical experiences. Dermatol Ther. 2016;29(6):424–432. |
||
|
Varothai S, Bergfeld WF. Androgenetic alopecia: an evidence-based treatment update. Am J Clin Dermatol. 2014;15(3):217–230. |
||
|
Rossi A, Cantisani C, Melis L, Iorio A, Scali E, Calvieri S. Minoxidil use in dermatology, side effects and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2012;6(2):130–136. |
||
|
Motofei IG, Rowland DL, Georgescu SR, Mircea T, Baleanu BC, Paunica S. Are hand preference and sexual orientation possible predicting factors for finasteride adverse effects in male androgenic alopecia? Exp Dermatol. 2016;25(7):557–558. |
||
|
Reijo Pera RA, Gleeson JG. Stems cells and regeneration: special review issue. Hum Mol Gen. 2008;17(R1):R1–R2. |
||
|
Jain R, De-Eknamkul W. Potential targets in the discovery of new hair growth promoters for androgenic alopecia. Expert Opin Ther Targets. 2014;18(7):787–806. |
||
|
Park BS, Kim WS, Choi JS, et al. Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia : evidence of increased growth factor secretion. Biomed Res. 2010;31(1):27–34. |
||
|
Fukuoka H, Suga H. Hair regeneration treatment using adipose-derived stem cell conditioned medium :follow-up with trichograms. Eplasty. 2015;15:65–72. |
||
|
Du Y, Roh DS, Funderburgh ML, et al. Adipose-derived stem cells differentiate to keratocytes in vitro. Mol Vis. 2010;16:2680–2689. |
||
|
Zhang P, Kling RE, Ravuri SK, et al. A review of adipocyte lineage cells and dermal papilla cells in hair follicle regeneration. J Tissue Eng. 2014;5:2041731414556850. |
||
|
Tsai SY, Sennett R, Rezza A, et al. Wnt/ß-catenin signaling in dermal condensates is required for hair follicle formation. Dev Biol. 2014;385(2):179–188. |
||
|
Choi YS, Zhang Y, Xu M, et al. Distinct functions for Wnt/ß-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell. 2013;13(6):720–733. |
||
|
Rao TP, Kuhl M. An updated overview on Wnt signaling pathways a prelude for more. Circ Res. 2010;106(12):1798–1806. |
||
|
Yano K, Brown LF, Detmar M. Control of hair growth and follicle size by VEGF-mediated angiogenesis. J Clin Invest. 2001;107(4):409–417. |
||
|
Rendl M, Polak L, Fuchs E. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 2008;22(4):543–557. |
||
|
Talavera-Adame D, Gupta A, Kurtovic S, Chaiboonma KL, Arumugaswami V, Dafoe DC. Bone morphogenetic protein-2/-4 upregulation promoted by endothelial cells in coculture enhances mouse embryoid body differentiation. Stem Cells Dev. 2013;22(24):3252–3260. |
||
|
Talavera-Adame D, Wu G, He Y, et al. Endothelial Cells in Co-culture Enhance Embryonic Stem Cell Differentiation to Pancreatic Progenitors and Insulin-Producing Cells through BMP Signaling. Stem Cell Rev. 2011;7(3):532–543. |
||
|
Talavera-Adame D, Ng TT, Gupta A, Kurtovic S, Wu GD, Dafoe DC. Characterization of microvascular endothelial cells isolated from the dermis of adult mouse tails. Microvascular Res. 2011;82(2):97–104. |
||
|
Gnedeva K, Vorotelyak E, Cimadamore F, et al. Derivation of hair-inducing cell from human pluripotent stem cells. PLoS One. 2015;10(1):1–14. |
||
|
Lavker RM, Sun T, Oshima H, et al. Hair follicle stem cells. J Investig Dermatol Symp Proc. 2003;8(1):28–38. |
||
|
Bernard B. Advances in understanding hair growth. F1000Res. 2016;5:1–8. |
||
|
Lay K, Kume T, Fuchs E. FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential. Proc Natl Acad Sci U S A. 2016;113(1): E1506–E1515. |
||
|
Leirós GJ, Attorresi AI, Balañá ME. Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/ß-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia. Br J Dermatol. 2012;166(5):1035–1042. |
||
|
Chacon-Martinez CA, Klose M, Niemann C, Glauche I, Wickström SA. Hair follicle stem cells= cultures reveal self-organizing plasticity of stem cells and their progeny. EMBO J. 2017;36(2):151–164. |
||
|
Soler AP, Gilliard G, Megosh LC, O’Brien TG. Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity. J Invest Dermatol. 1996;106(5):1108–1113. |
||
|
Hsu YC, Pasolli HA, Fuchs E. Dynamics between stem cells, nich and progeny in the hair follicle. Cell. 2011;144(1):92–105. |
||
|
Kang JI, Kim SC, Kim MK, et al. Effects of dihydrotestosterone on rat dermal papilla cells in vitro. Eur J Pharmacol. 2015;757:74–83. |
||
|
Yamana K, Labrie F, Luu-The V. Human type 3 5a-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride. Horm Mol Biol Clin Investig. 2010;2(3):293–299. |
||
|
Osada A, Iwabuchi T, Kishimoto J, Hamazaki TS, Okochi H. Long-term culture of mouse vibrissal dermal papilla cells and de novo hair follicle induction. Tissue Eng. 2007;13(5):975–982. |
||
|
Choi GS, Kim JH, Oh SY, et al. Safety and tolerability of the dual 5-alpha reductase inhibitor dutasteride in the treatment of androgenetic alopecia. Ann Dermatol. 2016;28(4):444–450. |
||
|
Carson C 3rd, Rittmaster R. The role of dihydrotestosterone in benign prostatic hyperplasia. Urology. 2003;61(4 Suppl 1):2–7. |
||
|
Kamimura A, Takahashi T. Procyanidin B-2, extracted from apples, promotes hair growth: a laboratory study. Br J Dermatol. 2002;146(1):41–51. |
||
|
Kamimura A, Takahashi T. Procyanidin B-3, isolated from barley and identified as a hair-growth stimulant, has the potential to counteract inhibitory regulation by TGF-beta1. Exp Dermatol. 2002;11(6):532–541. |
||
|
Ulbricht C, Basch E, Bent S, et al. Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration. J Soc Integr Oncol. 2006;4(4):170–186. |
||
|
Rondanelli M, Perna S, Peroni G, Guido D. A bibliometric study of scientific literature in Scopus on botanicals for treatment of androgenetic alopecia. J Cosmet Dermatol. 2015;15(2):120–130. |
||
|
Blume-Peytavi U, Kunte C, Krisp A, Garcia Bartels N, Ellwanger U, Hoffmann R. [Comparison of the efficacy and safety of topical minoxidil and topical alfatradiol in the treatment of androgenetic alopecia in women.] J Dtsch Dermatol Ges. 2007;5(5):391–395. German. |
||
|
Farivar S, Malekshahabi T, Shiari R. Biological effects of low level laser therapy. J Lasers Med Sci. 2014;5(2):58–62. |
||
|
Maiman TH. Biomedical lasers evolve toward clinical applications. Hosp Manage. 1966;101(4):39–41. |
||
|
Cung H, Dai T, Sharma SK, et al. The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng. 2013;40(2):516–533. |
||
|
Bjordal JM, Couppé C, Chow RT, Tunér J, Ljunggren EA. A systematic review of low level laser therapy with location-specific doses for pain from chronic joint disorders. The Aust J Physiother. 2003;49(2):107–116. |
||
|
Brosseau L, Welch V, Wells G, et al. Low level laser therapy (classes I, II and III) in the treatment of rheumatoid arthritis. Cochrane Database Syst Rev. 2005;19(2):CD002049. |
||
|
Cauwels RGEC, Martens LC. Low level laser therapy in oral mucositis: a pilot study. Eur Arch Paediatr Dent. 2011;12(2):118–123. |
||
|
Schindl A, Schindl M, Pernerstorfer-Schön H, Schindl L. Low-intensity laser therapy: a review. J Investig Med. 2000;48(5):312–326. |
||
|
Liu H, Colavitti R, Rovira II, Finkel T. Redox-dependent transcriptional regulation. Cir Res. 2005;97(10):967–974. |
||
|
Gupta AK, Lyons DCA, Abramovits W. Low-level laser/light therapy for androgenetic alopecia. Skinmed. 2014;12(3):145–147. |
||
|
Jimenez JJ, Wikramanayake TC, Bergfeld W, et al. Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study. Am J Clin Dermat. 2014;15(2):115–127. |
||
|
Chen CH, Hung HS, Hsu SH. Low-energy laser irradiation increases endothelial cell proliferation, migration, and eNOS gene expression possibly via PI3K signal pathway. Lasers Surg Med. 2008;40(1):46–54. |
||
|
Tuby H, Maltz L, Oron U. Modulations of VEGF and iNOS in the rat heart by low level laser therapy are associated with cardioprotection and enhanced angiogenesis. Lasers Surg Med. 2006;38(7):682–688. |
||
|
Avci P, Gupta GK, Clark J, Wikonkal N, Hamblin MR. Low-level laser (light) therapy (LLLT) for treatment of hair loss. Laser Surg Med. 2015;46(2):144–151. |
||
|
Rodrigues C, de Assis AM, Moura DJ, et al. New therapy of skin repair combining adipose-derived mesenchymal stem cells with sodium carboxymethylcellulose scaffold in a pre-clinical rat model. PloS One. 2014;9(5):e96241. |
||
|
Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Cir Res. 2007;100(9):1249–1260. |
||
|
Zhang H, Nan W, Wang S, et al. Epidermal growth factor promotes proliferation and migration of follicular outer root sheath cells via Wnt/ß-catenin signaling. Cell Physiol Biochem. 2016;39(1):360–370. |
||
|
Lee YR, Yamazaki M, Mitsui S, Tsuboi R, Ogawa H. Hepatocyte growth factor (HGF) activator expressed in hair follicles is involved in in vitro HGF-dependent hair follicle elongation. J Dermatol Sci. 2001;25(2):156–163. |
||
|
du Cros DL. Fibroblast growth factor influences the development and cycling of murine hair follicles. Dev Biol. 1993;156(2):444–453. |
||
|
Niimori D, Kawano R, Felemban A, et al. Tsukushi controls the hair cycle by regulating TGF-ß1 signaling. Dev Biol. 2012;372(1):81–87. |
||
|
Tomita Y, Akiyama M, Shimizu H. PDGF isoforms induce and maintain anagen phase of murine hair follicles. J Dermatol Sci. 2006;43(2):105–115. |
||
|
Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of stem cell – enriched human hair follicle bulge cells. J Clin Invest. 2006;116(1):249–260. |
||
|
Grayson WL, Zhao F, Bunnell B, Ma T. Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochem Biophys Res Commun. 2007;358(3):948–953. |
||
|
Potier E, Ferreira E, Andriamanalijaona R, et al. Hypoxia affects mesenchymal stromal cell osteogenic differentiation and angiogenic factor expression. Bone. 2007;40(4):1078–1087. |
||
|
Ren H, Cao Y, Zhao Q, et al. Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions. Biochem Biophys Res Commun. 2006;347(1):12–21. |
||
|
Su HY, Hickford JG, Bickerstaffe R, Palmer BR. Insulin-like growth factor 1 and hair growth. Dermatol Online J. 1999;5(2):1. |
||
|
Batch JA, Mercuri FA, Werther GA. Identification and localization of insulin-like growth factor-binding protein (IGFBP) messenger RNAs in human hair follicle dermal papilla. J Invest Dermatol. 1996;106(3):471–475. |
||
|
Osaka N, Takahashi T, Murakami S, et al. ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds. J Cell Biol. 2007;176(7):903–909. |
||
|
Yano K, Brown LF, Detmar M. Control of hair growth and follicle size by VEGF-mediated angiogenesis. J Clin Invest. 2001;107(4):409–417. |
||
|
Takakura N, Yoshida H, Kunisada T, Nishikawa S, Nishikawa SI. Involvement of platelet-derived growth factor receptor-a in hair canal formation. J Invest Dermatol. 1996;107(5):770–777. |
||
|
Panchaprateep R, Asawanonda P. Insulin-like growth factor-1: roles in androgenetic alopecia. Exp Dermatol. 2014;23(3):216–218. |
||
|
Castoreno AB, Eggert US. Small molecule probes of cellular pathways and networks. ACS Chem Biol. 2011;6(1):86–94. |
||
|
Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL. Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway. J Iinvest Dermatol. 2005;125(4):638–646. |
||
|
Nieves A, Garza LA. Does prostaglandin D2 hold the cure to male pattern baldness? Exp Dematol. 2014;(29):224–227. |
||
|
Nelson AM, Loy DE, Lawson JA, Katseff AS, Fitzgerald GA, Garza LA. Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor Gpr44. J Invest Dermatol. 2013;133(4):881–889. |
||
|
Sasaki S, Hozumi Y, Kondo S. Influence of prostaglandin F2alpha and its analogues on hair regrowth and follicular melanogenesis in a murine model. Exp Dermatol. 2005;14(5):323–328. |
||
|
Choi YM, Diehl J, Levins PC. Promising alternative clinical uses of prostaglandin F2a analogs: beyond the eyelashes. J Am Acad Dermatol. 2015;72(4):712–716. |
||
|
Colombe L, Michelet JF, Bernard BA. Prostanoid receptors in anagen human hair follicles. Exp Dermatol. 2008;17(1):63–72. |
||
|
Zhang Q, Major MB, Takanashi S, et al. Small-molecule synergist of the Wnt/beta-catenin signaling pathway. Proc Natl Acad Sci U S A. 2007;104(18):7444–7448. |
||
|
Fong P, Tong HH, Ng KH, Lao CK, Chong CI, Chao CM. In silicoprediction of prostaglandin D2 synthase inhibitors from herbal constituents for the treatment of hair loss. J Ethnopharmacol. 2015;175:470–480. |
||
|
Weng Z, Zhang B, Asadi S, et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PloS One. 2012;7(3):e33805. |
||
|
Norman P. Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs. Expert Opin Investig Drugs. 2014;23(1):55–66. |
||
|
Pettipher R. The roles of the prostaglandin D(2) receptors DP(1) and CRTH2 in promoting allergic responses. Br J Pharmacol. 2008;153(Suppl 1):S191–S199. |
||
|
Garza LA, Liu Y, Yang Z, et al. Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med. 2012;4(126):126ra34. |
||
|
Kwack MH, Shin SH, Kim SR, et al. I-Ascorbic acid 2-phosphate promotes elongation of hair shafts via the secretion of insulin-like growth factor-1 from dermal papilla cells through phosphatidylinositol 3-kinase. Br J Dermatol. 2009;160(6):1157–1162. |
||
|
Harel S, Higgins CA, Cerise JE, et al. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015;1(9):e1500973. |
||
|
Quintás-cardama A, Vaddi K, Liu P, et al. INCB018424 : therapeutic implications for the treatment of myeloproliferative neoplasms Preclinical characterization of the selective JAK1 / 2 inhibitor INCB018424 : therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2014;115(15):3109–3117. |
||
|
Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Hematology Am Soc Hematol Educ Program. 2014;2014(1):277–286. |
||
|
Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2012;186(7):4234–4243. |
||
|
Kontzias A, Laurence A, Gadina M, O’Shea JJ. Kinase inhibitors in the treatment of immune-mediated disease. F1000 Med Rep. 2012;4:5. |
||
|
Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013;2(3):1–8. |
||
|
Rushton DH. Nutritional factors and hair loss. Clin Exp Dermatol. 2002;27(5):396–404. |
||
|
Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell. 2001;104(2):233–245. |
||
|
Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 2001;105(4):533–545. |
||
|
Yamauchi K, Kurosaka A. Inhibition of glycogen synthase kinase-3 enhances the expression of alkaline phosphatase and insulin-like growth factor-1 in human primary dermal papilla cell culture and maintains mouse hair bulbs in organ culture. Arch Dermatol Res. 2009;301(5):357–365. |
||
|
Sotoodehnejadnematalahi F, Burke B. Structure, function and regulation of versican: the most abundant type of proteoglycan in the extracellular matrix. Acta Med Iran. 2013;51(11):740–750. |
||
|
Xu XR, Zhang D, Oswald BE, et al. Platelets are versatile cells: new discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond. Crit Rev Clin Lab Sci. 2016;53(6):409–430. |
||
|
Lacci KM, Dardik A. Platelet-rich plasma: support for its use in wound healing. Yale J Biol Med. 2010;83(1):1–9. |
||
|
Mussano F, Genova T, Munaron L, Petrillo S, Erovigni F, Carossa S. Cytokine, chemokine, and growth factor profile of platelet-rich plasma. Platelets. 2016;27(5):467–471. |
||
|
Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2016;(5):CD006899. |
||
|
Modarressi A. Platlet Rich Plasma (PRP) improves fat grafting outcomes. World J Plast Surg. 2013;2(1):6–13. |
||
|
Gentile P, Garcovich S, Bielli A, Scioli MG, Orlandi A, Cervelli V. The Effect of platelet-rich plasma in hair regrowth: a randomized placebo-controlled trial. Stem Cells Transl Med. 2015;4(11):1317–1323. |
||
|
Lynch MD, Bashir S. Applications of platelet-rich plasma in dermatology: a critical appraisal of the literature. J Dermatolog Treat. 2016;27(3):285–289. |
||
|
Trink A, Sorbellini E, Bezzola P, et al. A randomized, double-blind, placebo- and active-controlled, half-head study to evaluate the effects of platelet-rich plasma on alopecia areata. Br J Dermatol. 2013;169(3):690–694. |
||
|
Oh Y, Kim BJ, Kim MN. Depressed facial scars successfully treated with autologous platelet-rich plasma and light-emitting diode phototherapy at 830 nm. Ann Dermatol. 2014;26(3):417–418. |
||
|
Singhal P, Agarwal S, Dhot PS, Sayal SK. Efficacy of platelet-rich plasma in treatment of androgenic alopecia. Asian J Transfus Sci. 2015;9(2):159–162. |
||
|
Valente Duarte de Sousa IC, Tosti A. New investigational drugs for androgenetic alopecia. Expert Opin Investig Drugs. 2013;22(5):573–589. |
||
|
Alves R, Grimalt R. Randomized placebo-controlled, double-blind, half-head study to assess the efficacy of platelet-rich plasma on the treatment of androgenetic alopecia. Dermatol Surg. 2016;42(4):491–497. |
||
|
Cho JW, Kim SA, Lee KS. Platelet-rich plasma induces increased expression of G1 cell cycle regulators, type I collagen, and matrix metalloproteinase-1 in human skin fibroblasts. Int J Mol Med. 2012;29(1):32–36. |
||
|
Mehta V. Platelet-rich plasma: a review of the science and possible clinical applications. Orthopedics. 2010;33(2):111. |
||
|
Leo MS, Kumar AS, Kirit R, Konathan R, Sivamani RK. Systematic review of the use of platelet-rich plasma in aesthetic dermatology. J Cosmet Dermatol. 2015;14(4):315–323. |
- Published in Blog
The FDA Vs Stem Cell Treatments In The US
The FDA Vs Stem Cell Treatments In The US
Stem cell therapy has become a popular type of treatment for a number of conditions, including to assist in the regeneration of injured tissue or diseases cells in the human body. This therapy is classified as regenerative medicine. Several advancements have already been made in this medical field, and many had experienced positive results when they underwent stem cell therapy to assist in the treatment of degenerative conditions.
While stem cell therapy has been proven to provide an effective protocol in the recovery of stroke, neurological issues, and even to assist in repairing the damage that was dealt by a heart attack, recent reports have caused many to view these treatments in a negative perspective. This is due to the warnings that were recently issued by the FDA. Even though some have experienced side-effects due to the use of stem cell therapy, it is important to note that there are facilities within the US that can provide professional services that help to minimize the risk of these adverse events.
The FDA On Stem Cell Therapy In The United States
The Food and Drug Administration of the United States is involved in the analyzing and approval of medications and medical procedures that may be offered to patients in the country. To date, the FDA has shown some interest in stem cell therapy, providing approval for several clinical trials that looked at how effective this treatment is in providing a regenerating effect on the impact that certain conditions has in the human body. Only one particular treatment that involves stem cell therapy has been officially approved by the Food and Drug Administration, however.
Within the last few months, we have seen several concerning publications made by the FDA regarding stem cell therapies, reducing the hope that some patients might have gained.
On the 25th of June, 2019, the FDA published a statement that described a permanent injunction that will occur with the many stem cell clinics in the country. The FDA has stated that the action taken from their side is to assist in providing a layer of protection for patients, due to the risks involved with undergoing treatments that utilize products that have not gone through any type of approval process.
The specific company that was targeted in this statement and by the actions that were taken by the FDA is known as US Stem Cell Clinic LLC. The court ruled in favor of the FDA and US government earlier in June, finding the defendants, being US Stem Cell Clinic LLC, guilty of the claims that were made against them.
An earlier publication also confirmed that the Federal court has decided to rule the misbranding of the stem cell products released by the US Stem Cell Clinics company as a violation of laws that have been implemented to protect the people of the country.
News publications have also announced that the regulations and guidelines that have now been set out by the FDA might cause a significant decline in the availability of stem cell treatments to patients in the United States. The companies that have been targeted through these particular actions that the FDA has taken are primarily those that have been marketing products that have not gone through approval phases – and these products have been found to put the patient’s health at risk.
The Role Of Stem Cell Therapy In Disease
While some companies have been found guilty of using unapproved and even misleading products on patients, promoted as stem cell therapy, it is important to consider the reality of the situation as well. Stem cell therapy often referred to simply as Cell therapy, has been proven as a successful regime in the treatment of several conditions. Many of the conditions that have shown improvement with the use of this therapy were previously considered difficult, or sometimes even impossible, to effectively treat.
By 2012, the Worldwide Network for Blood and Marrow Transplantation, also known as the WBMT, announced that a total of one million stem cell therapy procedures had been done throughout the world. This was a significant milestone, and these procedures have helped to save a countless number of lives. Just in this report, the WBMT refers back to a case of Marta, a girl from Madrid, who had received stem cell therapy at a young age. This treatment was provided to Marta after she was diagnosed with Leukemia. In 2002, Marta was able to overcome Leukemia, thanks to the cell therapy that was provided to her.
While lymphoma and leukemia are the conditions where patients most frequently seek a clinic that can perform stem cell therapy on them, there are many other conditions that are treated with this procedure today. The perfection of the therapy has led to a treatment that can assist in reducing the effects of over 70 diseases that may otherwise have a significant impact on the human body.
GSCG Expands To Cancun, Meets The Demands Of US Patients
The Global Stem Cells Group had recently announced the opening of a new office that they have decided to establish in Cancun, Mexico. The decision was driven by the increasing demand for cell therapy procedures by patients in the United States and by the fact that there is currently a lack of facilities that are able to provide these individuals with the professional and quality services needed. Doctors specializing in regenerative medicine are also having a hard time fulfilling the needs of patients who wish to consider cell therapy as a potential treatment option.
This is not the only local office that GSCG now operates in Cancun, as the company now has two facilities within this particular location. These offices include a stem cells laboratory, as well as a general medical facility.
Over the years, GSCG has become an established name in the stem cell field, providing thousands of doctors the opportunity to offer cell therapy as a treatment option for patients with degenerative diseases. The use of this therapy may assist in the regeneration of damaged and diseased tissues in the patient’s body.
Even though a previous office had established a presence for GSCG in Cancun, it should be noted that the company announced that the opening of the new office means they have now officially created a permanent presence for the brand in the area.
The GSCG’s new facility in Cancun is equipped with the latest advancements that have been made in the field and provide quality services that ensure patients have a trusted medical facility where their patients can undergo cell therapy as part of a regenerative medicine treatment plan.
At the moment, doctors who are in the field of regenerative medicine within the United States can turn to this facility to offer their patients an additional treatment option, apart from the standard pharmaceutical protocols that have been established. The stem cell laboratory can assist in the analyzing of patient data and also in the process of finding a matching donor for the person who is in need of stem cell treatment.
GSCG’s facility is able to assist with the culturing of expanded autonomous cells, as well as other types of cells that may be utilized in the process of stem cell therapy. A detailed approach is taken, considering the age of the donor, as this would also provide an overview of the autonomous stem cell age. The patient being treated is also taken into close consideration, as there are different methods of introducing these stem cells to the body for enhanced efficacy.
A more aggressive method is often needed in those patients with conditions such as autism, Alzheimer’s disease, and kidney-related conditions. Other conditions can also be treated, such as pulmonary diseases, Parkinson’s disease. In cases of a stroke, the vascular arteries, along with the carotid artery, is targeted with the therapy for a more effective approach to assisting with the regeneration of damaged structures in the patient’s brain. This ultimately leads to a significant improvement in the delivery of stem cells to the patient’s body, which could enhance the overall efficacy expressed by the treatment.
When these procedures are provided to the patient through the GSCG, an appropriate ICU unit is made available to ensure the patient is provided with adequate care during the operation and recovery of the procedure.
The utilization of recent technological advancements at laboratories facilitated by GSCG can also assist in providing a more economical approach to cell therapy. The utilization of allogenic stem cell procedures can be addressed using techniques that will essentially offer a reduction in the costs involved.
Planar technologies may be utilized when the demand is less than one billion cells per annum, which can significantly reduce the costs of the process and, in turn, make these treatments available to patients at a lower price.
The utilization of autologous stem cell transplantation also offers an opportunity for patients to undergo stem cell therapy when a sibling does not provide an ideal match. Cells can be cultivated from the bone marrow and treated with specific drugs in order to yield targeted results. In the case of malignant cells in the body, bone marrow can be treated with monoclonal antibodies or cytotoxic drugs to target such cells when transplanted back into the patient.
Appropriate storage solutions are also taken into consideration to assist with the cultivation process, and to reduce the risk of enzymatic treatment leads to the differentiation of cells into other types. The culture condition becomes crucial for the expansion of stem cells. A PA6 conditioned medium, along with an enclosure of semi-permeable hollow fiber membranes, is one example of how the laboratory can keep certain stem cells from differentiating, while also assuring successful cultivation and expansion.
The GSCG’s Role In The New FDA Warnings
The fact that the FDA has announced the warnings against stem cell therapy products and had even taken action against a relatively popular company in the United States have now caused a limitation in access to these treatments. With a seizure of the services provided by companies that have been affected by the FDA’s actions and the knowledge of the misleading marketing information that was used in the campaigns initiated by these companies, patients might not be sure where to turn to right now.
The same problem is faced by many doctors in the field of regenerative treatments and medicine. Doctors in these fields need to ensure a facility they utilize to allow patients to undergo a treatment like a cell therapy can offer a safe procedure.
This is where the GSCG comes into the bigger picture. With the establishment of a permanent presence in Mexico, doctors are now given access to a facility that has an established history for providing quality stem cell therapy services to patients with qualifying diseases. The company is not only trusted but have been performing stem cell therapy procedures on patients that had led to successful results.
These treatments may help to assist in repairing neurological problems caused by disorders like Parkinson’s disease, stroke, or an injury to the spinal cord. They may also offer new hope to people with diabetes, heart disease, and even those who had previously suffered damage to their cardiovascular system due to a heart attack.
Conclusion
Even though recent publications from the FDA has caused concerns to be raised regarding stem cell therapy, many patients are still interested in undergoing these treatment procedures. A significant number of studies have provided evidence on the efficacy of treating tissue damage caused by various conditions through stem cell therapy. Patients interested in undergoing stem cell treatment are now advised to turn their interest to Stem Cells Centers in Cancun and related regions, where highly specialized and experienced doctors are able to provide a professional service.
- Published in Blog
EXOSOMES
One major aims of regenerative medicine is to replace lost tissue with new cellular material or to improve the regeneration of damaged, malfunctioning, diseases tissue and organs using stem cell transplantation. In view of this, the discovery of Extracellular vesicles (EVs) in the twentieth century have being considered as significant factors in inflammation and immune responses, antigen presentation, immunomodulation, coagulation, tissue regeneration, organ repair, cell-cell communication, senescence, proliferation and differentiation in the body [1]. Extracellular vesicles are believed to be involved in many biological processes and they can be modified to contain specific proteins, genetic lipids, and genetic materials including messenger RNA (mRNA), microRNA (mRNA), and other small non-coding RNAs, and genomic DNA (gDNA) from their progenitor cell.
Extracellular vesicles are classified into two groups which include; exosomes and ectosomes [2]. Exosomes are characterized with cup-shaped morphology, appearred as flattened spheres with diameters ranging from 30 to 150 nm. Similarly, exosomes have a characteristic lipid bilayer which has an average thickness of ∼5 nm. [3]. Thus, the lipid components of exosomes include ceramide (sometimes used to differentiate exosomes from lysosomes), cholesterol, sphingolipids, and phosphoglycerides with long and saturated fatty-acyl chains. The exosome is formed or derived from a multivesicular body (MVB) when the MVB fuses with the plasma membrane and is released into the extracellular environment.
Diagrammatic representation of a medium size Exosome.
Exosomes contain many types of biomolecule, including proteins, carbohydrates, lipids and nucleic acids which vary depending on the EV’s origin, its physiological and pathological state, and even the precise cellular release site. Thus, the protein composition within can also mark the existence of disease pathologies such as inflammatory diseases; however, exosomes also contain a number of common proteins as well as those that participate in vesicle formation and trafficking. Furthernore, exosome plays a role in intercellular communication by carrying proteins and RNAs between neighboring cells or even to distant organs, they also bind to cell membranes through receptor– ligand interaction and mediate antigen presentation, cancer progression etc.
Various techniques have being developed for the isolation of exosomes which includes; ultracentrifugation-based isolation techniques, size-based techniques, precipitation techniques, immune-affinity capture-based techniques, and some novel combination techniques [4]. Exosomes primarily exist in pellets after centrifugation 100000–200000×g and the use of Ultracentrifugation and ultrafiltration can be used to obtain purified exosomes in the laboratory, but this technology is difficult to apply on a large scale [5].
Exosomes can be stored at 4°C for up to 1 week for short-term while it can be stored at -80°C for long-term by suspending it in phosphate buffered saline.
More importantly, growing evidence has also suggested that exosomes play a key role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes in body fluids and blood in particular are potentially non-invasive or minimally invasive biomarkers for early diagnosis and prognosis of various types of cancer.[6] As the first step towards improving human health, exosomes have to be reliably and efficiently isolated from complex biological matrices like blood, urine, and cerebrospinal fluid since they are currently tested as next-generation biomarkers in those body fluids.
In conclusion, it is advantageous to use exosomes for cell based treatments because the use of exosomes can avoid problems associated with the transfer of cells, which may already have damaged or mutated DNA [7]. Also, exosomes are small and can easily circulate through capillaries, whereas the cells used in other cell-based therapies, such as MSCs, are too large to go through capillaries, and thus cannot get beyond first pass capillary beds, such as the lungs.
The level of MSCs in cell-based therapies may quickly diminish after transplant while, exosomes can achieve a higher “dose” than the transplanted MSCs [8]. Similarly, exosomes can also be utilized to tackle toxicity and immunogenicity problems resulting from such biomaterial treatments as nanoparticles [9].
CLINICAL APPLICATION
Ø Immuno-modulatory and anti-inflammatory properties of Exosomes could be the potential biological mechanisms for clinical treatment to promote bone regeneration. [10]
Ø Adipose-derived stem cell-derived exosomes promote fracture healing in animals by binding to polylactic acid-glycolic acid scaffolds.
Ø Exosome can be used for the treatment of chronic kidney disease, type 1 diabetes mellitus, and skin damage [11].
Ø MSCs-derived exosomes have shown therapeutical benefits in stroke and intravenous administration of MSCs-derived exosomes induced an increase of neurogenesis, neurite remodeling, and angiogenesis. [12]
Ø Administration of MSCs-derived exosomes’ has being observed in a traumatic brain injury model by showing an inflammation reduction and good outcomes.[13]
Ø The injection of MSCs-derived exosomes has also been shown to be a possible treatment for spinal cord injury (SCI), by reducing inflammation and by promoting neuro-regeneration in rats after injury [14].
Ø Exosomes can be used as a delivery system of therapeutic signals or drugs due to their low immunogenicity, ability to cross the blood-brain barrier (BBB), and long half-life in circulation.
- Published in Blog
MESENCHYMAL STEM CELLS
Over the last decade, cellular therapy has developed quickly at the level of in vitro and in vivo preclinical research and in clinical trials. Thus, one of the types of adult stem cells that have provided a great amount of interest in the field of regenerative medicine due to their unique biological properties is Mesenchymal stem cells (MSCs).
Mesenchymal stem cells (MSCs) are known to be multipotent stromal cells that can differentiate into a variety of cell types which include osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells which give rise to marrow adipose tissue). Furthermore, MSCs are responsible for tissue repair, growth, wound healing and cell substitution resulting from physiological or pathological causes; they have various therapeutic applications such as in the treatment of central nervous system afflictions like spinal cord lesions (1). Similarly, they are characterized by an extensive capacity for self-renewal, proliferation, potential to differentiate into multiple lineages and their immune-modulatory role on various cells.
Mesenchymal stem cells have the ability to expand in many folds in culture while retaining their growth and multilineage potential. Also, they can be identified by the expression of many molecules including CD105 (SH2) CD73 and CD34, CD45. Thus, these properties of MSCs make these cells potentially ideal candidates for tissue technology.
In addition, it has been discovered that MSCs, when transplanted systemically, have the ability to transport to sites of physical harm or damage in animals, suggesting that MSCs have migratory capacity. This migration property of MSCs is important in regenerative medicine, where various injection routes are utilized depending on the damaged tissue or organ.
The first source of Mesenchymal stem cells was in the bone marrow and considered to be the gold standard for clinical research, although various other sources have being discovered which include: Adipose tissue, Dental pulp, Mobilised Peripheral blood, Amniotic fluid, Joint synovium, synovial fluid, Endosteum, Periosteum, Menstrual blood and birth-derived tissues.
Cohnheim (German Biologist) hypothesized in the late nineteenth century that fibroblastic cells derived from bone marrow were involved in wound healing throughout the body, while in 1970, Alexander Friedenstein described a population of plastic-adherent cells that emerged from long-term cultures of bone marrow and other blood-forming organs, and he showed to have colony forming capacity and osteogenic differentiation characteristics in vitro as well as in vivo upon re-transplantation.
Arnold Caplan (1991), coined the term “mesenchymal stem cell and stated that the cells as multipotent mesenchymal cell populations which can differentiate into several tissue types, and demonstrated roles for MSCs in the regeneration of bone, cartilage or ligaments in animal and clinical studies. However, the first clinical trials of MSCs were completed in 1995 when a group of 15 patients were injected with cultured MSCs to test the safety of the treatment.
According to International Society for Cellular Therapy, the proposed minimum criteria to define MSCs include the following:
(a) The cells should exhibits plastic adherence
(b) The cell should possess specific set of cell surface markers, i.e. cluster of differentiation (CD) 73, D90, CD105 and lack expression of CD14, CD34, CD45 and human leucocyte antigen-DR (HLA-DR).
(c) The cells should have the ability to differentiate in vitro into adipocyte, chondrocyte and osteoblast.
Thus, these characteristics are valid for all MSCs, although few differences exist in MSCs isolated from various tissue origins.
Mesenchymal stem/stromal cells (MSCs) can be isolated from neonatal tissues, most of which are discarded after birth, including placental tissues, fetal membranes, umbilical cord, and amniotic fluid. Placenta is an ideal starting material for the large-scale manufacture of multiple cell doses of allogeneic MSC. The placenta is a fetomaternal organ from which either fetal or maternal tissue can be isolated.
MSC derived from placenta have long-term proliferation and immunomodulatory capacity, superior to bone marrow-derived MSC. The placenta is a fetomaternal organ consisting of both fetal and maternal tissue, and thus MSC of fetal or maternal origin can be, theoretically isolated. Thus, neonatal tissues are easily available and they have biological advantages in comparison to adult sources that make them a useful source for stem cells including MSCs. They appear to be more primitive and have greater multipotentiality than their adult counterparts.
Clinical Application
Ø MSCs have been widely used to treat immune-based disorders, such as Crohn’s disease, rheumatoid arthritis, diabetes, and multiple sclerosis.
Ø MSCs have been widely used as a treatment for numerous orthopedic diseases, including bone defects, osteoarthritis (OA), femoral head necrosis, degenerative disc, spinal cord injury, knee varus, osteogenesis imperfecta, and other systemic bone diseases.
Ø MSCs are promising cell source for treatment of autoimmune, degenerative and inflammatory diseases due to the homing ability, multilineage potential, secretion of anti-inflammatory molecules and immunoregulatory effects.
Ø MSCs play a key role in the maintenance of bone marrow homeostasis and regulate the maturation of both hematopoietic and non-hematopoietic cells.
Ø MSCs have been shown to be powerful tools in gene therapies, and can be effectively transduced with viral vectors containing a therapeutic gene, as well as with cDNA for specific proteins, expression of which is desired in a patient.
Ø It has been proved that MSCs can differentiate into insulin producing cells and have the capacity to regulate the immunomodulatory effects
REFERENCES
- Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin. 2013 Jun; 34(6):747-54
- Friedenstein AJ, Piatetzky II S, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16:381–90
- Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974;17:331–40.
- Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.
- Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.
- Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. Journal ofHematology & Oncology. Apr 30, 2012;5:19.
- Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D. and Horwitz, E. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular. Therapy position statement. Cytotherapy 8, 315–317
- Published in Blog
What Are The Best Options For Managing Chronic Pain?
Chronic pain. Roughly translated as a condition of persistent misery for people. It is a serious health condition that has both physical and psychological suffering and is often associated with a specific ailment like arthritis, migraine, frozen limb, etc. People who suffer from chronic pain perceive themselves to be in a state of constant agony and distress, which can affect their ability to lead a ‘normal’ life, from being able to go to work every day to social interaction.
There are several treatment options that people resort to for managing persistent pain conditions. In this article, we talk about those treatment options with the stem cell regeneration being the most current and promising one. Also, we will discuss the potential benefits and pros and cons of regenerative medicine.
What is chronic pain and how is it caused?
During ‘PAINWeek2017’ in Las Vegas, Dr. Jay Joshi, MD, explained the connection between inflammation and pain. He states that inflammation is triggered by various chemical and physical stimuli, and is a normal phenomenon of the body to protect the injured area and speed up the healing process. When inflammation exceeds its normal extent, it conversely delays the healing process and forms this cycle of non-resolving inflammation that leads to chronic pain.
Chronic pain is a multifactorial condition. It can be caused by medical harm, injury or nerve damage. However, it can also be caused by environmental factors, for example, back pain due to incorrect posture, or physiological factors such as aging, weak bones.
Common conditions that are related to chronic pain are:
- Osteoarthritis: the degeneration of cartilage in the joint and the corresponding bones, leading to pain and stiffness mainly in thumb, knee and hip joints.
- Migraine: a half-sided recurrent headache that gives a throbbing sensation and is accompanied by blurred vision and nausea.
- Multiple Sclerosis: a chronic, progressive condition that involves nerve cell sheath damage in the spinal cord and brain. Its symptoms include severe fatigue, speech disturbances, blurred vision and numbness.
- Neuropathy: a condition that involves damage to the peripheral nerves causing weakness, pain and numbness, particularly in the hands and feet.
- Fibromyalgia: a soft tissue disorder that involves widespread musculoskeletal pain also characterized by fatigue, sleep disturbance and mood swings.
According to a 2016 analysis by the National Health Interview Survey, approximately 50 million Americans suffer from chronic pain. It is considered to be one of the most common conditions that medical treatment is sought out for. Some of the repercussions of chronic pain that agonize people are:
- Depression and mood swings
- Poor performance
- Poor social life
- Restricted mobility
- Anxiety
- Poor self-perception about life
- Dependence on opioids
Although it is necessary to diagnose and treat the underlying cause of pain, doctors deal with pain as a separate entity and provide symptomatic treatments to save patients from the continuous discomfort it brings.
Management of Chronic Pain
Some of the common management strategies adopted by doctors are:
Analgesics
There are several over the counter pain killers available that are widely used by patients with chronic pain. These include paracetamol, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, naproxen, etc.
Although analgesics are considered safe, long term usage can produce a number of side effects. It can lead to liver damage and is specifically dangerous for patients with liver cirrhosis. Likewise, NSAIDs are known to affect the kidneys and increase the risk of a heart attack.
Anticonvulsants
Drugs that are originally used to treat epilepsy can also be an effective management strategy against chronic pain. For example, the second-generation anticonvulsants Gabapentin and Lyrica are approved by FDA for the treatment of pain. First-generation anticonvulsants such as carbamazepine and phenytoin are also considered effective. However, these first-generation drugs have more side effects when compared to second-generation drugs. They can cause side effects like ataxia, liver damage, sedation, etc.
Antidepressants
Doctors also prescribe antidepressants for the treatment of pain. These comprise of tricyclics like amitriptyline, imipramine or doxepin. These drugs can be given to patients with or without depression as it has distinct effects of pain relief and mood elevation.
Similarly, pain in fibromyalgia and diabetic nerve pain are treated with other types of antidepressants – serotonin and norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine. These are equally effective as tricyclics but have comparatively milder side effects.
Opioids
Opioids such as codeine, morphine, oxycodone, etc. are very effective against severe chronic pain conditions. However, these drugs are not available over the counter and not provided by the pharmacist without prescription because of their risk of addiction.
Nonetheless, experts state that if the dose is vigilantly managed, their potential benefits can outweigh the risks. That is why doctors carefully observe patients prescribed with opioids for chronic pain to avoid any untoward dependence.
Alternative medicine
If traditional medicine hasn’t worked, many people often resort to other naturally occurring remedies for its cure. Alternative medicine varies from herbal remedies and therapies that are naturally available in plants that have curative properties. Cannabinoids, Akuamma and Kratom plants are a few examples with such characteristics that are currently trending.
Could Stem Cell Regeneration (SCR) be the answer?
As the human central nervous system matures and becomes more complex, the regenerative ability of the body further reduces. Regenerative medicine caters for this by focusing on the 3 Rs; Replacement, Repair, and Restoration of tissues and their function. This can be directed for the treatment of non-resolving inflammation by generating ex vitro cells, tissues or organs which can then be transplanted into the body.
Stem cell therapy is a unique model of treatment that replaces injured or lost cells, which can help 1.5 billion people that are experiencing chronic pain worldwide, with 23-26% of the people suffering from lower backache alone. According to Dr. Jay in ‘PAINWeek2017’, there are two types of stem cell regenerative therapy: Autologous and Non-Autologous.
In autologous SCR, mesenchymal stem cells (MSCs) are derived from adipose tissue of the patient and transplanted back into the injured area, where they potentially differentiate into the respective cells. For the other type, the MSCs are derived from embryonic tissues.
Research published in Pain Physician Journal in 2017 shows that MSC therapy is a great alternative because they are readily available. In addition, their homing potential is also considered a pro and they can be grown using standard culture techniques. It has also shown that autologous SCR is potentially safe for both humans and animals.
There has been a reported reduction from pre to post-operative pain with the use of SCR. However, various complications have been acknowledged in studies. Firstly, there’s a risk of tumor formation at the site of transplantation. Secondly, there have been instances of undesired bone formation. Furthermore, there is also a risk of abnormal immune reactions to occur.
The effective results of cell-based therapy are promising, with evident results in the treatment of chronic pain conditions in osteoarthritis, degenerative disc disease as well as neuropathic pain. However, there is still a need for advanced clinical research to deepen the understanding of the mode of action of MSCs and their potential outcomes inside the human body.
- Published in Blog
Which are the best options For Treating Common Sports Injuries?
As physicians, we are constantly dealing with sports injuries. While they are typically not seen as life-threatening with high chances of recovery, they could potentially cause further problems down the line for the patient. Sports injuries can also take months to heal and getting patients back on their feet can take a lot of time, effort and money, which can be frustrating for patients who want to get back to playing football every weekend or for those who have a skiing holiday booked in the next month.
Recently, there has been a massive surge in the use of stem cells as an alternative treatment to common sports injuries. This article aims to outline the benefits and risks attached to using stem cells and how this alternative treatment may help patients who are suffering from common sports injuries.
What Are The Most Common Sports Injuries?
We are constantly treating sports injuries on a regular basis. Some of the most common sports injuries doctors typically deal with are:
Ankle Sprain
An ankle sprain occurs when the ligaments in the ankle are stretched and eventually torn due to twisting or falling onto the foot. Ankle sprains are common among athletes and sports enthusiasts, however, if left untreated, the ankle can weaken, making it more vulnerable to further damage. This leads to long term problems such as chronic ankle pain, arthritis, and ongoing instability.
A sprained ankle can be easily diagnosed when we see displays of swelling, bruising, stiffness and pain when we attempt to touch or move the ankle.
Groin Pull
A groin pull is basically a groin strain. Strains occur when the muscles are overstretched, moving in directions that are not normal for them or pulled too forcefully or suddenly. This leaves them torn and damaged and results in tenderness and bruising in the groin and inner thigh area. This injury is common in athletes that play sports which require a lot of quick side-to-side movements.
A groin pull can be easily diagnosed after a thorough physical examination of the symptoms and possible tests such as x-rays and MRI’s.
Hamstring Strain
A hamstring strain occurs when the three muscles in the back of the thigh are overstretched from movements such as hurdling and kicking the leg out sharply. As these muscles are naturally tight and susceptible to sprains, it can take from six to twelve months to heal and are vulnerable to recurring injuries. Poor or lack of stretching are the likely causes of a pulled hamstring.
Shin Splints
Shin Splints is an inflammation of the muscles in the lower leg when they are overworked and stressed. Shin splints are often found in athletes that engage in sports that require a lot of running, dodging or quick stops and starts.
Knee injury: ACL tear
An ACL knee injury is a tear or sprain of the ligament that holds the leg bone to the knee. Sudden stops or changes in direction can tear the ACL and make that dreaded “pop” sound. Almost immediately, the knee will swell, feel unstable and be too painful to bear weight. This injury is common in athletes that engage in sports such as soccer, basketball, and downhill skiing.
ACL tears are commonly seen as a severe sports injury and can be traditionally treated with rehabilitation programs and surgery to strengthen or completely replace the torn ligament.
Knee injury: Patellofemoral Syndrome
Patellofemoral Syndrome occurs when repetitive movements of the kneecap (patella) are made against the thigh bone (femur) which damages the tissue. This knee pain is common among young adults and can be caused by a number of factors such as weakness in the thigh or buttock muscles, tight hamstrings, short ligaments around the kneecap or alignment problems through the feet.
Tennis Elbow (epicondylitis)
Tennis Elbow is common for athletes that play sports such as tennis or golf that require the player to ‘grip’ tightly and repetitively for an extended amount of time. This results in the ligaments of the forearm becoming strained and inflamed, making it painful to make wrist or hand motions.
What Are The Traditional Treatment Options & Management Strategies For Sports Injuries?
Traditional treatment methods and strategies for treating mild sports injuries such as sprains and strains can be done at home. Traditional advice given by doctors can include taking rest, applying ice to reduce the swelling and dressing the injury with compression bandages to support and assist healing. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may also be prescribed to help reduce swelling and to relieve pain.
Moderate severity injuries may be traditionally treated with immobilization strategies such as the use of crutches or a cast brace to assist the ankle to heal for the first few weeks. This may be followed with rehabilitation exercises to strengthen the ankle and prevent stiffness and future problems.
Severe sports injuries such as knee injuries are traditionally treated with surgery or rehabilitation programs to replace or restore the torn ligaments or muscles. This also goes for those patients who experience persistent problems after months of nonsurgical treatment.
Whatever the severity level of the sports injury, the healing process can take up to several months before the muscle restores to its natural condition. Injuries can also leave muscles and ligaments permanently weakened and susceptible to further injury.
Is Stem Cell Therapy An Option For Treating Sports Injuries?
The use of stem cells to treat sports injuries are becoming more popular due to its ability to grow new blood vessels that facilitate faster and better healing, decrease or prevent inflammation and release proteins (cytokines) that can slow down tissue degeneration and reduce pain. Sports injuries that include damage to tendons, ligaments, muscles, and cartilage are reported to be seeing the best results from stem cell therapy.
Dr. Bill Johnson, MD of Innovations Medical sees stem cell therapy as a revolutionary alternative to painful surgery and long recovery and states that,
“Patients who undergo stem cell therapy for their sports injury report a reduction in their painful symptoms and increase range of motion and increased mobility. Stem cell therapy helps to quickly reduce joint inflammation, and many patients see improvements in 1 to 2 days. Anti-inflammatory results of the procedure can last for 2 to 3 months and many patients see a gradual improvement in their condition over time.”
Even celebrity athletes such as Peyton Manning and Ryan Tannehill have used stem cell treatment in conjunction with traditional treatments with success. Stem cells are placed directly into the joint via surgical application or injection to aid quicker healing and promote the growth of cells needed to restore strength and flexibility in muscles and ligaments.
However, using stem cells as an alternative method to treat sports injuries is still a controversial subject and is very much still debated among medical professionals. Research is still undergoing to show whether or not stem cell therapy is the best solution. Critics of this therapy argue the fact that stem cell therapy doesn’t work any better than a placebo and that there is no clear evidence that this type of therapy is safe. Unwanted side effects can include swelling and pain and if stem cells are used from other sources or manipulated in any way, this can result in a higher risk of developing tumors.
- Published in Blog
How To Effectively Treat Amyotrophic Lateral Sclerosis (ALS)
Although a rare neurologic condition, Amyotrophic Lateral Sclerosis (ALS) is the most common type of Motor Neuron Disease (MND), a condition that affects the voluntary muscles. This is a progressive disorder that leads to muscle weakness and depletion due to nerve dysfunction.
ALS is also called Lou Gehrig’s disease, named after the football player who had this condition. The literal meaning of Amyotrophic is ‘no muscle nourishment’ which becomes the cause of muscle atrophy. ‘Lateral’ refers to the group of nerves in the spinal cord that sends signals to the muscles. It is these nerves that degenerate, leading to sclerosis in this region. In later stages, this affects the nerves that control breathing and hence can be fatal.
The initial symptoms of ALS include stiffness and muscle weakness, which gradually involves all the muscles under voluntary control. The affected regions and progressive pattern vary from one person to another. Some having difficulty holding a pen or a cup while others finding difficulty speaking, chewing or even talking. Thus, ALS is an ailment that affects daily life and makes simple tasks painful and troublesome.
According to the Center for Disease Control and Prevention (CDC), 14,500 to 15,000 people had ALS in the United States in 2016, with approximately 5000 people having a confirmed diagnosis for the condition annually. Although the average survival rate is three to five years, patients can live for ten years or more.
Are there different types of ALS?
Amyotrophic Lateral Sclerosis has two types:
Sporadic ALS: this is the most common one and affects 95% of sufferers. This type occurs without a clear cause.
Familial ALS (FALS): This type occurs in 5-10% of sufferers. This type of ALS is genetic and runs in families. This occurs due to abnormal changes to a gene that is then passed in generations.
What are the symptoms of ALS?
Early signs and symptoms might be unnoticeable and become perceptible after some time. Most clinical signs are evident of upper motor neuron and lower motor neuron lesion. The limb onset ALS (70%) involves initial symptoms in the limbs while the bulbar onset ALS (25%) is characterized by speech and swallowing problems. This is followed by weakness in the limbs later. The remaining 5% of the patients have respiratory involvement in the early period. [5]
Most common symptoms include:
- Muscle weakness in the limbs (distal or proximal)
- Asymmetric progressive muscle wasting
- Difficulty in motor activities like walking, talking, chewing
- Weakness in arms, legs, hands, and feet
- Muscle cramps and twitching
- Slurred speech
- Fatigue
- Emotional liability (episodes of uncontrolled laughing and crying)
- Difficulty in maintaining posture and gait
- Difficulty in breathing and swallowing
With the progression of the disease, symptoms may spread to all parts of the body. In some patients, frontotemporal dementia may occur resulting in poor memory and decision-making abilities.
What Causes ALS?
The exact cause of ALS has not been known by scientists to date. However, research is being carried out to understand what causes ALS. There are several different factors such as:
Genetic changes
Studies have shown that 5 to 10% of cases of ALS are caused by genetic mutations. For example, changes to the gene that makes SOD1 protein causes damage to motor neurons.
Environmental factors
No major association has been established between environmental factors like toxins, viruses, diet or physical trauma and the risk of development of ALS. However, there is ongoing research on the subject. Studies have shown that some athletes are at a higher risk of acquiring ALS due to vigorous physical activity.
Chemical disturbance
Glutamate is the neurotransmitter that is in control of signals to and from the brain. Accumulation of this neurotransmitter within the spaces surrounding the nerves damages them.
Research has also shown mitochondrial structural and functional abnormalities, as well as defects in axonal structure and transport, could be the causative agents for ALS.
How Do We Diagnosis ALS?
When it comes to diagnosis, there are no specific tests that can provide a definitive diagnosis for ALS. However, doctors conduct a series of tests to rule other similar diseases. A full medical history check and a neurologic examination are undertaken at regular intervals to assess the progressive worsening of symptoms.
Running the following Image testing diagnostic tests can help reach a diagnosis:
- Electromyography (EMG) – EMG records the electrical activity of the muscle fibers.
- Nerve Conduction Study (NCS) – NCS assesses the electrical activity of the nerves and muscles.
- Magnetic Resonance Imaging (MRI) – MRI rules out other possible conditions such as a tumor or cyst in the spinal cord, cervical spondylosis, or a hernia in the neck that could be causing the nerve compression.
Laboratory tests such as blood screening and urine tests can also be carried out so that other diseases can be eliminated.
What Are The Treatment Options & Management Strategies For ALS?
ALS is managed through a multidisciplinary approach.
Unfortunately, there is no definitive cure for the disease at this time. Management of ALS is done through symptomatic treatment to ease the condition of the patients and prevent unnecessary complications:
Support – Physicians, psychologists, speech therapists, nutritionists, and home care assistance all play a vital role in making life easier for patients with ALS.
Medication – Riluzole (Rilutek) and Edaravone (Radicava) are the drugs approved by the U.S Food and Drug Administration (FDA) for treating ALS. Riluzole is believed to reduce glutamate levels thereby, decreasing damage to the motor neurons. Edaravone acts an antioxidant and is believed to expel free radicals and reduce the oxidative stress in the motor neurons.
Lifestyle Habits – Physiotherapists can recommend exercise and physical activity like walking, swimming, and bicycling that may improve muscle strength and help elevate mood without overstressing the muscles.
Speech Therapy – therapists can help patients with ALS to employ strategies to speak clearly. They may also recommend computerized aids such as speech synthesizers and eye-tracking technology to help people learn ways for responding by nonverbal means.
Diet – Nutritionists may formulate a diet plan for patients, which consists of food that is easy to swallow and provides enough nourishment and calories for the patients to maintain adequate energy levels and to prevent excessive weight loss
Breathing Support – Patients with ALS may suffer from shortness of breath and difficulty breathing during physical activity or while lying down. If this is the case, doctors can recommend Non-Invasive Ventilation (NIV) that provides breathing support through the nose or mouth. NIV improves quality of life and increases the number of years of survival for patients.
Is Stem Cell Therapy An Option?
As previously mentioned, there is no curable treatment for ALS available. However, scientists are researching Stem Cell Therapy as the new favorable approach in the treatment of neurologic disorders.
There is a rising interest in Stem Cell Therapy as a promising remedy for curing ALS. Mesenchymal stem cells are particularly believed to be the most suitable ones due to their availability, absence of ethical issues and positive results in various experiments.
Studies and clinical trials have begun to apprehend the benefits of MSC transplantation. They demonstrate that MSCs lead to a partial recovery of motor neurons and a delay in disease progression. Also, there has been no evidence of a major adverse effect after MSC transplantation.
When testing this newfound research on animals, the lifespan of the subjected animal has increased with MSC transplantation. These positive results have encouraged the administration of MSC in ALS patients.
However, despite the safe outcomes of MSC transplantation in humans, results show that there is only a partial improvement in ALS sufferers with only a few cases that showed a delay in disease progression. Hence, there is a need for further studies and trials on a higher number of human subjects for a better understanding of MSC effects so that more significant conclusions can be reached.
- Published in Blog
The Keto Diet: A Miracle Formula Or A Dangerous Risk?
The Keto Diet: A Miracle Formula Or A Dangerous Risk?
We live in a world overloaded with diets and eating plans that are all preaching miracle, long term results for weight loss and reducing risks of developing illnesses and diseases.
But, with so many different plans out there all claiming to produce the best results, it’s hard to know which one to recommend to your patients. The Paleo, the Atkins, the Pritikin Principle, the South Beach, WeightWatchers, The Zone Diet… the list goes on and on. Recently, many doctors are leaning more towards THE KETO DIET as a recommendation for not only their overweight patients; but patients that suffer from various illnesses and ailments.
WHAT IS A KETO DIET?
To put it simply, a ‘keto’ or ‘ketogenic’ diet is a low-carb, high-fat diet.
A reduction in carbohydrates puts the body into a metabolic state called ketosis. This is when the body produces small fuel molecules called ketones. Carbs are broken down into glucose and used for energy. So when someone deprives themselves of carbs, the body has no choice but to switch its fuel supply from glucose (blood sugar) to ketones found in body fat.
Therefore, as long as carbs are restricted, the body is constantly burning fat.
Kathleen M. Zelman, MPH, RD, LD told WebMD that a ketogenic diet is often used for losing weight, but it can help manage certain medical conditions such as epilepsy, heart disease, diabetes type 2, brain diseases and IBS.
WHAT ARE THE MAIN BENEFITS OF A KETO DIET?
Weight Loss & Appetite Suppression
The biggest benefit of the keto diet and the one most dieters are striving for is weight loss and suppression of appetite.
Typically, the body takes their fuel from our stores of glycogen, but with the reduction of carbohydrates in a keto diet, glucose levels are lowered and the body is forced to obtain its energy from body fat. This results in patients experiencing weight loss.
Food cravings and hunger is often the reason that our patients are failing at dieting. Another key reason why medical professionals have found the keto diet to be so successful is because of the effects it has on reducing cravings and tackling hunger.
Studies have proven that participants that follow a low-carb diet have reported a decrease in appetite and cravings compared to individuals following a low-fat diet. This is possibly down to high-fat foods slowing down the process of gastric emptying. Food that is high in fat passes through the gut at a much slower pace, leaviing the individual feeling satisfied for longer.
Diabetes Type 2
Diabetes Type 2 is triggered by spikes occurring in the patient’s blood sugar levels. Insulin is used to regulate and control these spikes. When a patient with type 2 diabetes follows a keto diet, the amount of glucose they are consuming dramatically decreases due to the lower intake of carbohydrates.
So the lower intake of glucose found in high carb food = the lower intake of insulin.
A study of 21 overweight men with type 2 diabetes who were put on a keto diet showed that most participants saw a reduction in their insulin medication or were taken off diabetes medication completely as a result of controlling their glucose levels by following a keto diet.
Epilepsy
A keto diet has been used to treat epilepsy since the 1920s and during a recent study, seventy percent of epileptic patients have reported less and more controlled seizures and a reduction in their medication since implementing a keto diet.
Epileptic seizures occur when a network of neurons fire unexpectedly due to the overexcitement of brain cells releasing neurotransmitters, like glutamate. The brain is then not able to suppress the spread of excitability like in non-epileptic people using inhibitory neurotransmitters like gamma-aminobutyric acid, or GABA.
What a keto diet can do to control seizures is to reduce the amount of glutamate in the brain and enhance the synthesis of GABA.
Alzheimer’s Disease & Dementia
A ketogenic diet can contribute towards keeping the brain young and healthy and reduce the risk of developing degenerative brain diseases such as Alzheimer’s disease and dementia.
Findings from a study found that keto diets can protect neurovascular function against cognitive decline by clearing out beta-amyloid protein in the brain. Beta-amyloid creates toxic plaques that interfere with neuronal signaling that results in Alzheimer’s disease and dementia. Improvements to blood flow to the brain, which contributes to healthy cognitive function, were also noted.
IBS & Other Gastronomical Conditions
Fifteen percent of the general population claim to suffer from IBS. It is one of the most common complaints taken to doctors. A lot of research has been undertaken in recent years around the effect that carbohydrates have on the gastrointestinal system.
Studies have found that when sufferers consume carbohydrates, they tend to ferment in the small intestine and causes gas and bloating. For IBS sufferers, carbs are poorly absorbed by the gut wall, causing fluid to remain in the intestinal space, resulting in diarrhea.
Therefore, when IBS sufferers follow a keto diet and reduce their intake of carbohydrates, they report significant improvements to their condition.
HOWEVER…
All these amazing results from consuming low-carb, high-fat foods sounds promising, right?
Well…
Medical professions at Harvard Medical School are urging medical professionals to be wary of recommending the keto diet to their patients. They have identified numerous risks associated with following a ketogenic diet.
Not only is the body being deprived of an essential food group – carbohydrates, but a keto diet is typically high in saturated fat. High levels of saturated fat can lead to high cholesterol and heart disease.
Other risks they have been identified with following a keto diet is:
A deficiency in micronutrients including selenium, magnesium, and vitamins B and C which are found in most of the fruit and vegetables that are restricted in a keto diet.
Liver problems due to the amount of fat the body needs to metabolize. This can cause existing liver problems to worsen.
Kidney problems due to the amount of protein the body needs to metabolize. A keto diet can put strain on the kidneys and make exisitng conditions worse.
Constipation. The keto diet is low in fibrous foods like grains and legumes. The digestive system relies on a steady flow of fiber to break down foods and get rid of body waste.
“The Keto Flu” is a term for the mood swings, body aches and brain fuzz that people experience when following a keto diet. The brain needs glucose to function and when it is deprived of this, it can cause irritability and tiredness.
We want to know your thoughts and opinions on the Keto Diet!
Have you ever recommended the keto diet to your patients? Do you see the benefits happening in your patients? Is it dangerous?
- Published in Blog
JAMES P. ALLISON, PhD. Nobel Prize in Medicine
JAMES P. ALLISON, PhD
Chair, department of immunology, and director.
Immunotherapy Platform, MD Anderson Cancer Center
Losing his mother to lymphoma and two uncles to melanoma and lung cancer taught James P. Alli- son, PhD, a difficult lesson at an early age. “My mother was treated with radiation and my uncle, who had lung cancer, was treated with chemotherapy. I saw the ravages of those treatments, which ultimately were unsuccessful,” he says.
Allison knew he wanted to work in cancer research, developing more effective and less toxic therapies. An undergraduate course at the University of Texas at Austin sparked his interest in T cells—warrior cells of the immune system that defend the body against infections and cancer.
In October, Allison won the 2018 Nobel Prize in Physiology or Medicine jointly with Japanese Tasuku Honjo, MD, PhD. Alison has spent more than 30 years studying how T cells work and what turns the immune system on and off against cancer. The 1980s discovered the T Cell antigen receptor, which he described as the cell’s “ignition switch.” A few years later, he showed that a molecule called CD28 acts as the “gas pedal.” Finally, he found that CTLA-4, a protein on the surface of T cells, is the “brake,” signaling the immune system to stop the millions of T cells from attacking the cancer.
The next step, he says, was to pre vent the brakes from engaging—“to give the T cells time to keep going and eliminate the tumors.” Allison’s work led to the development of drugs called checkpoint blockade antibodies, including ipilimumab (Yervoy) for melanoma. “When we started this work, the median life expectancy with metastatic melanoma was 11 months, and no drug had ever changed that,” he says. Among people treated with Yervoy, more than 20% are still alive three years later, and some have survived 10 years.
New drugs targeting another off-switch, PD-1, have since been developed to treat cancers of the head and neck, lung, kidney, and bladder, among others. Now Allison’s lab is studying different combinations of checkpoint blockades to see which patients will respond best to them. “I don’t think these approaches are going to replace any. of the traditional therapies,” he says, but, “I think that soon, immunotherapy is going to be part of every successful cancer therapy.”
- Published in Blog
Opioid Overdose Crisis in America.
However, despite the alarming rate of death from opioid overdose, this problem is not grabbing the headlines from the media for health stakeholders to pay more attention and look for ways to finding lasting solutions to the anomaly.
It is worthy to note that, while many people are addicted to opioids in the form of heroin and synthetic opioids, millions of people are out there, taking an overdose of opioids in the form of pain reliever prescription for chronic pains and other related health issues. Though, opioids are used in the treatment of chronic pain, research has suggested that they may not help relieve pain in the long-term. This has posed a serious threat to public health and economic welfare, not only for the United States but other affected countries as well.
According to the Centers for Disease Control and Prevention, the total “economic burden” of only opioid misuse prescription in the US is estimated as $78.5 billion per year, inclusive of lost productivity, criminal justice involvement, healthcare cost, and addiction treatment.
This article aims to look at how we come to this point, some facts about opioids in the United States, and some useful information about opioid overdose. Read on to uncover them all.
Opioids and Substance Abuse at a Glance.
Opiates, popularly known as narcotics, are commonly prescribed for quick pain relief and sleep inducement. Originally, it is derived from poppy plant seeds or their byproducts. Opiates occur naturally in the form of opium and morphine, but most opiates are synthetic. These drugs became highly addictive because they create an intense sense of euphoria and as well as safeness, when adding it to pain-relieving properties.
Most patients with pain disorders later turn to rely on pharmaceutical opiates like oxycodone and hydrocodone; hence, they become addicted to it. However, opioid overdose has been studied to cause a number of health problems in the users, and these health issues are not limited to serious disorders, but even death. One of the prolonged effects of opioid usages is the brain’s inability to produce endorphins naturally. Endorphins are known to be the body’s natural painkillers.
Initially, around late 1990s, when opioids were becoming popular among the people, pharmaceutical companies came out to allay the fear of the people and reassure the medical community that opiate users would not become addicted to opioids prescribed for pain relief; hence, healthcare service providers started prescribing the drugs to patients at greater rates. Subsequently, this act resulted in a extensive misuse and diversion of these drugs prior to the time it was discovered that opioid prescriptions could actually be highly addictive like other opiates.
Facts about Opioid Prescription and Misuse in America.
The rates of opioid overdose in the United States started increasing in 2017 with over 47,000 citizens died due to misuse of opioids, such as heroin, prescription opioids, illicitly manufactured fentanyl (one of the powerful opioid synthetics). In the same year, this number was estimated 1.7 million and 652,000 Americans suffered from prescription opioid pain relievers and heroin use disorder respectively. The question is, how does it start?
It all starts when the body cannot properly manage and regulate pain again. In this condition, an opiate user may become addicted to the drugs, as the drugs now used to relief their pain and at the same time, create a sense of contentment and happiness in using them. Over time, even after the pains have gone, an opiate user will require more of the substance to reach the same level of high that creates happiness and contentment which they first experienced; hence, the person is already “an opiate addict.” Withdrawing from its use makes it even worse, as their bodies begin to show some unpleasant symptoms that make the user seeking more to relieve the symptoms.
From here, opioid prescription and misuse have turned out to become a public health problem in the United States with alarming rates of death on a daily basis.
Below are some facts about the opioid crisis in the United States:
- According to WQAD Digital Team’s claim of IMS Health’s market research, the number of opioid prescriptions doctors dispensed increased from 112 million to 282 million from 1992 to 2012 respectively. However, according to IQVIA, the number has declined to 236 million in 2016 and further dropped by 10.2% in 2017.
- Centers for Disease Control and Prevention, about 68% of cases of estimated 70,200 drug overdose deaths recorded in 2017 were linked to the use of opioids. This is more than six times compared to that of 1999 (including illegal opioids such as heroin and illicitly manufactured fentanyl and prescription opioids).
- According to a review, about 21 – 29% of patients with chronic pain who take opioids prescription misuse them.
- Another study also claimed that roughly 80% of heroin users initially misused prescription opioids.
- The same study also claimed that about 8 – 12% of opiate users develop an opioid use disorder.
- According to the Centers for Disease Control and Prevention, there is a 30% increase in opioid overdoses in 45 states of the United States between July 2016 to September 2017.
- In another review, opioid overdoses were seen increasing by 70% in the Midwestern region between July 2016 to September 2017.
What is been doing about it?
With over two million opioid dependants in the United States, the U.S. Department of Health and Human Services (HHS) is making efforts to tackle the opioid crisis in America by focusing on five major areas. These include:
- Promoting and enlighten people on the use of overdose-reversing drugs.
- Giving people access to treatment and recovery therapies.
- Offering support for modern research on addiction and pain.
- Promoting public health surveillance to help people understand the epidemic better.
- Enhancing better pain management practices in the country.
In furtherance to the efforts of the U.S. Department of Health and Human Services (HHS), the National Institutes of Health (NIH)’s Director Francis S. Collins in April 2018’s National Rx Drug Abuse and Heroin Summit, announced the launch of a special program referred to HEAL (Helping to End Addiction Long-term) Initiative. HEAL is an aggressive effort set up to expedite scientific solutions to address the opioid crisis in the United States.
Final Words.
Just because media are not paying attention to the opioid crisis in the US does not mean things are working in the medical world. With the alarming rate of opioid overdose and an increasing number of Americans abusing prescription and becoming dependent on opioids, all hands must be on deck to find a lasting solution to the current problem. While different agencies and stakeholders are not relenting on their efforts, more medical developments and approaches are still required to achieve a good result.
- Published in Blog
