Potential of Nano-Engineered Stem Cells in the Treatment of Multiple Sclerosis: A Comprehensive Review.

Multiple sclerosis (MS) is a chronic and degrading autoimmune disorder mainly targeting the central nervous system, leading to progressive neurodegeneration, demyelination, and axonal damage. Current treatment options for MS are limited in efficacy, generally linked to adverse side effects, and do not offer a cure. Stem cell therapies have emerged as a promising therapeutic strategy for MS, potentially promoting remyelination, exerting immunomodulatory effects and protecting against neurodegeneration. Therefore, this review article focussed on the potential of nano-engineering in stem cells as a therapeutic approach for MS, focusing on the synergistic effects of combining stem cell biology with nanotechnology to stimulate the proliferation of oligodendrocytes (OLs) from neural stem cells and OL precursor cells, by manipulating neural signalling pathways-PDGF, BMP, Wnt, Notch and their essential genes such as Sox, bHLH, Nkx. Here we discuss the pathophysiology of MS, the use of various types of stem cells in MS treatment and their mechanisms of action. In the context of nanotechnology, we present an overview of its applications in the medical and research field and discuss different methods and materials used to nano-engineer stem cells, including surface modification, biomaterials and scaffolds, and nanoparticle-based delivery systems. We further elaborate on nano-engineered stem cell techniques, such as nano script, nano-exosome hybrid, nano-topography and their potentials in MS. The article also highlights enhanced homing, engraftment, and survival of nano-engineered stem cells, targeted and controlled release of therapeutic agents, and immunomodulatory and tissue repair effects with their challenges and limitations. This visual illustration depicts the process of utilizing nano-engineering in stem cells and exosomes for the purpose of delivering more accurate and improved treatments for Multiple Sclerosis (MS). This approach targets specifically the creation of oligodendrocytes, the breakdown of which is the primary pathological factor in MS.

Genomic diversity and differentiation of Alu insertion polymorphisms in a native British and four South Asian migrant populations.

BACKGROUND: Alu insertions are bi-allelic and primate-specific, this makes them a useful marker for studying genetic variation, migration patterns, forensic analyses, paternity, and evolutionary heritage; however, specific population studies are limited. AIM: The objective of this study is to document the level and extent of genetic variation at 39 different Alu loci in five populations (British, Indian Punjabi, Indian Gujarati, Pakistani, and Bangladeshi) from the East Midlands region of the UK. Genetic data on migrant populations is currently limited. SUBJECTS AND METHODS: DNA samples (n = 543) were analysed for 39 Alu insertion polymorphisms using specific primers and standard protocols. Data were analysed for population and forensic genetic parameters. RESULTS: All studied Alus were polymorphic in the British White population while South Asian migrant populations had a variable number of loci which were monomorphic. Highest heterozygosities and lowest match probabilities were observed in the British sample, while the Bangladeshi sample had the lowest heterozygosity and higher match probability. CONCLUSION: The analysed Alus insertions (TPA25, Ya5NBC123, Ya5NBC182, Ya5NBC241, and Ya5NBC242) are highly polymorphic and variable among migrant populations. These loci could be useful for population genomic and differentiation studies.

A susceptibility putative haplotype within NLRP3 inflammasome gene influences ischaemic stroke risk in the population of Punjab, India.

Despite strong genetic implications of NLRP3 inflammasome, its examination as genetic determinant of ischaemic stroke (IS) remains to be done in Punjab, which has been investigated in this study. In this case control study, 400 subjects (200 IS patients, 200 stroke free controls) were included. Contributions of 5 single nucleotide polymorphisms (SNPs) including a functional SNP within NLRP3 gene (rs10754558, rs4612666, rs2027432, rs3738488 and rs1539019) for the risk of IS were investigated through genetic models after correcting the effect of significant variables. Plasma levels of three pro-inflammatory markers, that is, C-reactive protein (CRP), interleukin-1beta (IL-1ß) and interleukin-18 (IL-18) were measured by enzyme-linked immunosorbent assays (ELISA). Minor alleles of 3 out of 5 SNPs (rs10754558, rs4612666 and rs1539019) exhibited association with IS risk in additive, recessive and multiplicative models. Multivariable regression analysis confirmed that higher levels of systolic blood pressure (ß ± SE: 1.42 ± 0.57, p = .013), CRP (ß ± SE: 1.22 ± 0.41, p = .003), IL-1ß (ß ± SE: 1.78 ± 0.88, p = .043) and IL-18 (ß ± SE: 1.13 ± 0.49, p = .021) were independent risk predictors for IS. Haplotype analysis revealed a susceptibility putative haplotype GTGTA, which approximately doubled the IS risk (OR: 1.98, 95% CI: 1.12-3.78, p = .04) in dominant mode after adjusting the effect with confounding variables. This susceptibility putative haplotype GTGTA was significantly associated with increased concentrations of CRP (ß = 1.21, p = .014) and IL-1ß (ß = 1.53, p = .034) in dose-dependent manner (less in carriers of 1 copy than those who had 2 copies of GTGTA). The present study has revealed a susceptibility putative haplotype GTGTA within NLRP3 gene, carriers of which have double the risk of IS by having increased plasma levels of CRP and IL-1ß in a dose-dependent manner.

Comparison of Telomere Length in Young and Master Endurance Runners and Sprinters.

It is unclear how running modality influences telomere length (TL). This single laboratory visit study compared the TL of master sprinters and endurance runners with their young counterparts. The correlation between leukocyte and buccal cell TL in athletes was also explored. Participants consisted of 11 young controls, 11 young sprinters, 12 young endurance runners, 12 middle-aged controls, 11 master sprinters, and 12 master endurance runners. Blood and buccal samples were collected and randomized for analysis of TL by quantitative polymerase chain reaction. Young endurance runners displayed longer telomeres than master athletes (p < .05); however, these differences were not significant when controlled for covariates (p > .05). A positive correlation existed between leukocyte and buccal cell TL in athletes (r = .567, p < .001). In conclusion, young endurance runners possess longer telomeres than master endurance runners and sprinters, a consequence of lower body mass index and visceral fat.

Promoter polymorphisms in IL-6 gene influence pro-inflammatory cytokines for the risk of osteoarthritis.

BACKGROUND: Interleukin-6 (IL-6) gene regulates IL-6 levels, interplay of which has been found to influence pathophysiology of osteoarthritis (OA). Polymorphism within promoter region of IL-6 gene and its association with plasma levels of pro-inflammatory cytokines; IL-6, interleukin 1-beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) remained to be investigated in Punjab region of India, where OA is highly prevalent. METHODS: Six single nucleotide polymorphisms (SNPs) in the promoter region of IL-6 gene; rs1800795 (-174G/C), rs1800796 (-572G/C), rs1800797 (-597G/A), rs2069827 (-1363G/T), rs12700386 (-2954G/C) and rs10499563 (-6331G/T) were investigated by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 279 confirmed osteoarthritis patients and 287 controls. Plasma levels of pro-inflammatory cytokines; IL-6, IL-1ß and TNF-α were measured by sandwich Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: Allele frequency spectrum after adjusting the effect of systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein (LDL), triglycerides (TG) and body mass index (BMI) revealed that major allele G of rs1800795 and T of rs10499563 were significantly associated with increased risk of OA (P < 0.01) in all the three genetic models; co-dominant (OR 4.08 & 4.12, P < 0.001), recessive (OR 3.00 & 2.51, P < 0.001) and dominant (OR 2.56 & 3.09, P < 0.05). Major allele G of rs1800796 and rs1800797 was observed to enhance OA risk in recessive mode (OR 1.75, P < 0.001 & 1.62, P = 0.01 respectively). Disease risk analysis after adjusting the effect of confounders exposed a susceptibility haplotype GGGGCT, which increased the OA risk by 2.27 times (OR 2.27, 95%CI: 1.26-4.10, P = 0.009) and a protective haplotype CGAGGC which significantly reduced the OA risk (OR 0.47, 95%CI 0.27-0.92, P = 0.031). Both of these haplotypes manifested in the recessive mode of inheritance. Subjects who had one copy of the susceptibility haplotype had lower values of IL-6 (3.6 pg/ml) and IL-1ß levels (3.2 pg/ml) than those who had 2 copies of it (4.4 pg/ml & 4.2 pg/ml respectively). IL-6 and IL-1ß levels were observed to be negatively associated with protective haplotype CGAGGC (P < 0.05). Carriers of 1 copy of this haplotype showed decreased IL-1ß levels than those who had none (1.00 pg/ml vs. 1.3 pg/ml respectively) which further decreased to 0.9 pg/ml in those subjects who carried two copies of protective haplotype. CONCLUSION: The present study discovered susceptibility (GGGGCT) and protective (CGAGGC) haplotypes within promoter region of IL-6 gene which influenced the plasma levels of IL-6 and IL-1ß for the risk of osteoarthritis in the population of Punjab, India.

Genetic variation and differentiation among a native British and five migrant South Asian populations of the East Midlands (UK) based on CODIS forensic STR loci.

BACKGROUND: Short Tandem Repeats (STRs) are widely used in population and forensic genetic studies. AIM: The objective of this study was to document the level and extent of genetic variation of the FBI Combined DNA Index System (CODIS) STR loci (D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820, D16S539, TH01, TPOX and CSF1PO) in 6 populations (British, Indian (Punjabis and Gujaratis), Pakistani, Bangladeshi and Sri Lankan) of the East Midlands (UK). There is a lack of genetic research on the migrant South Asian populations. SUBJECTS AND METHODS: DNA samples (N = 603) were analysed for 13 autosomal forensic STR loci along with the amelogenin locus following standard protocols. Data were analysed for genetic variation and a range of forensic indices. RESULTS: All loci were polymorphic in all populations with a variable degree of variation. Average observed heterozygosity was highest in Bangladeshi (0.803) and lowest in Punjabi (0.761). FGA locus had the highest power of discrimination (PD) in most populations. CONCLUSION: FGA locus was most polymorphic and discriminatory among migrant populations demonstrating it as the marker with the highest potential in forensic analyses. These results could be useful for population and forensic genomic studies.

True Interindividual Variability Exists in Postprandial Appetite Responses in Healthy Men But Is Not Moderated by the FTO Genotype.

BACKGROUND: After meal ingestion, a series of coordinated hormone responses occur concomitantly with changes in perceived appetite. It is not known whether interindividual variability in appetite exists in response to a meal. OBJECTIVES: The aim of this study was to 1) assess the reproducibility of appetite responses to a meal; 2) quantify individual differences in responses; and 3) explore any moderating influence of the fat mass and obesity associated (FTO) gene. METHODS: Using a replicated crossover design, 18 healthy men (mean ± SD age: 28.5 ± 9.8 y; BMI: 27.0 ± 5.0 kg/m2) recruited according to FTO genotype (9 AA, 9 TT) completed 2 identical control and 2 identical standardized meal conditions (5025 kJ) in randomized sequences. Perceived appetite and plasma acylated ghrelin, total peptide YY (PYY), insulin, and glucose concentrations were measured before and after interventions as primary outcomes. Interindividual differences were explored using Pearson's product-moment correlations between the first and second replicates of the control-adjusted meal response. Within-participant covariate-adjusted linear mixed models were used to quantify participant-by-condition and genotype-by-condition interactions. RESULTS: The meal suppressed acylated ghrelin and appetite perceptions [standardized effect size (ES): 0.18-4.26] and elevated total PYY, insulin, and glucose (ES: 1.96-21.60). For all variables, SD of change scores was greater in the meal than in the control conditions. Moderate-to-large positive correlations were observed between the 2 replicates of control-adjusted meal responses for all variables (r = 0.44-0.86, P ≤ 0.070). Participant-by-condition interactions were present for all variables (P ≤ 0.056). FTO genotype-by-condition interactions were nonsignificant (P ≥ 0.19) and treatment effect differences between genotype groups were small (ES ≤ 0.27) for all appetite parameters. CONCLUSIONS: Reproducibility of postprandial appetite responses is generally good. True interindividual variability is present beyond any random within-subject variation in healthy men but we detected no moderation by the FTO genotype. These findings highlight the importance of exploring individual differences in appetite for the prevention and treatment of obesity. This trial was registered at clinicaltrials.gov as NCT03771690.

Exploration of associations between the FTO rs9939609 genotype, fasting and postprandial appetite-related hormones and perceived appetite in healthy men and women.

BACKGROUND: The fat mass and obesity-associated gene (FTO) rs9939609 A-allele has been associated with obesity risk. Although the exact mechanisms involved remain unknown, the FTO rs9939609 A-allele has been associated with an impaired postprandial suppression of appetite. OBJECTIVES: To explore the influence of FTO rs9939609 genotype on fasting and postprandial appetite-related hormones and perceived appetite in a heterogeneous sample of men and women. DESIGN: 112 healthy men and women aged 18-50-years-old completed three laboratory visits for the assessment of FTO rs9939609 genotype, body composition, aerobic fitness, resting metabolic rate, visceral adipose tissue, liver fat, fasting leptin, and fasting and postprandial acylated ghrelin, total PYY, insulin, glucose and perceived appetite. Participants wore accelerometers for seven consecutive days for the assessment of physical activity and sedentary behaviour. Multivariable general linear models quantified differences between FTO rs9939609 groups for fasting and postprandial appetite outcomes, with and without the addition of a priori selected physiological and behavioural covariates. Sex-specific univariable Pearson's correlation coefficients were quantified between the appetite-related outcomes and individual characteristics. RESULTS: 95% confidence intervals for mean differences between FTO rs9939609 groups overlapped zero in unadjusted and adjusted general linear models for all fasting (P ≥ 0.28) and postprandial (P ≥ 0.19) appetite-related outcomes. Eta2 values for explained variance attributable to FTO rs9939609 were <5% for all outcomes. An exploratory correlation matrix indicated that associations between fasting and postprandial acylated ghrelin, total PYY and general or abdominal adiposity were also small (r = -0.23 to 0.15, P ≥ 0.09). Fasting leptin, glucose and insulin and postprandial insulin concentrations were associated with adiposity outcomes (r = 0.29 to 0.81, P ≤ 0.033). CONCLUSIONS: Associations between the FTO rs9939609 genotype and fasting or postprandial appetite-related outcomes were weak in healthy men and women.

Vitamin D receptor (VDR) gene polymorphism and osteoporosis risk in White British men.

In this study, VDR gene ApaI (rs7975232), BsmI (rs 1544410) and TaqI (rs731236) genotypes were compared in men with osteoporosis and male controls. Osteoporosis affects around 20% of all men and overall mortality in the first year after hip fracture is significantly higher in men than women, yet the genetic basis of osteoporosis is less well studied in males. This study consisted of White British males; 69 osteoporosis patients and 122 controls. BMDs at the lumbar spine (vertebrae L1-L4) and hip (femur neck) were measured by dual-energy X-ray absorptiometry (DEXA). The VDR gene ApaI, BsmI and TaqI genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and association analysis was carried out at genotype and haplotype level. Our study suggests that TaqI polymorphism CC genotype frequency is lower in controls and further analysis of genotypes and BMD revealed a significant effect of TaqI polymorphism on Lumbar spine BMD. Two haplotypes (GCC and AAT) were associated with increased osteoporosis risk. In conclusion, VDR gene TaqI polymorphism in recessive mode had a significant effect on lumbar spine BMD within our study. Haplotypes GCC and AAT increase the risk of osteoporosis among White British males.

The Role of TLR4, TNF-α and IL-1ß in Type 2 Diabetes Mellitus Development within a North Indian Population.

This study investigated the role of IL-1ß-511 (rs16944), TLR4-896 (rs4986790) and TNF-α-308 (rs1800629) polymorphisms in type 2 diabetes mellitus (T2DM) among an endogamous Northern Indian population. Four hundred fourteen participants (204 T2DM patients and 210 nondiabetic controls) were genotyped for IL-1ß-511, TLR4-896 and TNF-α-308 loci. The C allele of IL-1ß-511 was shown to increase T2DM susceptibility by 75% (OR: 1.75 [CI 1.32-2.33]). Having two parents affected by T2DM increased susceptibility by 5.7 times (OR: 5.693 [CI 1.431-22.648]). In this study, we have demonstrated a conclusive association with IL-1ß-511 locus and IL-1ß-511-TLR4-896 diplotype (CC-AA) and T2DM, which warrants further comprehensive analyses in larger cohorts.

Genetic variation of MHC Class I polymorphic Alu insertions (POALINs) in three sub-populations of the East Midlands, UK.

BACKGROUND: Alu elements are highly researched due to their useful nature as markers in the study of human population genetics. Recently discovered Major Histocompatibility Complex (MHC) polymorphic Alu insertions (POALINs) have not been examined extensively for genetic variation and their HLA associations. AIMS: The aim of this study is to assess the genetic variation between three populations using five recently discovered POALINs. METHODS AND SUBJECTS: The study examined 190 healthy, unrelated subjects from three different populations in the East Midlands (UK) for the presence or absence of five Alu elements (AluHG, AluMICB, AluHJ, AluTF and AluHF) via the polymerase chain reaction followed by gel electrophoresis. Data were analysed for genetic variation and phylogenetic analyses. RESULTS: All Alus were polymorphic in study populations. Appreciable allele frequency variation was observed at a number of loci. The British population was significantly different from both the Punjabi Jat Sikh and Gujarati Patel populations, although showing a closer genetic relationship to the Punjabi Jat Sikh population than the Gujarati Patel population (Nei's DA = 0.0031 and 0.0064, respectively). CONCLUSIONS: MHC POALINs are useful markers in the investigation of genetic variation and the assessment of population relationships, and may have some bearing on disease associations due to their linkage disequilibrium with HLA loci; this warrants further studies.

n-3 Fatty acids and asthma.

Asthma is one of the most common and prevalent problems worldwide affecting over 300 million individuals. There is some evidence from observational and intervention studies to suggest a beneficial effect of n-3 PUFA in inflammatory diseases, specifically asthma. Marine-based n-3 PUFA have therefore been proposed as a possible complementary/alternative therapy for asthma. The proposed anti-inflammatory effects of n-3 fatty acids may be linked to a change in cell membrane composition. This altered membrane composition following n-3 fatty acid supplementation (primarily EPA and DHA) can modify lipid mediator generation via the production of eicosanoids with a reduced inflammatory potential/impact. A recently identified group of lipid mediators derived from EPA including E-series resolvins are proposed to be important in the resolution of inflammation. Reduced inflammation attenuates the severity of asthma including symptoms (dyspnoea) and exerts a bronchodilatory effect. There have been no major health side effects reported with the dietary supplementation of n-3 fatty acids or their mediators; consequently supplementing with n-3 fatty acids is an attractive non-pharmacological intervention which may benefit asthma.

Genetic analysis of novel Alu insertion polymorphisms in selected indian populations.

OBJECTIVES: Indian subpopulations (Chenchu, Koya, and Lobana Sikh) were analyzed at the genetic level for 12 Alu polymorphisms. These markers were then utilized to establish levels of genetic identity between the Indian populations and more widely between the Indian populations and a European population. METHODS: Previously collected blood samples were extracted using the phenol-chloroform method. The samples were utilized as templates for PCR using Alu specific primers and then analyzed by agarose gel electrophoresis for the presence and absence of the approximately 300 bp insertions. Allele frequencies were calculated by the gene counting method and were tested for Hardy-Weinberg equilibrium, heterozygosities, inbreeding coefficient, and GST to assess the level of genetic differentiation. RESULTS: All of the Alu loci were polymorphic in the three Indian populations studied and their average observed heterozygosity ranged from 0.294 (Lobana Sikh) to 0.357 (Koya). Allele and genotype frequency variation at the 2b, 9a, and ACE loci led to statistically significant pairwise differences among the three study populations. Overall population heterogeneity was observed for 7 out of 12 Alu polymorphisms. CONCLUSION: The overall results show that these Indian samples, though displaying significant genetic variation and differences among themselves, form an Indian cluster, which as expected, is distinct from the European sample (Russian). As Alus are easily analyzed and quantified by standard and cost-effective methodologies, this finding further reinforces their utility as effective population genetic markers. Am. J. Hum. Biol., 2016. © 2016 Wiley Periodicals, Inc. Am. J. Hum. Biol. 28:941-944, 2016. © 2016Wiley Periodicals, Inc.

A novel haplotype within C-reactive protein gene influences CRP levels and coronary heart disease risk in Northwest Indians.

According to several epidemiological and clinical studies, the concentration of C-reactive protein (CRP) in blood is associated with the risk of coronary heart disease (CHD). However, these studies are limited in high incidence and prevalence area of North-West India. The present case control study investigated the contribution of three relevant CRP single nucleotide polymorphisms: -717A>G located in the promoter region (rs2794521), +1059G>C on exon2 (rs1800947) and +1444C>T in the 3' UTR (rs1130864) in 180 angiographically verified CHD cases and 175 control subjects. Minor allele frequencies (G, C and T) of rs2794521, rs1800947 and rs1130864 are observed to be 21.1, 11.7, 29.4 and 11.4, 10.0, 19.7 % in CHD cases and controls respectively. AA genotype of -717A>G and TT genotype of +1444C>T were significantly associated (P = 0.02 & 0.03 respectively) with the risk of CHD whereas, +1059G and +1444T were found to be strongly related (P = 0.023 & P = 0.008 respectively) with multivariable adjusted CRP levels. AGT Haplotype was significantly associated with the adjusted CRP levels (P < 0.05). Disease association analysis revealed that haplotype AGT influences CHD risk (OR 2.4, 95 % CI 1.23-4.84, P = 0.006) which exacerbates after correcting the confounding effects of risk variables (OR 2.5, 95 % CI 1.27-4.99, P = 0.004). With the global index of Akaike information criterion, it has been observed that the carrying each single unit of this susceptibility haplotype increases CHD risk by a value of 2.41 ± 0.439 (ß ± SE) in the recessive mode.

Unity in diversity: an overview of the genomic anthropology of India.

CONTEXT: India is considered a treasure for geneticists and evolutionary biologists due to its vast human diversity, consisting of more than 4500 anthropologically well-defined populations (castes, tribes and religious groups). Each population differs in terms of endogamy, language, culture, physical features, geographic and climatic position and genetic architecture. These factors contributed to India-specific genetic variations which may be responsible for various common diseases in India and its migratory populations. As a result, interpretations of the origins and affinities of Indian populations as well as health and disease conditions require complex and sophisticated genetic analysis. Evidence of ancient human dispersals and settlements is preserved in the genome of Indian inhabitants and this has been extensively analysed in conventional and genomic analyses. OBJECTIVE AND METHODS: Using genomic analyses of STRs and Alu on a set of populations, this study estimates the level and extent of genetic variation and its implications. RESULTS: The results show that Indian populations have a higher level of unique genetic diversity which is structured by many social processes and geographical attributes of the country. CONCLUSION: This overview highlights the need to study the anthropological structure and evolutionary history of Indian populations while designing genomic and epigenomic investigations.

Role of the Menstrual Cycle on Performance and Injury Risk: A Survey of Female Professional Rugby Players in the United Kingdom.

BACKGROUND: Female athletic performance and injury risk is impacted by variations in the menstrual cycle (MC), but the understanding of the impacts and mechanisms influenced by the menstrual cycle on exercise performance are not fully delineated. AIMS AND OBJECTIVES: Evaluate associations between the menstrual cycle, perceived performance, and injury risk of elite female rugby players using an online survey. METHODS: An anonymous online questionnaire was completed by 150 elite female rugby players from two English rugby leagues, the Betfred Women's Super League (BWSL) and the Allianz Premier 15s (AP15s). The collected data were analysed thematically. RESULTS: The Chi-square test was used to assess associations between age groups and contraception usage, weight change, and training and playing performance; none of the associations were statistically significant (all p values > 0.05). Thematic analysis of 11,660 words of data revealed four themes: (a) MC impact on training and competition, (b) education and period management plans, (c) openness of conversations and comfort taking time off, and (d) injury risk. The impacted performance areas were physical (83.7%), psychological (85.7%), and nutritional (80.3%); players experienced decreased appetite, nausea, fatigue, strength declines, heighted emotions, and worsened focus. In total, 87.8% of athletes perceived the MC to negatively impact performance, 85.7% of players desired to be educated further to prevent injuries, improve nutrition, and training adaptions, 51.7% of participants perceived risk of injury to be higher during MC, and 86.4% of participants did not feel comfortable taking time off due to the MC, worrying that selection would be affected and about opinions from others. CONCLUSION: A clear negative impact on perceived performance and injury risk was reported by survey participants. The interaction of physical, psychological, and nutritional factors, and a lack of awareness and education emphasise the need for further comprehensive studies and interventions, with measures such as MC monitoring and profiling, education, and training adaptions to develop openness, knowledge, and understanding.

Implications of siRNA Therapy in Bone Health: Silencing Communicates.

The global statistics of bone disorders, skeletal defects, and fractures are frightening. Several therapeutic strategies are being used to fix them; however, RNAi-based siRNA therapy is starting to prove to be a promising approach for the prevention of bone disorders because of its advanced capabilities to deliver siRNA or siRNA drug conjugate to the target tissue. Despite its 'bench-to-bedside' usefulness and approval by food and drug administration for five siRNA-based therapeutic medicines: Patisiran, Vutrisiran, Inclisiran, Lumasiran, and Givosiran, its use for the other diseases still remains to be resolved. By correcting the complications and complexities involved in siRNA delivery for its sustained release, better absorption, and toxicity-free activity, siRNA therapy can be harnessed as an experimental tool for the prevention of complex and undruggable diseases with a personalized medicine approach. The present review summarizes the findings of notable research to address the implications of siRNA in bone health for the restoration of bone mass, recovery of bone loss, and recuperation of bone fractures.

Influence of glutathione S-transferase polymorphisms (GSTT1, GSTM1, GSTP1) on type-2 diabetes mellitus (T2D) risk in an endogamous population from north India.

Glutathione S-transferases (GSTs) belong to a group of multigene and multifunctional detoxification enzymes, which defend cells against a wide variety of toxic insults and oxidative stress. Oxidative stress leads to cellular dysfunction which contributes to the pathophysiology of diseases such as cancer, atherosclerosis, and diabetes mellitus. It is important to assess whether the glutathione S-Transferase (GSTT1, GSTM1 and GSTP1) genotypes are associated with type 2 diabetes mellitus as deletion polymorphisms have an impaired capability to counteract the oxidative stress which is a feature of diabetes. GSTT1, GSTM1 and GSTP1 gene polymorphisms were analysed in 321 patients and 309 healthy controls from an endogamous population from north India. An association analysis was carried out at two levels (a) individual genes and (b) their double and triple combinations. The proportion of GSTT1 and GSTM1 null genotypes was higher in diabetics compared to controls (GSTT1 30.8 vs. 21.0 %; GSTM1 49.5 vs. 27.2 %). The frequency of the null genotype at both loci was higher in diabetics (19.6 vs. 7.8 %) leading to an odds ratio of 2.90 (CI 1.76-4.78, P < 0.0001). At GSTP1locus, patients had a higher frequency of the V/V genotype (15.6 vs. 7.5 %) and significant susceptible odds ratio (2.56, CI 1.47-4.48, P < 0.001). A combination of null genotypes at GSTT1 and GSTM1 loci and V/V genotype of GSTP1 locus showed highest odds ratio (9.64, CI 1.53-60.63, P < 0.01). Overall this study highlights that GST genes may play an important role in the pathogenesis of type 2 diabetes. The risk is higher in individuals carrying more than one susceptible genotype at these loci. The potential role of GST polymorphisms as markers of susceptibility to type 2 diabetes needs further investigations in a larger number of patients and populations.

'From death, lead me to immortality' - mantra of ageing skeletal muscle.

Skeletal muscle is a post-mitotic tissue maintained by repair and regeneration through a population of stem cell-like satellite cells. Following muscle injury, satellite cell proliferation is mediated by local signals ensuring sufficient progeny for tissue repair. Age-related changes in satellite cells as well as to the local and systemic environment potentially impact on the capacity of satellite cells to generate sufficient progeny in an ageing organism resulting in diminished regeneration. 'Rejuvenation' of satellite cell progeny and regenerative capacity by environmental stimuli effectors suggest that a subset of age-dependent satellite cell changes may be reversible. Epigenetic regulation of satellite stem cells that include DNA methylation and histone modifications which regulate gene expression are potential mechanisms for such reversible changes and have been shown to control organismal longevity. The area of health and ageing that is likely to benefit soonest from advances in the biology of adult stem cells is the emerging field of regenerative medicine. Further studies are needed to elucidate the mechanisms by which epigenetic modifications regulate satellite stem cell function and will require an increased understanding of stem-cell biology, the environment of the aged tissue and the interaction between the two.

Genetic Risk Scores for the Determination of Type 2 Diabetes Mellitus (T2DM) in North India.

BACKGROUND: Globally, type 2 diabetes mellitus (T2DM) is one of the fastest-growing noncommunicable multifactorial and polygenic diseases, which leads to many health complications and significant morbidity and mortality. South Asians have a high genetic predisposition to T2DM, with India being home to one in six diabetics. This study investigates the association of selected genetic polymorphisms with T2DM risk and develops a polygenic risk score (PRS). METHODS: A case-control study recruited fully consented participants from a population of Jat Sikhs in north India. DNA samples were genotyped for a range of polymorphisms and odds ratios were calculated under several genetic association models. Receiver operating characteristic (ROC) curves were produced for combinations of the PRS and clinical parameters. RESULTS: The GSTT1(rs17856199), GSTM1(rs366631), GSTP1(rs1695), KCNQ1(rs2237892), ACE(rs4646994), and TCF7L2(rs12255372; rs7903146; rs7901695) polymorphisms were associated with increased T2DM risk (p ≤ 0.05). No association was observed with IGF2BP2(rs4402960) or PPARG2(rs1801282). The weighted PRS was found to be significantly higher in patients (mean = 15.4, SD = 3.24) than controls (mean = 11.9, SD = 3.06), and t(454) = -12.2 (p < 0.001). The ROC curve analysis found the weighted PRS in combination with clinical variables to be the most effective predictor of T2DM (area under the curve = 0.844, 95%CI = 0.0.808-0.879). CONCLUSIONS: Several polymorphisms were associated with T2DM risk. PRS based on even a limited number of loci improves the prediction of the disease. This may provide a useful method for determining T2DM susceptibility for clinical and public health applications.