Navneet Kumar Dubey

Benzodiazepine Use and Risk of Dementia in the Elderly Population: A Systematic Review and Meta-Analysis

Background: Benzodiazepines are a widely used medication in developed countries, particularly among elderly patients. However, benzodiazepines are known to affect memory and cognition and might thus enhance the risk of dementia. The objective of this review is to synthesize evidence from observational studies that evaluated the association between benzodiazepines use and dementia risk. Summary: We performed a systematic review and meta-analysis of controlled observational studies to evaluate the risk of benzodiazepines use on dementia outcome. All control observational studies that compared dementia outcome in patients with benzodiazepine use with a control group were included. We calculated pooled ORs using a random-effects model. Ten studies (of 3,696 studies identified) were included in the systematic review, of which 8 studies were included in random-effects meta-analysis and sensitivity analyses. Odds of dementia were 78% higher in those who used benzodiazepines compared with those who did not use benzodiazepines (OR 1.78; 95% CI 1.33-2.38). In subgroup analysis, the higher association was still found in the studies from Asia (OR 2.40; 95% CI 1.66-3.47) whereas a moderate association was observed in the studies from North America and Europe (OR 1.49; 95% CI 1.34-1.65 and OR 1.43; 95% CI 1.16-1.75). Also, diabetics, hypertension, cardiac disease, and statin drugs were associated with increased risk of dementia but negative association was observed in the case of body mass index. There was significant statistical and clinical heterogeneity among studies for the main analysis and most of the sensitivity analyses. There was significant statistical and clinical heterogeneity among the studies for the main analysis and most of the sensitivity analyses. Key Messages: Our results suggest that benzodiazepine use is significantly associated with dementia risk. However, observational studies cannot clarify whether the observed epidemiologic association is a causal effect or the result of some unmeasured confounding variable. Therefore, more research is needed.

Cordyceps militaris Treatment Preserves Renal Function in Type 2 Diabetic Nephropathy Mice

Diabetic nephropathy is derived from long-term effects of high blood glucose on kidney function in type 2 diabetic patients. Several antidiabetic drugs and herbal medications have failed to prevent episodes of DN. Hence, this study aimed to further investigate the renal injury-reducing effect of antidiabetic CmNo1, a novel combination of powders of fruiting bodies and mycelia of Cordyceps militaris. After being administered with streptozotocin-nicotinamide and high-fat-diet, the diabetic nephropathy mouse model displayed elevated blood glucose and renal dysfunction markers including serum creatinine and kidney-to-body weight ratio. These elevated markers were significantly mitigated following 8 weeks CmNo1 treatment. Moreover, the chronic hyperglycemia-induced pathological alteration in renal tissue were also ameliorated. Besides, immunohistochemical study demonstrated a substantial reduction in elevated levels of carboxymethyl lysine, an advanced glycation end product. Elevated collagenous deposition in DN group was also attenuated through CmNo1 administration. Moreover, the enhanced levels of transforming growth factor-β1, a fibrosis-inducing protein in glomerulus were also markedly dampened. Furthermore, auxiliary risk factors in DN like serum triglycerides and cholesterol were found to be increased but were decreased by CmNo1 treatment. Conclusively, the results suggests that CmNo1 exhibit potent and efficacious renoprotective action against hyperglycemia-induced DN.

Functional Recovery in Osteoarthritic Chondrocytes Through Hyaluronic Acid and Platelet-Rich Plasma–Inhibited Infrapatellar Fat Pad Adipocytes

Background: Recent studies have shown evidence that higher adiposity in the infrapatellar fat pad (IFP) induces inflammatory phenotypes in the knee joint and thereby contributes to the development and progression of osteoarthritis (OA). In particular, IFP adipocyte–derived inflammatory cytokines participate in pathological events. Our previous research has already addressed the therapeutic efficacy of hyaluronic acid and platelet-rich plasma (HA+PRP), including the promotion of cartilage regeneration and the inhibition of inflammation. The current study aimed to explore the remedial action of coadministered HA+PRP in OA recovery via IFP adipocyte inhibition. Hypothesis: HA+PRP repairs OA articular cartilage by inhibiting the release of adipokines from IFP adipocytes. Study Design: Controlled laboratory study. Methods: IFP adipocytes and articular chondrocytes were obtained from 10 patients with OA, and the effects of releasates containing cytokines and adipokines in IFP adipocyte–derived conditioned medium (IACM) on articular chondrocytes and IFP adipocytes themselves were evaluated. The therapeutic efficacy of exogenous HA+PRP was determined through its administration to cocultured IFP adipocytes and articular chondrocytes and further demonstrated in a 3-dimensional (3D) arthritic neocartilage model. Results: The IACM and IFP adipocyte–induced microenvironment could induce dedifferentiated and inflammatory phenotypes in articular chondrocytes. HA+PRP decreased the inflammatory potential of IFP adipocytes through the profound inhibition of cytokines and adipokines. The IACM-mediated and -reduced cartilaginous extracellular matrix could also be recovered through HA+PRP in the 3D arthritic neocartilage model. Conclusion: IFP adipocyte–derived releasates mediated inflammatory response dedifferentiation in chondrocytes, which was recovered through HA+PRP administration. Clinical Relevance: Our findings demonstrated that HA+PRP effectively diminished IFP adipocyte–promoted inflammation in articular chondrocytes, indicating that the IFP could be a potential therapeutic target for OA therapy.

Hypoglycemic Activity through a Novel Combination of Fruiting Body and Mycelia of Cordyceps militaris in High-Fat Diet-Induced Type 2 Diabetes Mellitus Mice

Diabetes mellitus (DM) is currently ranked among leading causes of death worldwide in which type 2 DM is reaching an epidemic proportion. Hypoglycemic medications for type 2 DM have either proven inadequate or posed adverse effects; therefore, the Chinese herbal products are under investigation as an alternative treatment. In this study, a novel combination of fruiting body and mycelia powder of herbal Cordyceps militaris number 1 (CmNo1) was administered to evaluate their potential hypoglycemic effects in high-fat diet- (HFD-) induced type 2 DM in C57BL/6J mice. Body weight, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), and blood biochemistry indexes were measured. Results indicated that CmNo1 lowered the blood glucose level by increasing insulin sensitivity, while no change in body weight was observed. Increased protein expression of IRS-1, pIRS-1, AKT, pAKT, and GLUT-4 in skeletal muscle and adipose tissue was found indicating restoration of insulin signaling. Additionally, PPAR-γ expression in adipose tissue restored the triglyceride and cholesterol levels. Finally, our results suggest that CmNo1 possesses strong hypoglycemic, anticholesterolemic, and antihypertriglyceridemic actions and is more economical alternate for DM treatment.

Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review

Knee osteoarthritis (OA) is a chronic degenerative disorder which could be distinguished by erosion of articular cartilage, pain, stiffness, and crepitus. Not only aging-associated alterations but also the metabolic factors such as hyperglycemia, dyslipidemia, and obesity affect articular tissues and may initiate or exacerbate the OA. The poor self-healing ability of articular cartilage due to limited regeneration in chondrocytes further adversely affects the osteoarthritic microenvironment. Traditional and current surgical treatment procedures for OA are limited and incapable to reverse the damage of articular cartilage. To overcome these limitations, cell-based therapies are currently being employed to repair and regenerate the structure and function of articular tissues. These therapies not only depend upon source and type of stem cells but also on environmental conditions, growth factors, and chemical and mechanical stimuli. Recently, the pluripotent and various multipotent mesenchymal stem cells have been employed for OA therapy, due to their differentiation potential towards chondrogenic lineage. Additionally, the stem cells have also been supplemented with growth factors to achieve higher healing response in osteoarthritic cartilage. In this review, we summarized the current status of stem cell therapies in OA pathophysiology and also highlighted the potential areas of further research needed in regenerative medicine.

Non-invasive in vivo molecular imaging of intra-articularly transplanted immortalized bone marrow stem cells for osteoarthritis treatment

Pathophysiology of osteoarthritis (OA) is characterized by progressive loss of articular cartilage in the knee-joints. To impart regenerative ability in lowly metabolizing chondrocytes, the bone marrow stem cells (BMSCs) has recently been recognized as a superior alternative treatment for OA. However, study of primary BMSCs-mediated chondrogenesis is difficult due to progressive cellular aging and replicative senescence. To obtain a therapeutic cell population for OA, BMSCs were immortalized by human papilloma virus (HPV)-16 E6/E7 along with mCherry luciferase (mCL), a gene marker for non-invasive imaging, and designated as iBMSCs-mCL. Next, their cell morphology, population doubling time (PDT) and colony forming ability (CFU) were evaluated. Furthermore, pluripotency and immunophenotypic markers were investigated. To deduce therapeutic ability, iBMSCs-mCL were intra-articularly injected into right knee of anterior cruciate ligament transaction (ACLT)-OA mice model and tracked through non-invasive bioluminescence imaging. Cell morphology of iBMSCs-mCL was similar to parental BMSCs. PDT and CFU ability of iBMSCs-mCLs were significantly increased. Pluripotency and immunophenotypic markers were highly expressed in iBMSC-mCL. Long-term survival and tri-lineage differentiation particularly chondrogenic potential of iBMSCs-mCL were also demonstrated in vitro and then in vivo which was monitored through non-invasive imaging. Intensive bioluminescent signals in iBMSCs-mCL administered knee-joint indicated a marked in vivo survival and proliferation of iBMSCs-mCL. Immunohistochemical staining for type II collagen (IHC of Col II) and alcian blue & safranin o staining of proteoglycans also corroborated cartilage regeneration by iBMSCs-mCL. Conclusively, iBMSCs-mCL maintains stemness and in vivo cartilage regeneration potential suggesting a promising avenue for development of OA therapeutics.

Addressing Stem Cell Therapeutic Approaches in Pathobiology of Diabetes and Its Complications

High morbidity and mortality of diabetes mellitus (DM) throughout the human population is a serious threat which needs to be addressed cautiously. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are most prevalent forms. Disruption in insulin regulation and resistance leads to increased formation and accumulation of advanced end products (AGEs), which further enhance oxidative and nitrosative stress leading to microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular complications. These complications affect the normal function of organ and tissues and may cause life-threatening disorders, if hyperglycemia persists and improperly controlled. Current and traditional treatment procedures are only focused on to regulate the insulin level and do not cure the diabetic complications. Pancreatic transplantation seemed a viable alternative; however, it is limited due to lack of donors. Cell-based therapy such as stem cells is considered as a promising therapeutic agent against DM and diabetic complications owing to their multilineage differentiation and regeneration potential. Previous studies have demonstrated the various impacts of both pluripotent and multipotent stem cells on DM and its micro- and macrovascular complications. Therefore, this review summarizes the potential of stem cells to treat DM and its related complications.

Inhibition of chronic prostate inflammation by hyaluronic acid through an immortalized human prostate stromal cell line model

Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. A well-established in vitro cell model is required to determine the therapeutic mechanism of BPH inflammation. In this study, we attempted to establish an immortalized human prostate stromal cell line by transfecting with HPV-16 E6/E7 and designated as ihPSC. No significant difference was found in fibroblast-like morphology between primary hPSC and ihPSC. The ihPSC possessed a significantly higher cell proliferation rate than primary hPSC. The prostate-specific markers and proteins including cytoskeleton (α-SMA and vimentin) and smooth muscle (calponin), especially the androgen receptor (AR) were also examined in ihPSC, almost identical to the primary hPSC. To create an in vitro model featuring chronic prostatic inflammation, ihPSC was stimulated with IFN-γ+IL-17 and then treated with the high molecular weight hyaluronic acid hylan G-F 20 as an alternative strategy for inhibiting BPH inflammation. Hylan G-F 20 could dose-dependently diminish the inflammation-induced proliferation in ihPSC. The enhanced expressions of inflammatory molecules including IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), inducible nitrogen oxide synthase (iNOS), and Toll-like receptor 4 (TLR4) were all abolished by hylan G-F 20. For inflammatory signaling, hylan G-F 20 can also diminish the IFN-γ+IL-17-increased expression of iNOS and p65 in ihPSC. These findings suggest that ihPSC could provide a mechanism-based platform for investigating prostate inflammation. The hylan G-F 20 showed strong anti-inflammatory effects by decreasing inflammatory cytokines and signalings in the ihPSC, indicating its therapeutic potentials in BPH treatment in the future.

Correlation between Diabetes Mellitus and Knee Osteoarthritis: A Dry-To-Wet Lab Approach

Recent years have witnessed an increased prevalence of knee osteoarthritis (KOA) among diabetes mellitus (DM) patients—conditions which might share common risk factors such as obesity and advanced aging. Therefore, we conducted dry-to-wet lab research approaches to assess the correlation of type 1 DM (T1DM) and type 2 DM (T2DM) with KOA among all age and genders of Taiwanese population. The strength of association (odds ratio: OR) was analyzed using a phenome-wide association study portal. Populations of 37,353 T1DM and 1,218,254 T2DM were included. We observed a significant association of KOA with T1DM (OR: 1.40 (1.33–1.47), p< 0.0001) and T2DM (OR: 2.75 (2.72–2.78), p< 0.0001). The association between T1DM and KOA among the obese (OR: 0.99 (0.54–1.67), p = 0.0477) was insignificant compared to the non-obese (OR: 1.40 (1.33–1.48), p < 0.0001). Interestingly, a higher association between T2DM and KOA among non-obese persons (OR: 2.75, (2.72–2.79), p < 0.0001) compared to the obese (OR: 1.71 (1.55–1.89), p < 0.0001) was noted. Further, histopathologic and Western blot studies of diabetic mice knee joints revealed enhanced carboxymethyl lysine (advanced glycation end product), matrix metalloproteinase-1, and reduced cartilage-specific proteins, including type II collagen (Col II), SOX9, and aggrecan (AGN), indicating deteriorated articular cartilage and proteoglycans. Results indicate that DM is strongly associated with KOA, and obesity may not be a confounding factor.

NSC 95397 Suppresses Proliferation and Induces Apoptosis in Colon Cancer Cells through MKP-1 and the ERK1/2 Pathway

NSC 95397, a quinone-based small molecule compound, has been identified as an inhibitor for dual-specificity phosphatases, including mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is known to inactivate mitogen-activated protein kinases by dephosphorylating both of their threonine and tyrosine residues. Moreover, owing to their participation in tumorigenesis and drug resistance in colon cancer cells, MKP-1 is an attractive therapeutic target for colon cancer treatment. We therefore investigated the inhibitory activity of NSC 95397 against three colon cancer cell lines including SW480, SW620, and DLD-1, and their underlying mechanisms. The results demonstrated that NSC 95397 reduced cell viability and anchorage-independent growth of all the three colon cancer cell lines through inhibited proliferation and induced apoptosis via regulating cell-cycle-related proteins, including p21, cyclin-dependent kinases, and caspases. Besides, by using mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126, we provided mechanistic evidence that the antineoplastic effects of NSC 95397 were achieved via inhibiting MKP-1 activity followed by ERK1/2 phosphorylation. Conclusively, our results indicated that NSC 95397 might serve as an effective therapeutic intervention for colon cancer through regulating MKP-1 and ERK1/2 pathway.