Therapeutic Potential of Plant Metabolites in Bone Apoptosis: A Review.

Osteoporosis is one of the skeletal diseases of major health concern worldwide. Homeostasis of bone occurs with the help of cells, namely, osteoblasts and osteoclasts. Physiological and pathological conditions involve the death of the cells by apoptosis, autophagy, and necrosis. Apoptosis is a key factor in the growth, development, and maintenance of the skeleton. Apoptosis is generated by two pathways: the intrinsic (mitochondria) and extrinsic (death receptor) pathways. Osteoblast apoptosis is governed by the factors like B cell lymphoma 2 (Bcl-2) family proteins, extracellular signal-regulated kinase (ERK), mitogen-activated protein kinases (MAPK), phosphoinositide- 3-kinase/ protein kinase B (PI3-K/Akt), Janus kinase 2 (JAK2), bone morphogenetic protein (BMP), and bone matrix protein. Cytokines interact with osteocytes and induce apoptosis. A pro-inflammatory signal stimulates osteocyte apoptosis and increases osteocyte cytokines production. Current therapies have adverse effects which limit their applications. Various plant metabolites have shown beneficial effects on bone. The present review converses about normal bone metabolism and the mechanism of apoptosis leading to bone deterioration. Furthermore, it discusses the role of plant metabolites on bone apoptosis with related indications of efficacy in various experimental models.

Harnessing immunotherapy to combat COVID-19: A modern snake oil or silver bullet?

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has emerged into a global health and economic menace. Amidst the COVID-19 turmoil, recent failures/uncertain outcomes in clinical trials involving the anti-malarial (hydroxychloroquine), anti-viral (remdesivir) or the combination of anti-malarial/antibiotic (hydroxychloroquine/azithromycin) regimens have predisposed the physicians to distrust these "highly-touted" drugs for COVID-19. In this milieu, immunotherapy might be a credible modality to target or modify specific/non-specific immune responses that interfere with the survival of intracellular pathogens. This scientific review throws light on the epidemiology of COVID-19, its pathogenesis and the current clinical scenario of immunotherapeutics including convalescent plasma (CP), type-1 interferons (IFN-I) and human monoclonal antibodies (mAbs) to combat COVID-19. The treatment outcomes underscore that immunotherapy might be a reliable tool to assuage COVID-19-associated immunopathology. However, specific patient pool studies are warranted to ascertain the precise (re)purposing of immunotherapeutics for COVID-19.

3,4-Dihydroxyphenylethanol Assuages Cognitive Impulsivity in Alzheimer's Disease by Attuning HPA-Axis via Differential Crosstalk of α7 nAChR with MicroRNA-124 and HDAC6.

Cognitive impulsivity, a form of suboptimal cost-benefit decision making, is an illustrious attribute of an array of neurodegenerative diseases including Alzheimer's disease (AD). In this study, a delay discounting paradigm was used to assess the effect of 3,4-dihydroxyphenylethanol (DOPET) on cognitive impulsivity, in an oA42i (oligomeric amyloid ß1-42 plus ibotenic acid) induced AD mouse model, using a nonspatial T-maze task. The results depicted that oA42i administration elevated cognitive impulsivity, whereas DOPET treatment attenuated the impulsive behavior and matched the choice of the sham-operated controls. In addition, DOPET treatment has ameliorated the anxiety-like behavior in the oA42i-challenged mice. Probing the molecular signaling cascades underpinning these functional ramifications in the oA42i-challenged mice revealed reduced cholinergic (α7 nAChR; alpha 7 nicotinic acetylcholine receptor) function, dysregulated hypothalamic-pituitary-adrenal (HPA) axis (manifested by amplified glucocorticoid receptor expression and plasma corticosterone levels), and also aberrations in the neuroepigenetic (microRNA-124, HDAC6 (histone deacetylase 6), and HSP90 (heat-shock protein 90) expressions) as well as nucleocytoplasmic (importin-α1 expression and nuclear ultra-architecture) continuum. Nonetheless, DOPET administration ameliorated these perturbations and the observations were in line with that of the sham-operated mice. Further validation of the results with organotypic hippocampal slice cultures (OHSCs) confirmed the in vivo findings. We opine that HPA-axis attunement by DOPET might be orchestrated through the α7 nAChR-mediated pathway. Based on these outcomes, we posit that 3,4-dihydroxyphenylethanol might be a potential multimodal agent for the management of cognitive impulsivity and neuromolecular quagmire in AD.

3,4-dihydroxyphenylethanol attenuates spatio-cognitive deficits in an Alzheimer's disease mouse model: modulation of the molecular signals in neuronal survival-apoptotic programs.

Alzheimer's disease (AD), the most common type of dementia, is a devastating neurodegenerative disease characterized by progressive neuro-cognitive dysfunction. In our study, we investigated the potential of 3,4-dihydroxyphenylethanol (DOPET), a dopamine metabolite, and also a polyphenol from olive oil, in ameliorating soluble oligomeric amyloid ß1-42 plus ibotenic acid (oA42i)-induced neuro-behavioral dysfunction in C57BL/6 mice. The results depicted that intracerebroventricular injection of oA42i negatively altered the spatial reference and working memories in mice, whereas DOPET treatment significantly augmented the spatio-cognitive abilities against oA42i. Upon investigation of the underlying mechanisms, oA42i-intoxicated mice displayed significantly activated death kinases including JNK- and p38-MAPKs with concomitantly inhibited ERK-MAPK/RSK2, PI3K/Akt1, and JAK2/STAT3 survival signaling pathways in the hippocampal neurons. Conversely, DOPET treatment reversed these dysregulated signaling mechanisms comparable to the sham-operated mice. Notably, oA42i administration altered the Bcl-2/Bad levels and activated the caspase-dependent mitochondria-mediated apoptotic pathway involving cytochrome c, apoptotic protease activating factor-1, and caspase-9/3. In contrary, DOPET administration stabilized the dysregulated activities of these apoptotic/anti-apoptotic markers and preserved the mitochondrial ultra-architecture. Besides, we observed that oA42i intoxication substantially down-regulated the expression of genes involved in the regulation of survival and memory functions including sirtuin-1, cyclic AMP response element-binding protein (CREB), CREB-target genes (BDNF, c-Fos, Nurr1, and Egr1) and a disintegrin and metalloprotease 10. Fascinatingly, DOPET treatment significantly diminished these aberrations when compared to the oA42i group. Taken together, these results accentuate that DOPET may be a multipotent agent to combat AD.

Immunopotentiation of hepatitis B vaccine using biodegradable polymers as an adjuvant.

BACKGROUND/PURPOSE: The purpose of this research was to develop an alternative adjuvant for hepatitis B vaccine (HBsAg) that elicits a long-lasting immune response after a single administration. In this study, the suitability of Poly (D, L)-lactide-co-glycolic acid (PLGA), Poly lactic acid (PLA) and Chitosan polymers as adjuvants for HBsAg were investigated. METHODS: We used solvent evaporation and emulsion cross-linking techniques to encapsulate HBsAg into the different polymeric systems. The newly developed microparticles were evaluated for vaccine content, particle size distribution, in vitro release and immunogenicity. RESULTS: HBsAg-encapsulated PLGA and PLA microparticles were smooth and spherical. However, Chitosan microparticles were homogeneous, and almost spherical, with rough surfaces. The vaccine loading and release patterns varied with the type of polymer used. In this study, Chitosan polymeric microparticles released antigen until day 63 post-injection; however, the release period of the PLGA and PLA systems was shorter. A significant increase in the level of antibodies to HBsAg was induced by all the polymeric microparticles. CONCLUSION: The results indicate that Chitosan microparticles are a more efficient adjuvant for HBsAg than PLGA and PLA polymeric microparticles.