A glucuronated flavone TMMG spatially targets chondrocytes to alleviate cartilage degeneration through negative regulation of IL-1ß.

Chondrocytes are the only resident cell types that form the extracellular matrix of cartilage. Inflammation alters the anabolic and catabolic regulation of chondrocytes, resulting in the progression of osteoarthritis (OA). The potential of TMMG, a glucuronated flavone, was explored against the pathophysiology of OA in both in vitro and in vivo models. The effects of TMMG were evaluated on chondrocytes and the ATDC5 cell line treated with IL-1ß in an established in vitro inflammatory OA model. An anterior cruciate ligament transection (ACLT) model was used to simulate post-traumatic injury in vivo. Micro-CT and histological examination were employed to examine the micro-architectural status and cartilage alteration. Further, serum biomarkers were measured using ELISA to assess OA progression. In-vitro, TMMG reduced excessive ROS generation and inhibited pro-inflammatory IL-1ß secretion by mouse chondrocytes and macrophages, which contributes to OA progression. This expression pattern closely mirrored osteoclastogenesis prevention. In-vivo results show that TMMG prevented chondrocyte apoptosis and degradation of articular cartilage thickness, subchondral parameters, and elevated serum COMP, CTX-II, and IL-1ß which were significantly restored in 5 and 10 mg.kg-1day-1 treated animals and comparable to the positive control Indomethacin. In addition, TMMG also improved cartilage integrity and decreased the OARSI score by maintaining chondrocyte numbers and delaying ECM degradation. These findings suggest that TMMG may be a prospective disease-modifying agent that can mitigate OA progression.

A novel BMP2 secretagogue ameliorates glucocorticoid induced oxidative stress in osteoblasts by activating NRF2 dependent survival while promoting Wnt/ß-catenin mediated osteogenesis.

In our previous study, a novel BMP2 secretagogue was synthesized belonging to a class of galloyl conjugates of flavanones, with remarkable osteogenic potential that promoted bone regeneration. We aimed to establish the protective effect of our compound against bone loss that co-exists with excess Glucocorticoid (GC) therapy. GC therapy induces osteoblast damage leading to apoptosis by increasing reactive oxygen species (ROS). Our results delineate that compound 5e (a BMP2 secretagogue) activates NRF2 signalling to counter the disturbed cellular redox homeostasis and escalate osteoblast survival as assessed by Western blot and immunocytochemistry. Depletion of NRF2 by siRNA blocked activation of the NRF2/HO-1 pathway, magnified oxidative stress, increased apoptosis and abrogated the protective effects of compound 5e. 5e, on the other hand, increased ALP, mineralization activity, and promoted osteoblast differentiation by activating WNT/ß-catenin signalling in BMP2 dependent manner, validated by Western blot of WNT3A, SOST, GSK3-ß and ß-catenin nuclear translocation. Treatment of 5e in presence of BMP inhibitor noggin attenuated the osteogenic efficacy and minimized Wnt//ß-catenin signalling in presence of dexamethasone. Our compound prevents GC challenged trabecular and cortical bone loss assessed by micro-CT and promotes bone formation and osteocyte survival determined by calcein labelling and TUNEL assay in GC treated animals. The osteogenic potential of the compound was authenticated by bone turnover markers. On a concluding note, compounds with BMP upregulation can be potential therapeutics for the prevention and treatment of glucocorticoid-induced osteoporosis.

Nanoparticles of naturally occurring PPAR-γ inhibitor betulinic acid ameliorates bone marrow adiposity and pathological bone loss in ovariectomized rats via Wnt/ß-catenin pathway.

AIMS: Postmenopausal osteoporosis is one of the world's biggest yet unnoticed health issues. After ovariectomy, declined estrogen level significantly contributes to the elevation of bone marrow adiposity and bone loss leading to osteoporosis. Therapeutics to prevent osteoporosis addressing various aspects are now in short supply. In this study we made an approach to synthesize nanoparticles of naturally occurring PPAR-γ inhibitor, betulinic acid (BA/NPs) and tested the same in altered bone metabolisms developed after ovariectomy. MAIN METHODS: The osteogenic efficacy of BA/NPs was established in human and rat primary osteoblast cells using qRT-PCR and immunoblot analysis. Furthermore, lineage allocations of multipotent bone marrow stromal cells were evaluated. Various aspects of altered bone metabolism after ovariectomy such as bone marrow adiposity and pathological bone loss were evaluated using µCT and histological assessments. KEY FINDINGS: BA/NPs exert potential osteogenic efficacy by modulating key osteogenic markers such as RUNX2 and BMP2. Mechanistically BA/NPs regulate osteoblastogenesis through Wnt/ß-catenin signaling. Further, BA/NPs showed the potential to inhibit the differentiation of multipotent BMSCs towards adipogenesis while favouring the osteogenic lineage via Wnt/ß-catenin pathway. In the in vivo study, increased bone marrow adiposity was reduced in ovariectomized rats after BA/NPs treatment as assessed by histology and µCT analysis. Loss of bone mineral density as a hallmark of pathological bone loss was also abrogated by BA/NPs. Furthermore, increased obesity after OVX was also prevented in BA/NPs treated animals. SIGNIFICANCE: Our findings imply that BA/NPs could be used further as a viable drug lead to counteract various pathophysiological challenges after menopause.

Circulating microRNAs as biomarkers of environmental exposure to polycyclic aromatic hydrocarbons: potential and prospects.

Exposure to polycyclic aromatic hydrocarbons (PAHs) produced from various pyrogenic and petrogenic sources in the environment has been linked to a variety of toxic effects in the human body. Genome-wide analyses have shown that microRNAs (miRNAs) can function as novel and minimally invasive biomarkers of environmental exposure to PAHs. The objective of this study is to explore miRNA signatures associated with early health effects in response to chronic environmental exposure to PAHs. We systematically searched Scopus and PubMed databases for studies related to exposure of PAHs with changes in miRNA expression patterns that represent early health effects in the exposed population. Based on previous studies, we included 15 cell-based and 9 each of animal model and human population-based studies for assessment. A total of 11 differentially expressed PAH-responsive miRNAs were observed each in two or more cell-based studies (miR-181a and miR-30c-1), animal model studies (miR-291a and miR-292), and human population-based studies (miR-126, miR-142-5p, miR-150-5p, miR-24-3p, miR-27a-3p, miR-28-5p, and miR-320b). In addition, miRNAs belonging to family miR-122, miR-199, miR-203, miR-21, miR-26, miR-29, and miR-92 were found to be PAH-responsive in both animal model and cell-based studies; let-7, miR-126, miR-146, miR-30, and miR-320 in both cell-based and human population-based studies; and miR-142, miR-150, and miR-27 were found differentially expressed in both animal model and human population-based studies. The only miRNA whose expression was found to be altered in all the three groups of studies is miR-34c. Association of environmental exposure to PAHs with altered expression of specific miRNAs indicates that selective miRNAs can be used as early warning biomarkers in PAH-exposed population.

Biochemical composition, transmission and diagnosis of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory infection caused by severe acute respiratory syndrome virus (SARS-CoV-2), a novel human coronavirus. COVID-19 was declared a pandemic by World Health Organization in March 2020 for its continuous and rapid spread worldwide. Rapidly emerging COVID-19 epicenters and mutants of concerns have created mammoth chaos in healthcare sectors across the globe. With over 185 million infections and approximately 4 million deaths globally, COVID-19 continues its unchecked spread despite all mitigation measures. Until effective and affordable antiretroviral drugs are made available and the population at large is vaccinated, timely diagnosis of the infection and adoption of COVID-appropriate behavior remains major tool available to curtail the still escalating COVID-19 pandemic. This review provides an updated overview of various techniques of COVID-19 testing in human samples and also discusses, in brief, the biochemical composition and mode of transmission of the SARS-CoV-2. Technological advancement in various molecular, serological and immunological techniques including mainly the reverse-transcription polymerase chain reaction (RT-PCR), CRISPR, lateral flow assays (LFAs), and immunosensors are reviewed.