Tanshinone IIA from Salvia miltiorrhiza alleviates follicular maturation arrest symptoms in zebrafish via binding to the human androgen receptors and modulating Tox3 and Dennd1a.

Follicular maturation arrest is a prevalent endocrine disorder characterized by hormonal imbalance, ovarian dysfunction, and metabolic disturbances leading to Polycystic ovarian syndrome (PCOS). Tanshinone IIA (TIIA), a bioactive compound derived from Salvia miltiorrhiza, has shown promising therapeutic potential in various diseases, including cardiovascular diseases and cancer. However, its effects on reproductive health and gynecological disorders, particularly PCOS, remain poorly understood. In this study, we investigated the potential therapeutic effects of TIIA on ovarian function. Using a combination of experimental and computational approaches, we elucidated the molecular mechanisms underlying TIIA's pharmacological impact on ovarian function, follicular development, and androgen receptor signaling. Molecular docking and dynamics simulations revealed that TIIA interacts with the human androgen receptor (HAR), modulating its activity and downstream signaling pathways. Our results demonstrate that TIIA treatment alleviates PCOS-like symptoms in a zebrafish model, including improved follicular development, lowered GSI index, improved antioxidant status (SOD, CAT), decreased LDH levels, and enhanced AChE levels by regulating Tox3 and Dennd1a pathway. Our findings suggest that TIIA may hold promise as a novel therapeutic agent for the management of PCOS or ovulation induction.

Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties.

The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC50 < 25 nM). The validation of cellular target engagement for these compounds was achieved through the employment of the ULK1 NanoBRET intracellular kinase assay. Notably, we have successfully solved the crystal structure of the lead compound, MR-2088, bound to the active site of ULK1. Moreover, the combination treatment of MR-2088 with known KRAS→RAF→MEK→ERK pathway inhibitors, such as trametinib, showed promising synergistic effect in vitro using H2030 (KRASG12C) cell lines. Lastly, our findings underscore MR-2088's potential to inhibit starvation/stimuli-induced autophagic flux, coupled with its suitability for in vivo studies based on its pharmacokinetic properties.

Impact of COVID-19 lockdown on the particulate matter over Perungudi, Chennai, India.

The nationwide lockdown of Phase-1 in India was started from March 25 to April 14, 2020 and Phase-2 from April 15 to May 3, 2020 with severe restrictions on public activities in India. Utilizing the particulate matter PM10 and PM2.5 data recorded during this adverse time, the present study is undertaken to assess the impact of phase 1 and 2 lockdown on the air quality of Perungudi, Chennai, India. The data obtained from the Tamil Nadu Pollution Control Board was assessed for lockdown phase. We compared particulate matter data for the unlock phase with a coinciding period in March 2020 to determine the changes in pollutant concentrations during the lockdown period of April 2020. The descriptive analysis of PM continuous data was performed to determine the mean, standard deviation, variance, skew and kurtosis to identify the nature of data. Correlogram analysis gives the information that the data under study has non-stationary behaviour and not random. Along with this linear regression analysis were performed to determine the relationship and trend for the data. The results revealed decreasing trend in the concentrations (PM10, PM2.5).

Influence of Moringa oleifera biodiesel-diesel-hexanol and biodiesel-diesel-ethanol blends on compression ignition engine performance, combustion and emission characteristics.

In the current work, the influences of Moringa oleifera biodiesel-diesel-hexanol and Moringa oleifera biodiesel-diesel-ethanol blends on compression ignition engine characteristics were experimentally investigated. Experiments were conducted on a diesel engine at 0%, 25%, 50%, 75% and 100% load conditions run at a constant speed of 1500 rpm. The results revealed that B90-D5-H5 acquired the lowest BSFC and maximum BTE of 0.375 kg kW-1 h-1 and 28.8%, respectively, and B100 had the highest BSFC of 0.425 kg kW-1 h-1. B90-D5-H5 had the highest cylinder peak pressure of 74 bar at 4°CA aTDC. The maximum heat release rate (HRR) and longer ignition delay (ID) period of 44 J per °CA and 14.4°CA, respectively, were attained in the B90-D5-H5 blend. At 100% load condition, the lowest amount of carbon monoxide (CO) of 0.32% vol. was acquired in the B80-D5-E15 blend. The maximum nitric oxide (NO) emission of 1090 ppm was also acquired in the B80-D5-E15 blend. B100 had the lowest NO of 846 ppm; B80-D5-E15 had the lowest unburned hydrocarbon (UBHC) emission of 34 ppm at 100% load and the lowest smoke opacity of 34%. Biodiesel-diesel-alcohol blends improve engine performance and decrease emissions compared to the conventional diesel. The utilization of biodiesel-diesel-alcohol blends reduces the consumption of diesel. Hence, ethanol and hexanol are recommended as potential alternative additives in biodiesel-diesel blends to improve engine performance and reduce emissions.

Analysis of microarray data for identification of key microRNA signatures in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is one of the most malignant types of glioma known for its reduced survival rate and rapid relapse. Previous studies have shown that the expression patterns of different microRNAs (miRNA/miR) play a crucial role in the development and progression of GBM. In order to identify potential miRNA signatures of GBM for prognostic and therapeutic purposes, we downloaded and analyzed two expression data sets from Gene Expression Omnibus profiling miRNA patterns of GBM compared with normal brain tissues. Validated targets of the deregulated miRNAs were identified using MirTarBase, and were mapped to Search Tool for the Retrieval of Interacting Genes/Proteins, Database for Annotation, Visualization and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes databases in order to construct interaction networks and identify enriched pathways of target genes. A total of 6 miRNAs were found to be deregulated in both expression datasets studied. Pathway analysis demonstrated that most of the target genes were enriched in signaling cascades connected to cancer development, such as 'Pathways in cancer', 'Focal adhesion' and 'PI3K-Akt signaling pathway'. Of the five target genes that were enriched in the glioblastoma pathway, in the WikiPathway database, both HRas proto-oncogene, GTPase and MET proto-oncogene, receptor tyrosine kinase target genes of hsa-miR-139-5p, were found to be significantly associated with patient survival. The present study may thus form the basis for further exploration of hsa-miR-139-5p, not only as a therapeutic agent, but also as a diagnostic biomarker for GBM as well as a predictive marker for patient survival.

Evaluation of immune response elicited by inulin as an adjuvant with filarial antigens in mice model.

Filariasis caused by infectious parasitic nematodes has been identified as the second leading source of permanent and long-term disability in Sub-Saharan Africa, Asia and Latin America. Several vaccine candidates were identified from infective third-stage larvae (L3) which involves in the critical transition from arthropod to human. Hitherto studies of these antigens in combination with alum adjuvant have shown to elicit its characteristic Th2 responses. Inulin is a safe, non-toxic adjuvant that principally stimulates the innate immune response through the alternative complement pathway. In the present study, the immune response elicited by inulin and alum as adjuvants were compared with filarial antigens from different aetiological agents: secreted larval acidic protein 1 (SLAP1) from Onchocerca volvulus and venom allergen homologue (VAH) from Brugia malayi as single or as cocktail vaccines in mice model. The study revealed that inulin can induce better humoral response against these antigens than alum adjuvant. Antibody isotyping disclosed inulin's ability to elevate the levels of IgG2a and IgG3 antibodies which mediates in complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC), respectively, in mice. Splenocyte analysis showed that T cells prestimulated with inulin have higher stimulation index (P < 0.05) than alum except for BmVAH antigen. In vitro ADCC assay showed that inulin formulation had induced higher cytotoxicity with filarial antigens (as single P < 0.01 and as cocktail P < 0.05, respectively) than alum. The results had confirmed the capability of inulin to deplete the levels of Treg and brought a balance in Th1/Th2 arms against filarial antigens in mice.