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Abstract Background Tuberculosis (TB) is a leading cause of infection related mortality. Isoniazid is one of the frontline drugs for anti-TB therapy. Hepatotoxicity induced by isoniazid is a major cause of drug-discontinuation which may lead to development of resistant TB or increased mortality. Purpose To characterize pharmacological properties of plant-based prescription medicine, Livogrit Vital (LVV) against isoniazid-induced liver injury (IILI) using HepG2 cells. Method Phytometabolite characterization of LVV was performed by High-performance liquid chromatography (HPLC). The effects of LVV on cytosafety, IC50 shift, oxidative stress, ER stress, apoptosis, liver injury markers, and accumulation of isoniazid and hydrazine was performed on HepG2 cells induced with isoniazid. Silymarin was used as the positive control. Results HPLC based phytometabolite characterization of LVV revealed the presence of several anti-oxidant, anti-apoptotic, and hepatoprotective compounds. In isoniazid-induced HepG2 cells, LVV reduced cytotoxicity of isoniazid and shifted its IC50 value. Treatment with LVV reduced ROS generation and lipid peroxidation; enhanced GSH enzyme levels in isoniazid-induced HepG2 cells. As per the mechanistic evaluation, LVV modulated gene expression level of Caspase-3, FGF21, and IRE-1α. LVV treatment also normalized isoniazid-induced elevated Caspase-3 activity and cPARP1 protein levels, indicating its potentials to regulate liver cell apoptosis. Concomitantly, biomarkers of hepatotoxicity, ALT and GGT, also decreased by LVV treatment. Interestingly, LVV treatment reduced intracellular accumulation of isoniazid and its toxic metabolite hydrazine, in isoniazid-stimulated HepG2 cells. Conclusion Treatment of hepatic cells with the herbo-vitamin medicine, Livogrit Vital, regulates IILI by modulation of oxidative and ER stress, apoptosis, and bioaccumulation of isoniazid and hydrazine. Collectively, Livogrit Vital could well be explored as an adjuvant hepatoprotective agent alongwith anti-TB medicines.

Abstract Cisplatin-induced nephrotoxicity restricts its clinical use against solid tumors. The present study elucidated the pharmacological effects of Renogrit, a plant-derived prescription medicine, using cisplatin-induced human renal proximal tubular (HK-2) cells and Caenorhabditis elegans. Quantification of phytochemicals in Renogrit was performed on HPTLC and UHPLC platforms. Renogrit was assessed in vitro in HK-2 cells post-exposure to clinically relevant concentration of cisplatin. It was observed that renoprotective properties of Renogrit against cisplatin-induced injury stem from its ability to regulate renal injury markers (KIM-1, NAG levels; NGAL mRNA expression), redox imbalance (ROS generation; GST levels), and mitochondrial dysfunction (mitochondrial membrane potential; SKN-1, HSP-60 expression). Renogrit was also found to modulate apoptosis (EGL-1 mRNA expression; protein levels of p-ERK, p-JNK, p-p38, c-PARP1), necroptosis (intracellular calcium accumulation; RIPK1, RIPK3, MLKL mRNA expression), mitophagy (lysosome population; mRNA expression of PINK1, PDR1; protein levels of p-PINK1, LC3B), and inflammation (IL-1β activity; protein levels of LXR-α). More importantly, Renogrit treatment did not hamper normal anti-proliferative effects of cisplatin as observed from cytotoxicity analysis on MCF-7, A549, SiHa, and T24 human cancer cells. Taken together, Renogrit could be a potential clinical candidate to mitigate cisplatin-induced nephrotoxicity without compromising the anti-neoplastic properties of cisplatin.

Objectives. Knee injuries are prevalent among professional tennis players and have a significant impact on their athletic performance and longevity. This study aimed to evaluate the dynamic and postural balance differences between injured and healthy professional tennis players, reflecting the broader implications of knee injuries on player stability and performance. Materials and methods. A total of 80 professional tennis players, comprising 40 individuals in the knee injury group (IG) and 40 individuals in the non-injury group (NIG), were selected to participate in this cross-sectional study. Participants’ postural sway was assessed under various conditions, including standing on different surfaces with open and closed eyes using a Wii Balance Board. The Y-Balance Test was performed to evaluate the player’s dynamic balance. An Independent t-test was used to examine the difference in postural sway and dynamic balance between the two groups. Results. The results of this study indicated that players with knee injuries showed significantly worse performance in both dynamic balance (p

Introduction: According to the World Health Organisation (WHO) global Tuberculosis (TB) report in 2019, 10 million new cases of Tuberculosis were detected worldwide, with India being one of the significant contributors. After achieving some milestones in TB control, the Government of India launched the National Tuberculosis Elimination Program (NTEP) to end TB by 2025. The role of private practitioners in the success of national health programs in India cannot be overemphasised, considering they cater to three times more population than the public sector. Aim: To understand the knowledge and perceived bottlenecks of private practitioners in achieving the goals of NTEP. Materials and Methods: A web-based cross-sectional survey was conducted by Community Medicine Department of Pramukhswami Medical College, Bhaikaka University, Karamsad, Anand, Gujarat, India, using a semi-structured questionnaire among randomly selected 110 doctors affiliated with the Indian Medical Association (IMA) from October 2020 to December 2020. The survey questionnaire was prepared by an experienced TB Chest expert and consensually validated. It covered all aspects of the Revised National TB Control Program (RNTCP) training modules. Descriptive statistics (Mean, SD, Frequency (%), etc.,) along with independent t-test and Analysis of Variance (ANOVA) were used to present the profile of the participants as well as associated factors with the knowledge score. A p-value of less than 0.05 was considered statistically significant. Results: Out of 110 invitations, 97 (88%) doctors responded. Most of the respondents were males 71 (73%), specialists (81, 83.5%), and had been practicing for more than 20 years (66, 68%). The mean (SD) score was 3.31±1.27 out of six for Multiple Choice Questions and 8.05±3.77 out of 15 for True/False questions. Only 37 (38%) participants scored above the passing benchmark of 60%, indicating a substantial knowledge gap. A higher Outpatient Department (OPD) strength (>50 patients per day) and attending a TB training program by the Government were associated with a higher total score (p=0.018). Conclusion: The knowledge of private practitioners about the diagnosis and management of Tuberculosis was found to be suboptimal. Participants also expressed a few systemic challenges like poor communication and the complexity of the system in the notification of Tuberculosis cases. Innovative training programs, proper communication, and supportive supervision will help in engaging the private practitioners to achieve TB elimination goals.

Abstract Palmitic acid (PAM) can be provided in the diet or synthesized via de novo lipogenesis (DNL), primarily, from glucose. Preclinical work on the origin of brain PAM during development is scarce and contrasts results in adults. In this work, we use naturally occurring carbon isotope ratios (13C/12C; δ13C) to uncover the origin of brain PAM at postnatal days 0, 10, 21 and 35, and RNA sequencing to identify the pathways involved in maintaining brain PAM, at day 35, in mice fed diets with low, medium, and high PAM from birth. Here we show that DNL from dietary sugars maintains the majority of brain PAM during development and is augmented in mice fed low PAM. Importantly, the upregulation of hepatic DNL genes, in response to low PAM at day 35, demonstrates the presence of a compensatory mechanism to maintain total brain PAM pools compared to the liver; suggesting the importance of brain PAM regulation.

Abstract Heterogeneous response to Enzalutamide, a second-generation androgen receptor signaling inhibitor, is a central problem in castration-resistant prostate cancer (CRPC) management. Genome-wide systems investigation of mechanisms that govern Enzalutamide resistance promise to elucidate markers of heterogeneous treatment response and salvage therapies for CRPC patients. Focusing on the de novo role of MYC as a marker of Enzalutamide resistance, here we reconstruct a CRPC-specific mechanism-centric regulatory network, connecting molecular pathways with their upstream transcriptional regulatory programs. Mining this network with signatures of Enzalutamide response identifies NME2 as an upstream regulatory partner of MYC in CRPC and demonstrates that NME2-MYC increased activities can predict patients at risk of resistance to Enzalutamide, independent of co-variates. Furthermore, our experimental investigations demonstrate that targeting MYC and its partner NME2 is beneficial in Enzalutamide-resistant conditions and could provide an effective strategy for patients at risk of Enzalutamide resistance and/or for patients who failed Enzalutamide treatment.