Diagnostic accuracy of left ventricular outflow tract velocity time integral versus inferior vena cava collapsibility index in predicting post-induction hypotension during general anesthesia: an observational study.

BACKGROUND: Point of care ultrasound (POCUS) is being explored for dynamic measurements like inferior vena cava collapsibility index (IVC-CI) and left ventricular outflow tract velocity time integral (LVOT-VTI) to guide anesthesiologists in predicting fluid responsiveness in the preoperative period and in treating post-induction hypotension (PIH) with varying accuracy. METHODS: In this prospective, observational study on included 100 adult patients undergoing elective surgery under general anesthesia, the LVOT-VTI and IVC-CI measurements were performed in the preoperative room 15 minutes prior to surgery, and PIH was measured for 20 minutes in the post-induction period. RESULTS: The incidence of PIH was 24%. The area under the curve, sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the two techniques at 95% confidence interval was 0.613, 30.4%, 93.3%, 58.3%, 81.4%, 73.6% for IVC-CI and 0.853, 83.3%, 80.3%, 57.1%, 93.8%, 77.4% for LVOT-VTI, respectively. In multivariate analysis, the cutoff value for IVC-CI was >51.5 and for LVOT-VTI it was ≤17.45 for predicting PIH with odd ratio [OR] of 8.491 (P=0.025) for IVCCI and OR of 17.427 (P<0.001) for LVOT. LVOT-VTI assessment was possible in all the patients, while 10% of patients were having poor window for IVC measurements. CONCLUSIONS: We recommend the use of POCUS using LVOT-VTI or IVC-CI to predict PIH, to decrease the morbidity of patients undergoing surgery. Out of these, we recommend LVOT-VTI measurements as it has showed a better diagnostic accuracy (77.4%) with no failure rate.

Impact of covid-19 pandemic on quality of life and psychosocial difficulties among liver transplant recipients.

Background: The first wave of the COVID-19 pandemic affected health in all domains i.e., physical, mental, and social aspects. Liver transplant (LT) recipients faced a multitude of challenges during the first wave of lockdown. The aim was to identify the psychosocial difficulties and quality of life during the first year of the pandemic. Methods: A cross-sectional survey was conducted on LT recipients with a predefined structured questionnaire that included clinical, COVID-19 anxiety scale, and Post-Transplant Quality of life questionnaire (pLTQ). Results: A total of 109 patients were studied; with a mean age of 50.5 ± 11.1 years, with a median post-transplant follow-up of 52.4 months and a live donor transplant in the majority (79.8%). Almost all (99.1%) could come to the hospital for regular follow-up, prior to the pandemic. But during the first wave only 57% could maintain planned hospital visits and about 88% could not pursue their regular activities, and 39% missed their routine exercise because of imposed restrictions. Similarly, financial implications were responsible for 4% defaulting from treatment; while 7.3% managed by curtailing supportive drugs (on their own) leading to deranged liver tests in 4.6%; requiring immediate attention. The psychosocial difficulties raised the stress of pandemic (median score 18), and impacted quality of life (mean total pLTQ score 4.7 ± 0.9). Conclusions: For LT recipients, the first wave of COVID-19 pandemic affected their physical, mental, financial, and social wellbeing; in addition to the disease itself. Awareness, psychosocial support, and comprehensive care are some unmet needs for this special group; especially when it is expected that subsequent waves may continue to occur.

ZRC3308 Monoclonal Antibody Cocktail Shows Protective Efficacy in Syrian Hamsters against SARS-CoV-2 Infection.

We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZRC3308-B10 in the ratio 1:1 for COVID-19 treatment. The mAbs were designed to have reduced immune effector functions and increased circulation half-life. mAbs showed good binding affinities to non-competing epitopes on RBD of SARS-CoV-2 spike protein and were found neutralizing SARS-CoV-2 variants B.1, B.1.1.7, B.1.351, B.1.617.2, and B.1.617.2 AY.1 in vitro. The mAb cocktail demonstrated effective prophylactic and therapeutic activity against SARS-CoV-2 infection in Syrian hamsters. The antibody cocktail appears to be a promising candidate for prophylactic use and for therapy in early COVID-19 cases that have not progressed to severe disease.

Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4.

BACKGROUND AND OBJECTIVES: MicroRNA (miRNA) that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNA (mitomiR). Albeit mitomiRs have been shown to modulate gene expression, their functional impact within mitochondria is unknown. The main objective of this study is to investigate whether the mitochondrial genome is regulated by miR present inside the mitochondria. METHODS AND RESULTS: Here, we report mitomiR let-7a regulates mitochondrial transcription in breast cancer cells and reprogram the metabolism accordingly. These effects were mediated through the interaction of let-7a with mtDNA, as studied by RNA pull-down assays, altering the activity of Complex I in a cell line-specific manner. Our study, for the first time, identifies the role of mitomiR (let-7a) in regulating the mitochondrial genome by transcriptional repression and its contribution to regulating mitochondrial metabolism of breast cancer cells. CONCLUSION: These findings uncover a novel mechanism by which mitomiR regulates mitochondrial transcription.

Immunogenic potential of DNA vaccine candidate, ZyCoV-D against SARS-CoV-2 in animal models.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), initially originated in China in year 2019 and spread rapidly across the globe within 5 months, causing over 96 million cases of infection and over 2 million deaths. Huge efforts were undertaken to bring the COVID-19 vaccines in clinical development, so that it can be made available at the earliest, if found to be efficacious in the trials. We developed a candidate vaccine ZyCoV-D comprising of a DNA plasmid vector carrying the gene encoding the spike protein (S) of the SARS-CoV-2 virus. The S protein of the virus includes the receptor binding domain (RBD), responsible for binding to the human angiotensin converting enzyme (ACE-2) receptor. The DNA plasmid construct was transformed into E. coli cells for large scale production. The immunogenicity potential of the plasmid DNA has been evaluated in mice, guinea pig, and rabbit models by intradermal route at 25, 100 and 500 µg dose. Based on the animal studies proof-of-concept has been established and preclinical toxicology (PCT) studies were conducted in rat and rabbit model. Preliminary animal study demonstrates that the candidate DNA vaccine induces antibody response including neutralizing antibodies against SARS-CoV-2 and also elicited Th-1 response as evidenced by elevated IFN-γ levels.

Transcriptional regulation of endothelial-to-mesenchymal transition in cardiac fibrosis: role of myocardin-related transcription factor A and activating transcription factor 3.

The etiology of cardiac fibrogenesis is quite diverse, but a common feature is the presence of activated fibroblasts. Experimental evidence suggests that a subset of cardiac fibroblasts is derived via transition of vascular endothelial cells into fibroblasts by endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype. Molecular mechanisms and the transcriptional mediators controlling EndMT in heart during development or disease remain relatively undefined. Myocardin-related transcription factor A facilitates the transcription of cytoskeletal genes by serum response factor during fibrosis; therefore, its specific role in cardiac EndMT might be of importance. Activation of activating transcription factor 3 (ATF-3) during cardiac EndMT is speculative, since ATF-3 responds to a transforming growth factor ß (TGF-ß) stimulus and controls the expression of the primary epithelial-to-mesenchymal transition markers Snail, Slug, and Twist. Although the role of TGF-ß in EndMT-mediated cardiac fibrosis has been established, targeting of the TGF-ß ligand has not proven to be a viable anti-fibrotic strategy owing to the broad functional importance of this ligand. Thus, targeting of downstream transcriptional mediators may be a useful therapeutic approach in attenuating cardiac fibrosis. Here, we discuss some of the transcription factors that may regulate EndMT-mediated cardiac fibrosis and their involvement in type 2 diabetes.

miR-30c Mediates Upregulation of Cdc42 and Pak1 in Diabetic Cardiomyopathy.

AIM: Cardiac hypertrophy and myocardial fibrosis significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Altered expression of several genes and their regulation by microRNAs has been reported in hypertrophied failing hearts. This study aims to examine the role of Cdc42, Pak1, and miR-30c in the pathogenesis of cardiac hypertrophy in DCM. METHODS: DCM was induced in Wistar rats by low-dose streptozotocin-high-fat diet for 12 weeks. Cardiac expression of Cdc42, Pak1 and miR-30c, and hypertrophy markers (ANP and ß-MHC) was studied in DCM vs control rats and in high-glucose (HG)-treated H9c2 cardiomyocytes. RESULTS: Diabetic rats showed cardiomyocyte hypertrophy, increased heart-to-body weight ratio, and an increased expression of ANP and ß-MHC. Cardiac expression of Cdc42 and Pak1 genes was increased in diabetic hearts and in HG-treated cardiomyocytes. miR-30c was identified to target Cdc42 and Pak1 genes, and cardiac miR-30c expression was found to be decreased in DCM rats, patients with DCM, and in HG-treated cardiomyocytes. miR-30c overexpression decreased Cdc42 and Pak1 genes and attenuated HG-induced cardiomyocyte hypertrophy, whereas miR-30c inhibition increased Cdc42 and Pak1 gene expression and myocyte hypertrophy in HG-treated cardiomyocytes. CONCLUSION: Downregulation of miR-30c mediates prohypertrophic effects of hyperglycemia in DCM by upregulation of Cdc42 and Pak1 genes.

Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity.

Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and 8c strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and 8c treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and 8c revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development.

Synthesis and evaluation of antiproliferative activity of a novel series of hydroxychavicol analogs.

We have recently demonstrated that hydroxychavicol is a major constituent and the most active biophenolic of Piper betel leaves with significant antiproliferative activity in the micro molar range. Herein we present the design, synthesis and evaluation of fifteen novel hydroxychavicol analogs with varying antiproliferative activities in cancer cell lines from two representative tissue types, namely, the prostate and cervix that show very encouraging results compared to the parent compounds. Our long range goal is to develop a structure-activity guided relationship to gain mechanistic insights into novel molecular targets of this class of bioactive molecules for rational drug development. Cytotoxicity-guided experimentation on these novel analogs yielded the following structural factors as the key activity regulators: 1) unlike the hydroxyl substituent at position-4, the position-3 hydroxyl is vital for enhanced activity 2) acetoxyl groups are dispensable for activity as corroborated earlier by others 3) allylic double bonds at 2'C-3'C serve to positively influence antiproliferative activity 4) long saturated side chains at 1'-position negatively regulate antiproliferative activity and 5) maneuvering position-4 with a benzyl group positively impacted the biological activity profile. Most amphiphilic compounds showed moderate to good therapeutic potential as expected on the basis of medicinal chemistry principles. Intriguingly, the most active compound with ten-fold higher activity than the parent molecule was realized by sheer serendipity to employ a silica gel based rearrangement that was further explored using nuclear magnetic resonance spectroscopy and density functional theory calculations. This is the first report to describe strategies for optimal synthesis of a novel series of 15 analogs based upon hydroxychavicol, a simple phytochemical of immense anticancer potential.

Benefits of whole ginger extract in prostate cancer.

It is appreciated far and wide that increased and regular consumption of fruits and vegetables is linked with noteworthy anticancer benefits. Extensively consumed as a spice in foods and beverages worldwide, ginger (Zingiber officinale Roscoe) is an excellent source of several bioactive phenolics, including non-volatile pungent compounds such as gingerols, paradols, shogaols and gingerones. Ginger has been known to display anti-inflammatory, antioxidant and antiproliferative activities, indicating its promising role as a chemopreventive agent. Here, we show that whole ginger extract (GE) exerts significant growth-inhibitory and death-inductory effects in a spectrum of prostate cancer cells. Comprehensive studies have confirmed that GE perturbed cell-cycle progression, impaired reproductive capacity, modulated cell-cycle and apoptosis regulatory molecules and induced a caspase-driven, mitochondrially mediated apoptosis in human prostate cancer cells. Remarkably, daily oral feeding of 100 mg/kg body weight of GE inhibited growth and progression of PC-3 xenografts by approximately 56 % in nude mice, as shown by measurements of tumour volume. Tumour tissue from GE-treated mice showed reduced proliferation index and widespread apoptosis compared with controls, as determined by immunoblotting and immunohistochemical methods. Most importantly, GE did not exert any detectable toxicity in normal, rapidly dividing tissues such as gut and bone marrow. To the best of our knowledge, this is the first report to demonstrate the in vitro and in vivo anticancer activity of whole GE for the management of prostate cancer.

In silico identification of putative drug targets from different metabolic pathways of Aeromonas hydrophila.

Aeromonas hydrophila is a major pathogen both of aquatic and terrestrial organisms, including humans. Infection with A. hydrophila results in severe economic losses to the aquaculture industry. In humans, Aeromonas hydrophila infections are known to cause gastroenteritis and wound infections. Investigations for developing a potential vaccine for its control are underway. The availability of the complete sequence information of A. hydrophila strain ATCC 7966T genome has made it possible to carry out the in silico analysis of its genome for various aspects of its biology. Keeping in view the possible risks that A. hydrophila poses to humans, in silico analysis of the A. hydrophila genome was carried out for the identification of potential vaccine and drug targets. Our study revealed 2097 genes which are non-homologous to human genome. Screening these genes using the Database of Essential Genes (DEG) resulted in the identification of 379 genes as essential genes of the bacteria. Further analysis of the identified essential genes, using the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways database, revealed 87 enzymes of A. hydrophila that may be used as drug targets, as they are not present in humans. Of these, 15 enzymes belong to pathways present only in the bacteria, whereas 72 enzymes are from the pathways that are common to both human and the bacteria. These can be used as a platform for further investigation to develop effective drugs against A. hydrophila.