Real-world utilization pattern of dydrogesterone in 7287 Indian women with obstetric and gynecological conditions: data from multicentric, retrospective study.

Objective: Despite the literature on dydrogesterone, studies on dydrogesterone utilization patterns are largely lacking in Indian patients. Methods: This was a multi-center, retrospective, observational, cross-sectional, and descriptive study across 817 centers in India. Data of patients who received dydrogesterone in past and provided consent for future use of their medical record for research purpose was were retrieved and analyzed. Results: Data of 7287 subjects (aged 29.55±4.84 years) was analyzed. Threatened abortion was the most common indication for which the subjects received dydrogesterone (46.9%) followed by recurrent pregnancy loss. Polycystic ovary syndrome (PCOS), thyroid disorders and anemia were the most common comorbid conditions and prior pregnancy loss, advanced maternal age and obesity were the most common risk factors seen in subjects who received dydrogesterone. Total 27.5% of subjects received a loading dose of dydrogesterone, and majority (64%) received 40 mg as loading dose. 10 mg dose was used as maintenance or regular dose in 81.4% of the subjects. Twice daily (BID) was the most common dosing frequency (66.6%). The most common concomitant medications being taken by the subjects on dydrogesterone included folic acid (45.1%), iron supplements (30.3%) and calcium and vitamin D3 supplements (25.5%). Another progesterone preparation (oral, injection, vaginal, tubal) other than dydrogesterone was used concurrently in 7.8% of subjects. Conclusion: The study helped to identify the patient population that is benefitted by dydrogesterone and the preferred indications, risk factors, comorbid conditions and concomitant medication used in this patient population at real-life scenario.

Characterization of rusk incorporated with black rice (Oryza sativa L.) for its physicochemical and functional properties, in-vitro starch digestibility, and anti-inflammatory efficacy.

BACKGROUND: The consumption of bakery goods is gradually increasing due to their accessibility, convenience, distinctive flavor, and affordability. The food industry is experimenting with novel methods of fortification, supplementation, enrichment, and adding value to bakery ingredients. The present investigation assessed the physicochemical, morphological, and sensorial properties, and anti-inflammatory efficacy of rusks with black rice incorporated. RESULTS: The addition of black rice flour significantly increased (P < 0.05) the total ash (from 1.34 to 1.78 g·kg-1 ), crude protein (from 5.68 to 75 g·kg-1 ), and total fat (from 11.93 to 12.80 g·kg-1 ) content but the carbohydrate content of the rusk decreased significantly (from 76.23 to 71.42 g·kg-1 ). Similarly, the phenolic and flavonoid content increased and showed excellent free-radical scavenging activity after black rice incorporation. The inclusion of black rice flour led to improved functional properties while decreasing the rate of starch digestion and the eGlycemic Index (eGI) score. The sensory scores declined after black rice incorporation but for all rusk samples acceptability was above the lowest level (i.e., ≥5). CONCLUSION: This study demonstrated that the incorporation of black rice flour into refined wheat flour can enhance the nutritional value of rusk and that it is possible to prepare rusk and other bakery goods using up to 30% black rice with taste and other sensory attributes similar to control rusk. © 2023 Society of Chemical Industry.

Metabolomic approach for phytochemical assessment of Murraya koenigii fruits during different maturity stages.

A detailed metabolomic study was performed on various maturation stages of Murraya koenigii fruit pulps, seed, and leaf. Among the fruit pulps, stage 6 had the highest TPC (13.27 mg/g of GAE) and TFC content (6.16 mg/g RE). The extracts also showed promising free radical scavenging activity, especially in the seed (IC50DPPH 427 µg/mL). Metabolomics study revealed the identification of 133 metabolites in fruit pulps, seeds and leaves using the METLIN database. In silico PASS software analysis predicted the antimutagenic property of myricetin and bismurrayaquinone A. Pathway analysis revealed the phenylpropanoid biosynthesis pathway as one of the major pathways present in the fruit pulps. This detailed metabolic report of M. koenigii fruit maturation report brings a new insight into phytochemicals and their distribution in seed, pulps and leaves along with nutritive values and can be considered for nutritive and therapeutic purposes.

A Prospective Study on Correlation of MERI (Middle Ear Risk Index) Score with Surgical Outcome of Tympano-mastoid Surgery in Patients of CSOM.

Chronic otits media (COM) is surgically treatable disease which includes complete removal of disease and improving hearing via ossicular reconstruction. Therefore, thorough assessment of the disease, ossicles and various factors causing it plays a major role in surgical outcome prediction. MERI (Middle ear risk index) is one such tool being used worldwide. Our aim was to evaluate the surgical outcome of tympanomastoid surgery using MERI and find out correlation between them as well as categorize cases into their severity score in a developing country. Observational prospective study conducted in a tertiary care center. 200 patients were included. After complete history and examination, they were given MERI scores and prediction of surgical outcome was done. Postoperatively it was compared with the real outcome of the surgery. Out of 200 patients, 71.5% had mild, 15.5% had moderate and 13% had severe MERI scores preoperatively. There was a success rate of 88.5% in graft uptake and the mean score of hearing benefit (A-B gain) among patients was 8.75 ± 8.82 dB postoperatively. MERI may be used as a prognostic indicator for predicting surgical outcome. Based on the MERI score, chances of surgical success and hearing benefit can be explained to the patient with certain limitations.

Assessment of nutritional properties and phenolic characterization of freshly harvested Dendrocalamus hamiltoni shoots and processed bamboo candy.

The free and bound phenolic constituents in Dendrocalamus hamiltonii shoots were evaluated and compared to processed bamboo candy. Preliminary proximate analysis revealed a percent reduction in moisture and protein with a less significant change in fibre content. The fresh free phenolic extract (FFPE) exhibited a total phenolics of 131.22 mg GAE/g and recovered 48.29 mg GAE/g phenolic content in bound fraction (FBPE). Results demonstrated higher loss of free phenolics after processing compared to bound fraction (CBPE). Although similar results were observed in total flavonoid content. Antioxidant activity was reduced after candy processing, with fresh shoots having the lowest percent inhibition (IC50) against DPPH· and ABTS· radicals. Although both free and bound fractions of candy demonstrated effective antioxidant activity. HPLC analysis revealed that FFPE contained more chlorogenic acid (0.14 mg/10 g) and cinnamic acid (0.75 mg/10 g) than CFPE. Quercetin was undetected in all free fractions but was found in bound form.

Orexin system in buffalo ovarian follicles and effect of orexin on oestradiol production.

Orexin is a ligand for orexin receptors OX1R and OX2R; it is a neuropeptide with pleiotropic functions, including regulation of reproduction. The current study was carried out to investigate the mRNA expression of the prepro-orexin gene (PPO) and orexin receptors (OX1R and OX2R) in ovarian follicles during different stages of their development in the ovary of water buffalo (Bubalus bubalis) and to determine the role of orexin on oestradiol production. Ovarian follicles were classified into four groups based on size and oestradiol (E2 ) level in the follicular fluid (FF) as follows: (i) small or F1, (ii) medium or F2, (iii) large or F3, and (iv) dominant/pre-ovulatory follicle or F4. In follicles, the mRNA expression of PPO and OX1R was greater in F3 and F4 follicles in granulosa cells (GC) and theca interna (TI) cells. OX2R expression did not vary among the different follicular stages in GC. Orexin-A and orexin receptors were localized in the cytoplasm of GC and TI, and intensity was higher in F3 and F4 follicles. In addition, we cultured GC and treated them at 0.1, 1.0, and 10 ng/mL orexin-A alone or in the presence of FSH (30 ng/mL) or IGF-I (10 ng/mL) for 48 h. There was a significant (p < .05) increase in oestradiol (E2 ) secretion and cytochrome P0450 family 19 subfamily A member 1 (CYP19A1) expression from GC at 1.0 and 10.0 ng/mL orexin-A in the presence of 30 ng/mL follicle-stimulating hormone (FSH) or 10 ng/mL insulin-like growth factor-I (IGF-I). In conclusion, the present study provided evidence that the orexin system is expressed in buffalo ovarian follicles, and orexin-A in the presence of FSH and IGF-I has a stimulatory effect on oestradiol secretion from the GC of water buffalo.

A Comprehensive Molecular and Clinical Investigation of Approved Anti-HCV Drugs Repurposing against SARS-CoV-2 Infection: A Glaring Gap between Benchside and Bedside Medicine.

The limited availability of effective treatment against SARS-CoV-2 infection is a major challenge in managing COVID-19. This scenario has augmented the need for repurposing anti-virals for COVID-19 mitigation. In this report, the anti-SARS-CoV-2 potential of anti-HCV drugs such as daclatasvir (DCV) or ledipasvir (LDP) in combination with sofosbuvir (SOF) was evaluated. The binding mode and higher affinity of these molecules with RNA-dependent-RNA-polymerase of SARS-CoV-2 were apparent by computational analysis. In vitro anti-SARS-CoV-2 activity depicted that SOF/DCV and SOF/LDP combination has IC50 of 1.8 and 2.0 µM, respectively, comparable to remdesivir, an approved drug for COVID-19. Furthermore, the clinical trial was conducted in 183 mild COVID-19 patients for 14 days to check the efficacy and safety of SOF/DCV and SOF/LDP compared to standard of care (SOC) in a parallel-group, hybrid, individually randomized, controlled clinical study. The primary outcomes of the study suggested no significant difference in negativity after 3, 7 and 14 days in both treatments. None of the patients displayed any worsening in the disease severity, and no mortality was observed in the study. Although, the post hoc exploratory analysis indicated significant normalization of the pulse rate showed in SOF/DCV and SOF/LDP treatment vs. SOC. The current study highlights the limitations of bench side models in predicting the clinical efficacy of drugs that are planned for repurposing.

Dietary fiber from fruit waste as a potential source of metabolites in maintenance of gut milieu during ulcerative colitis: A comprehensive review.

The prevalence of inflammatory bowel disease, particularly ulcerative colitis (UC), has increased dramatically in the past few years owing to a changed lifestyle. Despite various therapeutic treatments, management of the disease is still an issue due to several limitations, including cost and adverse reactions. In this regard, researchers and consumers are inclined towards natural herbal medicines and prophylactic agents. Of these, dietary fiber (DF) (polysaccharides) has become an important topic of interest owing to various putative health attributes, particularly for diseases associated with the large intestine, such as UC. To fulfil industrial and scientific demands of dietary fibers, waste utilization can prove advantageous. Here, the present review highlights recent comprehensive advances in dietary fiber from waste resources in improving UC. Additionally, their role in the gut-associated microbiome, pathway for metabolites synthesis, inflammation, and its mediators. Moreover, here we also discussed short-chain fatty acids (SCFAs) transport and epithelial barrier function along with the mechanism of inflammation regulation. Collectively, it depicts dietary fiber from waste resources that could regulate various cellular processes and molecular mechanisms involved in perpetuating UC and can be used as a promising therapeutic candidate.

Recent developments in citrus bioflavonoid encapsulation to reinforce controlled antioxidant delivery and generate therapeutic uses: Review.

Citrus fruits contain numerous antioxidative biomolecules including phenolic acids, flavonols, flavanones, polymethoxyflavones (PMFs), and their derivatives. Previous in vitro and in vivo studies thoroughly investigated the antioxidant and therapeutic potential of bioflavonoids extracted from different citrus varieties and fruit fractions. Major bioflavonoids such as hesperidin, naringin, naringenin, and PMFs, had restricted their incorporation into food and health products due to their poor solubility, chemical stability and bioavailability. Considering these limitations, modern encapsulation methodologies such as hydrogelation, liposomal interactions, emulsifications, and nanoparticles have been designed to shield bioflavonoids with improved target distribution for therapeutic enhancements. The size, durability, and binding efficiency of bioflavonoid-loaded encapsulates were acquired by the optimized chemical and instrumental parameters such as solubility, gelation, dispersion, extrusion, and drying. Bioflavonoid-enriched encapsulates have been also proven to be effective against cancer, inflammation, neurodegeneration, and various other illnesses. However, in the future, newer natural binding agents with higher binding capacity might accelerate the encapsulating potential, controlled release, and enhanced bioavailability of citrus bioflavonoids. Overall, these modern encapsulation systems are currently leading to a new era of diet-based medicine, as demand for citrus fruit-based nutritional supplements and edibles grows.

Expression and localization of apelin and apelin receptor (APJ) in buffalo ovarian follicles and corpus luteum and the in-vitro effect of apelin on steroidogenesis and survival of granulosa cells.

Apelin is an adipose tissue-derived hormone with many physiological functions, including the regulation of female reproduction. It acts through an orphan G protein-coupled receptor APJ/APLNR. The present study aimed to investigate the expression of apelin and its receptor APJ in the ovarian follicles and corpus luteum (CL) and the role of apelin on steroidogenesis and cell survival. Ovarian follicles were classified into four groups based on size and estradiol (E2) level in the follicular fluid as follows: (i) F1 (4-6 mm; <0.5 ng/mL) (ii) F2 (7-9 mm; 0.5-5 ng/mL) (iii) F3 (10-13 mm; 5-40 ng/mL) and (iv) F4 (dominant/pre-ovulatory follicle) (>13 mm; >180 ng/mL). The corpora lutea (CL) were categorized into early (CL1), mid (CL2), late luteal (CL3), and regressing (CL4) CL stages. Expression of apelin increased with follicle size, with significantly greatest in the dominant or pre-ovulatory follicle (P < 0.05). Expression of APJ was greater in large and dominant follicles than in small and medium follicles (P < 0.05). In CL, the mRNA and protein abundance of apelin and apelin receptor was greater during mid (CL2) and late luteal (CL3) stages as compared to early (CL1) and regressing (CL4) stages (P < 0.05). Both the factors were localized in granulosa and theca cells of follicles and small and large luteal cells of CL. The pattern of the intensity of immunofluorescence was similar to mRNA and protein expression. Granulosa cells were cultured in vitro and treated at 1, 10, and 10 ng/mL apelin-13 either alone or in the presence of the follicle-stimulating hormone (FSH) (30 ng/mL) or insulin-like growth factor-I (IGF-I) (10 ng/mL) for 48 h. The luteal cells were treated with apelin-13 at 1, 10, and 100 ng/mL doses for 48 h. Apelin treatment at 10 and 100 ng/ml significantly (P < 0.05) increased E2 secretion, cytochrome P450 aromatase or CYP19A1 expression in GC. In luteal cells, apelin at 10 ng/mL and 100 ng/mL significantly (P < 0.05) increased progesterone (P4) secretion and HSD3B1 expression. In GCs, apelin, either alone or in combination, increased PCNA expression and inhibited CASPASE3 expression suggesting its role in cell survival. In conclusion, this study provides novel evidence for the presence of apelin and receptor APJ in ovarian follicles and corpora lutea and the stimulatory effect on E2 and P4 production and promotes GC survival in buffalo, suggesting the role of apelin in follicular and luteal functions in buffalo.

Comparative metabolomics of Himalayan crab apple (Malus baccata) with commercially utilized apple (Malus domestica) using UHPLC-QTOF-IMS coupled with multivariate analysis.

A comprehensive UHPLC-QTOF-IMS based metabolomics investigation in skin and pulp of Malus domestica and Malus baccata was performed. M. domestica fruit parts had higher phenolic contents (25.75-43.05 mg GAE/g) as compared to M. baccata (18.10-28.37 mg GAE/g) and flavonoid content (1.34-9.59 mg RE/g) followed by promising antioxidant activity (MD_Skin DPPH 119.41 µg/mL and MB_Skin DPPH 148.24 µg/mL). Targeted metabolomics quantified higher chlorogenic acid in MD_pulp (929.54 mg/100 g) and phloridzin in MD_skin (722.54 mg/100 g). Amino acids, sugars, flavonoids, vitamins, nucleosides, quinones, fatty acids, and derivatives are among the 248 distinctive metabolites identified using non-targeted metabolomics. Multivariate data analysis, VIP projection and pathway interaction studies demonstrated the metabolic changes and differential distribution in both fruits. Using KEGG pathway enrichment analysis, the biosynthesis of flavone and flavonols is the most prevalent in both fruits. The current study found that M. baccata has a comparable metabolite distribution and should be considered for health-beneficial products.

Acrylamide mitigation in foods using recombinant L-asparaginase: An extremozyme from Himalayan Pseudomonas sp. PCH182.

Acrylamide has received worldwide attention due to its existence in commonly consumed foods. L-asparaginase reduces acrylamide formation in foods by hydrolyzing available L-asparagine. Herein, L-asparaginase (Ps-ASNase II) of Pseudomonas sp. PCH182 was expressed in Escherichia coli (E. coli), purified, and evaluated for acrylamide reduction in food samples. The monomeric 37 kDa Ps-ASNase II protein was purified to homogeneity with a 70 % yield. The enzyme was active at a wide pH range (5.0-11.0) and temperature (10-80 °C) with optimum activity at 45 °C in 50 mM Tris-HCl (pH 8.5) after 10 min. The Km and Vmax for L-asparagine were 0.52 ± 0.06 mM and 42.55 ± 4.0 U/mg, respectively. Also, the half-life and Kd value of the enzyme at 37 °C was 458 min and 1.51 × 10-3/min, suggesting its higher stability. Consistently, the enzyme retained 62 % residual activity after 60 days of storage at 4 °C. The Ps-ASNase II enzyme (5 U/mL) treatment of raw potato chips resulted in 90 % asparagine hydrolysis exhibiting high efficiency. Ps-ASNase II (5 U/mL) treated potato chips significantly reduced acrylamide content by 73 % at 37 °C within 24 min compared to untreated controls. Collectively, these findings verified Ps-ASNase's effectiveness and capability to lower acrylamide formation in fried potato chips without altering the food product's nutritional profile.

Computational analysis of mechanical behavior and potential energy of thermoresponsive copper-tantalum nanoalloy.

Temperature, strain rate, and defects are important considerations in determining the mechanical properties of materials. The mechanical properties of nanocrystalline copper-tantalum (Cu-Ta) alloy are investigated using classical molecular dynamics simulation approach in which embedded atom method of potential with periodic boundary conditions in all directions has been adopted. Numerical simulation has been performed to predict the mechanical properties of nanocrystalline copper-tantalum alloy. The virtual tensile test has been conducted at a fixed strain rate and increasing temperature where the discreet change in temperature from 50 to 1600 K has been used as a controlling parameter. The strain rate is fixed in the direction of the principal crystallographic planes and has not been affected by the change in temperature. The mechanical properties of the Cu-Ta nanocrystalline alloy such as yield strength, ultimate strength, and Young's modulus are observed. Further, simulations are carried out to analyze the vacancy formation energy with vacancy concentration and potential energy response at discrete temperatures. Nanocrystalline Cu-Ta alloy is observed to be more susceptible to failure at high temperatures. Particularly at 300 K, the strength of nanocrystalline Cu-Ta is 6 GPa which decreases to 4 GPa at 1200 K.

Pomegranate Peel Extract Decreases Plaque Necrosis and Advanced Atherosclerosis Progression in Apoe -/- Mice.

Atherosclerosis is a chronic lipid-driven inflammatory condition of the arteries and is a leading cause of stroke, myocardial infarction, and other peripheral arterial diseases. Plant products rich in polyphenols such as pomegranate juice and peel extract are known to have beneficial effects in suppressing atherogenesis. However, the mechanism of action and its effect on advanced atherosclerosis progression which results in adverse clinical outcomes are not well understood. Herein, we use a standardized hydroethanolic extract of Punica granatum (pomegranate) peel in the Apoe -/- a murine model of advanced atherosclerosis. It was observed that the pomegranate peel extract fed mice have decreased plaque necrosis and elevated lesional collagen content which was associated with a favorable metabolic profile including lowering of blood glucose, cholesterol, and triglyceride. The decrease in plaque necrosis was linked with increased lesional macrophage efferocytosis efficiency which was associated with enhanced expression of the efferocytosis receptor Mertk. Using in vitro studies, we show that pomegranate peel extract blocks the shedding of Mertk and preserves macrophage efferocytosis efficiency. These data identify a novel mechanism by which pomegranate peel extract promotes the resolution of inflammation in atherosclerosis.

A comparative metabolomic investigation in fruit sections of Citrus medica L. and Citrus maxima L. detecting potential bioactive metabolites using UHPLC-QTOF-IMS.

The current study focused on targeted and non-targeted metabolomics of Citrus fruit parts (exocarp, mesocarp, endocarp, and seeds) to gain a comprehensive metabolomic insight. Sections of the Citrus fruit were preliminarily examined for proximate compositions (moisture, ash, fibre, fat, and protein). Whereas ultrasonication-assisted solvent extraction revealed a higher phenolic and flavonoid content at 80% (v/v) ethanolic medium, with the highest amount in the exocarp. Using targeted metabolomics, hesperidin (3307.25 mg/100 g), naringin (4803.73 mg/100 g) were detected in C. medica and C. maxima at greater levels, respectively. Further quantitative analysis revealed the presence of phenolic acids (gallic acid, trans-ferulic acid, p-coumaric acid, trans-cinnamic acid), and polymethoxyflavones (nobiletin, and tangeretin) and detected in the order of exocarp > mesocarp > endocarp > seeds. Using an untargeted metabolomics approach, metabolite discriminations among Citrus fruit sections were illustrated by Venn-diagram, heatmap, PCA, o-PLSDA, correlation matrices, and S-plot. UHPLC-QTOF-IMS revealed 48 metabolites including phenolics, vitamins, and amino acids. Furthermore, the METLIN database leads to the identification of 202 unknown metabolites. The metabolite biosynthesis and corresponding metabolite presence in Citrus fruit sections were confirmed using pathway enrichment and mass fragmentation analysis. Finally, potential biological activities were determined using in silico PASS software approach, and free radical scavenging potential was confirmed using in vitro assays for future preventive and therapeutic applications of the identified metabolites.

Combined Application of MMT K10 Supported Copper Oxide Nanoparticles for Complete Removal of Cr(VI) from Aqueous Solution and Their Antibacterial Potential.

Montmorillonite K10 (MMT K10) supported copper oxide nanoparticles (CuONPs) were synthesized by incorporating CuONPs onto the surface of MMT K10 by reducing the metal precursor with the help of hydrazine hydrate. Effects of various factors on the efficiency of composite to remove hexavalent chromium were studied to find out the optimum conditions for maximum removal. Under optimum conditions 15 mg of the synthesized nanocomposite was found capable to almost completely remove (99.9 %) hexavalent chromium in 30 min from a 10 ppm aqueous chromium solution and that too in a wide range of pH from 2.88 to 5.56. The synthesized MMT K10 supported CuONPs were characterized by UV, SEM-EDX, FTIR and XRD studies. The average particle size of supported CuONPs was found to be 22.9 nm. Antibacterial potential of the prepared composite was also studied for one Gram-positive bacterium Staphylococcus aureus (ATCC 25323) and one Gram-negative bacterium Pseudomonas aeruginosa (ATCC 27853). The prepared nanocomposite was found to have excellent bactericidal potential and its statistical analysis was performed using t-test which indicates both bacterial strains of Pseudomonas aeruginosa and Staphylococcus aureus show different zone of inhibition for different concentrations.

Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating multiple targets.

BACKGROUND: During cancer cachexia, cytokines released from tumour cells can alter body's metabolism, which can lead to onset of this disease process. Biological basis of cachexia is multifactorial; hence, it is important to identify and modulate multiple targets to curtail the process of cachexia. Previously, we reported that the nuclear sirtuin, SIRT6, blocks expression of myostatin, a negative regulator of muscle growth, through modulation of the NF-κB signalling. This study was undertaken to test whether muscle-specific over-expression of SIRT6 can block the cancer-associated muscle wasting in vivo and to identify additional relevant targets of SIRT6, which can explain its ability to maintain muscle health. METHODS: We generated a skeletal muscle-specific SIRT6 over-expressing transgenic mouse line (Sk.T6Tg) expressing SIRT6 at a moderate (two-fold to four-fold) level, compared with its control littermates. To generate a cancer-cachexia model, B16F10 mouse melanoma cells were injected subcutaneously in the flanks of mice. Gastrocnemius muscle tissues from non-tumour and tumour controls and Sk.T6Tg mice (n = 5-20) were analysed by histology, immunoblotting, and RT-qPCR. Plasma samples of mice were evaluated using cytokine arrays and ELISA in both non-tumour and tumour conditions. RESULTS: Our results demonstrate dual benefits of muscle-specific moderate over-expression of SIRT6 in a mouse model of cancer-cachexia. In tumour-bearing mice, SIRT6 over-expression preserved muscle weight (P < 0.001) and fibre size (P < 0.005) as well as suppressed tumour growth (P < 0.05). SIRT6 over-expression significantly reduced myostatin expression and plasma free fatty acids levels but maintained plasma insulin levels in tumour-bearing mice. These positive effects of SIRT6 were associated with downregulation of the circulatory chemokine, CXCL10, and the myokine, WNT4. SIRT6 also upregulated expression of GLUT4, the major glucose transporter in the skeletal muscle. These results for the first time demonstrate that SIRT6 regulates multiple targets to limit tumour growth and cancer-associated muscle atrophy. CONCLUSION: Given the multifactorial nature of cachexia, SIRT6, which concurrently controls multiple pathways, can be a valuable therapeutic target to overcome this debilitating syndrome.

The nuclear sirtuin SIRT6 protects the heart from developing aging-associated myocyte senescence and cardiac hypertrophy.

Sirtuins have been shown to regulate the aging process. We have previously demonstrated that Sirt6 blocks the pressure overload-induced cardiac hypertrophy in mice. Here, we show that Sirt6 can also mitigate aging-induced cardiomyocyte senescence and cardiac hypertrophy. We found that aging is associated with altered Sirt6 activity along with development of cardiac hypertrophy and fibrosis. Compared to young mice (4-months), the hearts of aged mice (24-months) showed increased levels of mitochondrial DNA damage, shortened telomere length, and increased accumulation of 8-oxo-dG adducts, which are hallmarks of aging. The aged hearts also showed reduced levels of NAD+ and altered levels of mitochondrial fusion-fission proteins. Similar characteristics were observed in the hearts of Sirt6 deficient mice. Additionally, we found that doxorubicin (Dox) induced cardiomyocyte senescence, as measured by expression of p16INK4a, p53, and ß-galactosidase, was associated with loss of Sirt6. However, Sirt6 overexpression protected cardiomyocytes from developing Dox-induced senescence. Further, compared to wild-type mice, the hearts of Sirt6.Tg mice showed reduced expression of aging markers, and the development of aging-associated cardiac hypertrophy and fibrosis. Our data suggest that Sirt6 is a critical anti-aging molecule that regulates various cellular processes associated with aging and protects the heart from developing aging-induced cardiac hypertrophy and fibrosis.

Is nuclear sirtuin SIRT6 a master regulator of immune function?

The ability to ward off pathogens with minimal damage to the host determines the immune system's robustness. Multiple factors, including pathogen processing, identification, secretion of mediator and effector molecules, and immune cell proliferation and differentiation into various subsets, constitute the success of mounting an effective immune response. Cellular metabolism controls all of these intricate processes. Cells utilize diverse fuel sources and switch back and forth between different metabolic pathways depending on their energy needs. The three most critical metabolic pathways on which immune cells depend to meet their energy needs are oxidative metabolism, glycolysis, and glutaminolysis. Dynamic switching between these metabolic pathways is needed for optimal function of the immune cells. Moreover, switching between these metabolic pathways needs to be tightly regulated to achieve the best results. Immune cells depend on the Warburg effect for their growth, proliferation, secretory, and effector functions. Here, we hypothesize that the sirtuin, SIRT6, could be a negative regulator of the Warburg effect. We also postulate that SIRT6 could act as a master regulator of immune cell metabolism and function by regulating critical signaling pathways.

Safety and efficacy of Sofosbuvir and Velpatasvir in children with active hepatitis C virus infection undergoing haploidentical transplantation.

Direct Acting Antivirals (DAA) have changed the landscape of hepatitis C virus (HCV) infection with high cure rates across genotypes. However, the use of these agents in the setting of allogeneic hematopoietic cell transplantation (HCT) has been limited. In this context, we report the outcome of five children (5-12 years) with relapsed and refractory leukemia and active HCV infection (genotype 1b), who underwent urgent haploidentical HCT and were treated with Sofosbuvir and Velpatasvir (Sof-Vel) from initiation of treatment to 24 weeks post-HCT. All achieved complete virologic response (VR) at a median of 2 weeks, with normalization of liver enzymes. There were no adverse events related to the use of Sof-Vel, with no major fluctuations in cyclosporine levels. Two of the patients developed chronic GVHD and one relapsed. Sof-Vel was continued in one of them along with sirolimus without affecting drug levels. With a median follow-up of 15 months, four patients are disease free with sustained VR. Our study shows that combination of Sof-Vel might be effective in inducing rapid complete and sustained VR during HCT without any major untoward drug interaction.