Pharmacological Insights: Mitochondrial ROS Generation by FNC (Azvudine) in Dalton's Lymphoma Cells Revealed by Super Resolution Imaging.

Nucleoside analogs are a common form of chemotherapy that disrupts DNA replication and repair, leading to cell cycle arrest and apoptosis. Reactive oxygen species (ROS) production is a significant mechanism through which these drugs exert their anticancer effects. This study investigated a new nucleoside analog called FNC or Azvudine, and its impact on ROS production and cell viability in Dalton's lymphoma (DL) cells. The study found that FNC treatment resulted in a time- and dose-dependent increase in ROS levels in DL cells. After 15 and 30 min of treatment with 2 and 1 mg/ml of FNC, mitochondrial ROS production was observed in DL cells. Furthermore, prolonged exposure to FNC caused structural alterations and DNA damage in DL cells. The results suggest that FNC's ability to impair DL cell viability may be due to its induction of ROS production and indicate a need for further investigation.

Mitochondrial-mediated apoptosis as a therapeutic target for FNC (2'-deoxy-2'-b-fluoro-4'-azidocytidine)-induced inhibition of Dalton's lymphoma growth and proliferation.

PURPOSE: T-cell lymphomas, refer to a diverse set of lymphomas that originate from T-cells, a type of white blood cell, with limited treatment options. This investigation aimed to assess the efficacy and mechanism of a novel fluorinated nucleoside analogue (FNA), 2'-deoxy-2'-ß-fluoro-4'-azidocytidine (FNC), against T-cell lymphoma using Dalton's lymphoma (DL)-bearing mice as a model. METHODS: Balb/c mice transplanted with the DL tumor model received FNC treatment to study therapeutic efficacy against T-cell lymphoma. Behavioral monitoring, physiological measurements, and various analyses were conducted to evaluate treatment effects for mechanistic investigations. RESULTS: The results of study indicated that FNC prevented DL-altered behavior parameters, weight gain and alteration in organ structure, hematological parameters, and liver enzyme levels. Moreover, FNC treatment restored organ structures, attenuated angiogenesis, reduced DL cell viability and proliferation through apoptosis. The mechanism investigation revealed FNC diminished MMP levels, induced apoptosis through ROS induction, and activated mitochondrial-mediated pathways leading to increase in mean survival time of DL mice. These findings suggest that FNC has potential therapeutic effects in mitigating DL-induced adverse effects. CONCLUSION: FNC represents an efficient and targeted treatment strategy against T-cell lymphoma. FNC's proficient ability to induce apoptosis through ROS generation and MMP reduction makes it a promising candidate for developing newer and more effective anticancer therapies. Continued research could unveil FNC's potential role in designing a better therapeutic approach against NHL.

FNC (4'-azido-2'-deoxy-2'-fluoro(arbino)cytidine) as an Effective Therapeutic Agent for NHL: ROS Generation, Cell Cycle Arrest, and Mitochondrial-Mediated Apoptosis.

Cytotoxic nucleoside analogs (NAs) hold great promise in cancer therapeutics by mimicking endogenous nucleosides and interfering with crucial cellular processes. Here, we investigate the potential of the novel cytidine analog, 4'-azido-2'-deoxy-2'-fluoro(arbino)cytidine (FNC), as a therapeutic agent for Non-Hodgkin lymphoma (NHL) using Dalton's lymphoma (DL) as a T-cell lymphoma model. FNC demonstrated dose- and time-dependent inhibition of DL cell growth and proliferation. IC-50 values of FNC were measured at 1 µM, 0.5 µM, and 0.1 µM after 24, 48, and 72 h, respectively. Further elucidation of FNC's mechanism of action uncovers its role in inducing apoptosis in DL cells. Notable DNA fragmentation and nuclear condensation point to activated apoptotic pathways. FNC-induced apoptosis was concomitant with changes in cellular membranes, characterized by membrane rupture and altered morphology. The robust anticancer effects of FNC are linked to its capacity to induce reactive oxygen species (ROS) production, prompting oxidative stress-mediated apoptosis. Additionally, FNC disrupted mitochondrial membrane potential (MMP), leading to mitochondrial dysfunction, further promoting apoptosis. Dysregulation of apoptotic genes, with upregulation of Bax and downregulation of Bcl-2 and Bcl-xl, implicates the mitochondrial-mediated apoptosis pathway. Furthermore, FNC-induced G2/M phase cell cycle arrest was mediated through modulation of the cell cycle inhibitor p21. Overall, this study highlights the potential of FNC as a promising therapeutic agent for NHL.

Emission inventory of inorganic trace gases from solid residential fuels over the National Capital Territory of India.

In developing nations, solid residential fuels are the major sources of primary energy for various domestic activities. To date, the emission inventory of inorganic trace gases over National Capital Territory (NCT) was prepared using either default or country-specific emission factors. In this paper, we report (for the first time) the spatial variation of emission factors (EFs) of inorganic trace gases (SO2, NO, NO2, CO, CO2, and CH4) from the residential fuels used in slums and rural areas of NCT determined using dilution chamber in the laboratory. 147 residential fuel samples, including fuelwood, dung cake, crop residues, coal, etc., were collected at 149 NCT locations out of 675 slum clusters and 146 rural villages. The range of EF(s) of SO2 (0.02 ± 0.01 to 0.04 ± 0.01 g kg-1), CH4 (0.10 to 0.34 g kg-1), NO2 (0.01 to 0.02 g kg-1) is lower than the CO (3.55 ± 1.72 to 6.07 ± 1.53 g kg-1) and CO2 (0 to 129.45 ± 46.94 g kg-1). The north and north west districts of NCT are emission hotspots for CH4, NO, and NO2 emissions, whereas, the southern and northern areas of NCT are for CO2. These citywide emission inventories (0.05° × 0.05°) of inorganic trace gases are prepared using laboratory-determined EFs and available consumption data determined by recent survey information. Among solid residential fuels, fuel wood, and dung cake are two major contributors to inorganic trace gases in NCT.

Illuminating the Role of Mo Defective 2D Monolayer MoTe2 toward Highly Efficient Electrocatalytic O2 Reduction Reaction.

The fuel cell is one of the solutions to current energy problems as it comes under green and renewable energy technology. The primary limitation of a fuel cell lies in the relatively slow rate of oxygen reduction reactions (ORR) that take place on the cathode, and this is an all-important reaction. An efficient electrocatalyst provides the advancement of green energy-based fuel cell technology, and it can speed up the ORR process. The present work provides the study of non-noble metal-based electrocatalyst for ORR. We have computationally designed a 3 × 3 supercell model of metal defective (Mo-defective) MoTe2 transition metal dichalcogenide (TMD) material to study its electrocatalytic activity toward ORR. This work provides a comprehensive analysis of all reaction intermediates that play a role in ORR on the surfaces of metal-deficient MoTe2. The first-principles-based dispersion-corrected density functional theory (in short DFT-D) method was implemented to analyze the reaction-free energies (ΔG) for each ORR reaction step. The present study indicates that the ORR on the surface of metal-defective MoTe2 follows the 4e- transfer mechanism. This study suggests that the 2D Mo-defective MoTe2 TMD has the potential to be an effective ORR electrocatalyst in fuel cells.

Potential implications of protein kinase Cα in pathophysiological conditions and therapeutic interventions.

PKCα is a molecule with many functions that play an important role in cell survival and death to maintain cellular homeostasis. Alteration in the normal functioning of PKCα is responsible for the complicated etiology of many pathologies, including cancer, cardiovascular diseases, kidney complications, neurodegenerative diseases, diabetics, and many others. Several studies have been carried out over the years on this kinase's function, and regulation in normal physiology and pathological conditions. A lot of data with antithetical results have therefore accumulated over time to create a complex framework of physiological implications connected to the PKCα function that needs comprehensive elucidation. In light of this information, we critically analyze the multiple roles played by PKCα in basic cellular processes and their molecular mechanism during various pathological conditions. This review further discusses the current approaches to manipulating PKCα signaling amplitude in the patient's favour and proposed PKCα as a therapeutic target to reverse pathological states.

Safety Assessment of a Nucleoside Analogue FNC (2'-deoxy-2'- ß-fluoro-4'-azidocytidine ) in Balb/c Mice: Acute Toxicity Study.

OBJECTIVES: The present study aimed to provide an insight into the acute toxicity of a novel fluorinated nucleoside analogue (FNA), FNC (Azvudine or2'-deoxy-2'-ß-fluoro-4'-azidocytidine). FNC showed potent anti-viral and anti-cancer activities and approved drug for high-load HIV patients, despite, its acute toxicity study being lacking. MATERIALS AND METHODS: OECD-423 guidelines were followed during this study and the parameters were divided into four categories - behavioral parameters, physiological parameters, histopathological parameters, and supplementary tests. The behavioral parameters included feeding, body weight, belly size, organ weight and size, and mice behavior. The physiological parameters consisted of blood, liver, and kidney indicators. In histopathological parameters hematoxylin and eosin staining was performed to analyse the histological changes in the mice organs after FNC exposure. In addition, supplementary tests were conducted to assess cellular viability, DNA fragmentation and cytokine levels (IL-6 and TNF-α) in response to FNC. RESULTS: In the behavioral parameters FNC induced changes in the mice-to-mice interaction and activities. Mice's body weight, belly size, organ weight, and size remained unchanged. Physiological parameters of blood showed that FNC increased the level of WBC, RBC, Hb, and neutrophils and decreased the % count of lymphocytes. Liver enzymes SGOT (AST), and ALP was increased. In the renal function test (RFT) cholesterol level was significantly decreased. Histopathological analysis of the liver, kidney, brain, heart, lungs, and spleen showed no sign of tissue damage at the highest FNC dose of 25 mg/kg b.wt. Supplementary tests for cell viability showed no change in viability footprint, through our recently developed dilution cum-trypan (DCT) assay, and Annexin/PI. No DNA damage or apoptosis was observed in DAPI or AO/EtBr studies. Pro-inflammatory cytokines IL-6 and TNF-α increased in a dose-dependent manner. CONCLUSION: This study concluded that FNC is safe to use though higher concentration shows slight toxicity.

Moringa oleifera L. leaf extract induces cell cycle arrest and mitochondrial apoptosis in Dalton's Lymphoma: An in vitro and in vivo study.

ETHNOPHARMACOLOGICAL RELEVANCE: The present work is based on a wide spectrum of evidences available from scientific literature which reflects nutritional and medicinal values of natural products such as plants and their extracts. Moringa oleifera is one such popular plant species amidst indigenous tribal communities which is frequently used to treat ailments such as piles, sore throat, eye and ear infections and even poisonous bites of tropical fauna such as insects or snakes. Furthermore decoction of leaf and bark was used to cure fever and cough. Evidences further reveal that Moringa oleifera L. (Family Moringaceae), is widely distributed not only over the Indian sub-continent, but also over Philippines, Central America, Saudi Arabia and the Caribbean Islands and have been traditionally used to treat cancers since ancient times. However, therapeutic effects of Moringa oleifera on Non-Hodgkin Lymphoma (NHL) are yet to be established. AIM OF THE STUDY: The study aims to investigate the anti-cancer effects of Moringa oleifera leaf extract against murine NHL Non-Hodgkin cells in vitro and in vivo. MATERIAL AND METHODS: The pharmacologically active compounds of Moringa oleifera leaf extract were identified by GC-HRMS analysis. Tests of Moringa oleifera leaf extract's cytotoxicity against DL cells were carried out using the MTT assay. Chromatin condensation along with other morphological alterations were visualized through Fluorescence microscopy. Changes in the mitochondrial membrane potential (ΔΨm), the cell cycle, and apoptosis were analysed through flow cytometer. We tried to identify proteins involved in apoptosis and cell cycle through Western blotting using BALB/c mice as a model organism. RESULTS: GC-HRMS study revealed that a methanol based leaf extract of Moringa oleifera (MOML) comprises of a variety of bioactive chemicals. Our results indicate that MOML successfully reduced the proliferation of DL cells by lowering ΔΨm, changing overall cell morphology. DL cells treated with MOML showed arrested cell cycle at the G2/M phase and substantially up-regulated the expression of p53 and p21. Elevated levels of Bax, Cyt-c, and Caspase-3 and lowered expression levels of Bcl-2 protein suggested induction of apoptosis. Mechanistically, the anticancer efficacy of MOML is attributed to MEK/ERK-mediated pathway inactivation in DL cells. It is also interesting to note that MOML-mediated inhibition of DL growth was accompanied by apoptosis induction and improvement in hematological parameters in DL-bearing mice. CONCLUSION: Our finding suggested that MOML induces apoptosis and abrogates the growth of Dalton's lymphoma both in vitro and in vivo.

Red-emitting polyaniline-based nanoparticle probe for pH-sensitive fluorescence imaging.

Fluorescent probes based on semiconducting polymer nanoparticles (NPs) such as polyaniline (PANI) usually require external fluorophore doping to provide fluorescence function. Direct use of PANI-based NPs for bioimaging applications has been limited by PANI's weak blue fluorescence and aggregation-induced quenching in physiological medium. In this report, we developed a facile solid-state synthesis method to produce fluorescent polyaniline nanoparticles (FPNs) that are not only water-soluble but also exhibit high intensity and pH-sensitive red fluorescence. The FPNs showed high photoluminescence quantum yield (PLQY) of 19.3 % at physiological pH, which makes FPNs ideal for application as fluorescent nanoprobes in bioimaging. Moreover, we performed an in-depth study of photoluminescence dependence on pH and the phenomena of exciton-polaron quenching at low pH was highlighted. We also found that the ratio of emission intensity at 600 nm and 650 nm increased from 0.04 to 1.65 as pH was raised from 2.6 to 11.8, which could find its application in ratiometric pH sensing. FPNs exhibited excellent biocompatibility with >85 % cell viability for fibroblasts NIH/3 T3 and prostate cancer 22RV1 cells even at concentrations as high as 1000 µg/mL. In addition, fluorescence microscopy demonstrated concentration-dependent red fluorescence in the cytoplasm owing to the cellular uptake of FPNs in prostate cancer cells.

Coronary Artery Bypass Grafting among Patients Undergoing Cardiac Surgery in a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

INTRODUCTION: Among all cardiac surgeries, coronary artery bypass graft is frequently performed and is expected to improve the quality of life in patients with coronary artery disease. This study aimed to look at the prevalence of the patients undergoing coronary artery bypass grafting among cardiac surgery cases at a tertiary care hospital. METHODS: This was a descriptive cross-sectional study conducted at the Cardio-Thoracic and Vascular Surgery department of a tertiary care hospital among 92 patients who underwent cardiac surgery. Participants were enrolled after the ethical clearance from the Institutional Review Committee (Reference number: 574/2019). Epidemiological characters, functional New York Heart Association classification, and left ventricular function were evaluated. Data were entered in Microsoft Excel 2010 and analyzed using Statistical Package for the Social Sciences version 20. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. RESULTS: The prevalence of coronary artery bypass graft in patients undergoing cardiac surgery was 49 (53.2%) (43.0-63.4 at 95% Confidence Interval). The mean age of 49 patients was 58.87 years. Hypertension 43 (88%), Dyslipidemia 34 (69%) and Type 2 Diabetes Mellitus 25 (51%) were major comorbidities. The mean preoperative and postoperative ejection fraction was 48.2±10.5% and 52.6±6.0% respectively. The preoperative median New York Heart Association class was 3 whereas the post-operative class was 1. Mortality was seen in one (2.04%) patient. CONCLUSIONS: The prevalence of coronary artery bypass graft in the patient undergoing cardiac surgery was lower than noted in other studies.

Chemical properties of emissions from solid residential fuels used for energy in the rural sector of the southern region of India.

In the present study, we have estimated the emission factors (EFs) of particulate matter (PM), organic and elemental carbon (OC and EC), oxide of sulfur and nitrogen, and water-soluble ionic species emitted from residential fuels (fuelwood, crop residue, dung cake) used in the rural sector of five states (Kerala, Karnataka, Andhra Pradesh, Telangana, Tamil Nadu) of the southern region of India. Average EFs of PM, OC, and EC from fuelwood (FW), crop residues (CR), and dung cakes (DC) from southern region of India are estimated as follows: PM: 6.35 ± 5.64 g/kg (FW), 6.99 ± 5.46 g/kg (CR), 9.69 ± 3.73 g/kg (DC); OC: 1.60 ± 1.72 g/kg (FW), 1.50 ± 1.52 g/kg (CR), 3.54 ± 0.75 g/kg (DC); and EC: 0.46 ± 0.53 g/kg (FW), 0.29 ± 0.17 g/kg (CR), 0.21 ± 0.11 g/kg (DC), respectively. Similarly, the average EFs of SO2, NOx from FW, CR, and DC are determined to be as follows: SO2: 0.40 ± 0.37 g/kg (FW), 1.17 ± 0.25 g/kg (CR), and 0.18 ± 0.10 g/kg (DC); NOx: 1.11 ± 1.22 g/kg (FW), 0.69 ± 0.37 g/kg (CR), and 0.91 ± 0.54 g/kg (DC), respectively. PO43- shows the highest EF from FW (646.02 ± 576.35 mg/kg), CR (531.06 ± 678.29 mg/kg) among all anions followed by Cl- (FW: 512.91 ± 700.35 mg/kg, CR: 661.61 ± 865.46 mg/kg and DC: 104.16 ± 54.01 mg/kg); whereas, Na+ shows highest EF from FW (254.05 ± 298.50 mg/kg) and CR (249.36 ± 294.85 mg/kg) among all cations. The total emissions of trace gases, PM, and their chemical composition from FW, CR, and DC have been calculated using laboratory-generated EFs over the southern region of India. CR (1595.58 ± 14.24 Gg) contributes to higher emission of PM as compared to FW (218.78 ± 53.93 Gg), whereas the contribution from DC is negligible.

Gridded distribution of total suspended particulate matter (TSP) and their chemical characterization over Delhi during winter.

In the present study, total suspended particulate matter (TSP) samples were collected at 47 different sites (47 grids of 5 × 5 km2 area) of Delhi during winter (January-February 2019) in campaign mode. To understand the spatial variation of sources, TSP samples were analyzed for chemical compositions including carbonaceous species [organic carbon (OC), elemental carbon (EC), and water-soluble organic carbon (WSOC)], water-soluble total nitrogen (WSTN), water-soluble inorganic nitrogen (WSIN), polycyclic aromatic hydrocarbons (16 PAHs), water-soluble inorganic species (WSIS) (F-, Cl-, SO42-, NO2-, NO3-, PO43-, NH4+, Ca2+, Mg2+, Na+, and K+), and major and minor trace elements (B, Na, Mg, Al, P, S, Cl, K, Ca, Ti, Fe, Zn, Cr, Mn, Cu, As, Pd, F, and Ag). During the campaign, the maximum concentration of several components of TSP (996 µg/m3) was recorded at the Rana Pratap Bagh area, representing a pollution hotspot of Delhi. The maximum concentrations of PAHs were recorded at Udhyog Nagar, a region close to heavily loaded diesel vehicles, small rubber factories, and waste burning areas. Higher content of Cl- and Cl-/Na+ ratio (>1.7) suggests the presence of nonmarine anthropogenic sources of Cl- over Delhi. Minimum concentrations of OC, EC, WSOC, PAHs, and WSIS in TSP were observed at Kalkaji, representing the least polluted area in Delhi. Enrichment factor <5.0 at several locations and a significant correlation of Al with Mg, Fe, Ti, and Ca and C/N ratio indicated the abundance of mineral/crustal dust in TSP over Delhi. Principal component analysis (PCA) was also performed for the source apportionment of TSP, and extracted soil dust was found to be the major contributor to TSP, followed by biomass burning, open waste burning, secondary aerosol, and vehicular emissions.

Eluxadoline-induced Recurrent Pancreatitis in a Young Female without a Gallbladder: A Case Report and Literature Review.

Eluxadoline is a mixed opioid receptor agonist and antagonist approved for the treatment of diarrhea-predominant irritable bowel syndrome (IBS). It is believed to decrease visceral hypersensitivity without completely inhibiting intestinal motility. Pooled safety data from two phase three randomized trials have reported few cases of pancreatitis especially in patients with sphincter of Oddi (SO) dysfunction and cholecystectomy patients. We present a rare case of eluxadoline-induced recurrent pancreatitis in a 31-year-old female without a gallbladder. Her medical history was significant for irritable bowel syndrome with diarrhea (IBS-D), cholecystectomy, and depression. She was started on 75 mg of eluxadoline (the recommended dose for IBS-D patients without a gallbladder) three weeks prior to the first episode of pancreatitis. She had a recurrent episode of pancreatitis after few weeks and her symptoms and lipase levels improved significantly two days after stopping eluxadoline. The exact mechanism of eluxadoline to cause pancreatitis is unknown but it is believed to increase SO contractions. The absence of gallbladder prevents cholecystokinin mediated relaxation of the SO thus contributing more to spasms with eluxadoline. Few cases of severe pancreatitis and death have been reported even with the reduced dose of eluxadoline recommended for cholecystectomy patients. This case highlights the importance of considering drug-induced pancreatitis and avoidance of eluxadoline even in reduced doses in patients without a gallbladder.

Prediction of in vivo drug performance using in vitro dissolution coupled with STELLA: a study with selected drug products.

Prediction of the in vivo performance of the drug product from the in vitro studies is the major challenging job for the pharmaceutical industries. From the current regulatory perspective, biorelevant dissolution media should now be considered as quality control media in order to avoid the risk associated. Physiological based pharmacokinetic models (PBPK) coupled with biorelevant dissolution medium is widely used in simulation and prediction of the plasma drug concentration and in vivo drug performance. The present investigation deals with the evaluation of biorelevant dissolution media as well as in vivo drug performance by PBPK modelling using STELLA® simulation software. The PBPK model was developed using STELLA® using dissolution kinetics, solubility, standard gastrointestinal parameters and post-absorptive disposition parameters. The drug product selected for the present study includes Linezolid film-coated immediate-release tablets (Zyvox), Tacrolimus prolonged-release capsules (Advagraf), Valganciclovir tablets (Valcyte) and Mesalamine controlled-release capsules (Pentasa) each belonging to different biopharmaceutics classification system (BCS). The simulated plasma drug concentration was analyzed and pharmacokinetic parameters were calculated and compared with the reported values. The result from the present investigation indicates that STELLA® when coupled with biorelevant dissolution media can predict the in vivo performance of the drug product with prediction error less than 20% irrespective of the dosage form (immediate release versus modified release) and BCS Classification. Thus, STELLA® can be used for in vivo drug prediction which will be helpful in generic drug development.

A rare association of pyloric stenosis and situs inversus: impact on diagnosis and treatment.

A rare case of 23 days old boy is reported having congenital hypertrophic pyloric stenosis with situs inversus. Incidentally detected secondary diagnosis obscured the primary diagnosis by altering the physical examination findings. Diagnosis was made by ultrasonography (USG) which revealed congenital hypertrophic pyloric stenosis with situs inversus. Clinical details, diagnosis and management are discussed.