Variable antiviral activity of islatravir against M184I/V mutant HIV-1 selected during antiretroviral therapy.

BACKGROUND: Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. METHODS: HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. RESULTS: In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. CONCLUSIONS: Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic.

Psychiatric comorbidities among people with epilepsy: A population-based assessment in disadvantaged communities.

Psychiatric disorders are frequent among people with epilepsy but often under-recognized. The diagnosis and treatment of these disorders in low- and low-middle-income countries (LMICs) are challenging. METHODS: This cross-sectional survey included people recruited during a community epilepsy screening program involving 59,509 individuals from poor communities in Ludhiana in Northwest India. Adults (age ≥18 years) with confirmed epilepsy on antiseizure medications were screened for depression and anxiety using the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Generalized Anxiety Disorder-7 (GAD-7) twice over two years of follow-up. They were later interviewed for symptoms using the Brief Psychiatric Rating Scale, which was then confirmed by assessments by an experienced psychiatrist. RESULTS: Of the 240 people with confirmed epilepsy, 167 (70%) were adults, of whom, 116 (70%) eventually participated in the study. The NDDI-E with a cut-off of 15 identified depression in 14 (12%) of 116 people after one year of follow-up and 17 (15%) at two years. The GAD-7 using a cut-off of 6 identified 22 (19%) at one year and 32 (28%) with anxiety at two years. The area under the curves for NDDI-E was estimated as 0.62 (95%CI, 0.51-0.73; SE: 0.06; p = 0.04) and for GAD-7 as 0.62 (95%CI, 0.46-0.78; SE: 0.08; p = 0.12). Brief Psychiatric Rating Scale identified 63 (54%) people with psychiatric symptoms, for whom, a psychiatric diagnosis was confirmed in 60 (52%). A psychiatric diagnosis was associated with education below high school [Odds Ratio (OR): 2.59, 95%CI, 1.12-5.1; p = 0.03], later age of seizure onset (OR, 1.05, 95%CI: 1.0-1.10; p = 0.04), seizure frequency of at least one/year at enrolment (OR, 2.36, 95%CI: 1.0-5.58; p = 0.05) and the use of clobazam (OR, 5.09, 95%CI, 1.40-18.42; p = 0.01). CONCLUSION: Depression and anxiety are common in people with epilepsy. Our findings underscore the low yields of screening instruments, NDDI-E and GAD-7, and comparatively better professionally-administered diagnostic assessments in resource-limited settings in LMICs. Moreover, previously established cut-offs do not apply to the community studied.

Genome-wide analysis of PTR transporters in Candida species and their functional characterization in Candida auris.

The peptide transport (PTR) or proton-dependent oligopeptide transporter (POT) family exploits the inwardly directed proton motive force to facilitate the cellular uptake of di/tripeptides. Interestingly, some representatives are also shown to import peptide-based antifungals in certain Candida species. Thus, the identification and characterization of PTR transporters serve as an essential first step for their potential usage as antifungal peptide uptake systems. Herein, we present a genome-wide inventory of the PTR transporters in five prominent Candida species. Our study identifies 2 PTR transporters each in C. albicans and C. dubliniensis, 1 in C. glabrata, 4 in C. parapsilosis, and 3 in C. auris. Notably, despite all representatives retaining the conserved features seen in the PTR family, there exist two distinct classes of PTR transporters that differ in terms of their sequence identities and lengths of certain extracellular and intracellular segments. Further, we also evaluated the contribution of each PTR protein of the newly emerged multi-drug-resistant C. auris in di/tripeptide uptake. Notably, deletion of two PTR genes BNJ08_003830 and BNJ08_005124 led to a marked reduction in the transport capabilities of several tested di/tripeptides. However, all three genes could complement the role of native PTR2 gene of Saccharomyces cerevisiae, albeit to varied levels. Besides, BNJ08_005124 deletion also resulted in increased resistance toward the peptide-nucleoside drug Nikkomycin Z as well as the glucosamine-6-phosphate synthase inhibitor, L-norvalyl-N3-(4-methoxyfumaroyl)-L-2,3-diaminopropionoic acid (Nva-FMDP), pointing toward its predominant role in their uptake mechanism. Altogether, the study provides an important template for future structure-function investigations of PTR transporters in Candida species. KEY POINTS: • Candida genome encodes for two distinct classes of PTR transporters. • Candida auris encodes for 3 PTR transporters with different specificities. • BNJ08_005124 in C. auris is involved in the uptake of Nikkomycin Z and Nva-FMDP.

Genomic landscape of the DHA1 family in Candida auris and mapping substrate repertoire of CauMdr1.

The last decade has witnessed the rise of an extremely threatening healthcare-associated multidrug-resistant non-albicans Candida (NAC) species, Candida auris. Since besides target alterations, efflux mechanisms contribute maximally to antifungal resistance, it is imperative to investigate their contributions in this pathogen. Of note, within the major facilitator superfamily (MFS) of efflux pumps, drug/H+ antiporter family 1 (DHA1) has been established as a predominant contributor towards xenobiotic efflux. Our study provides a complete landscape of DHA1 transporters encoded in the genome of C. auris. This study identifies 14 DHA1 transporters encoded in the genome of the pathogen. We also construct deletion and heterologous overexpression strains for the most important DHA1 drug transporter, viz., CauMdr1 to map the spectrum of its substrates. While the knockout strain did not show any significant changes in the resistance patterns against most of the tested substrates, the ortholog when overexpressed in a minimal background Saccharomyces cerevisiae strain, AD1-8u-, showed significant enhancement in the minimum inhibitory concentrations (MICs) against a large panel of antifungal molecules. Altogether, the present study provides a comprehensive template for investigating the role of DHA1 members of C. auris in antifungal resistance mechanisms. KEY POINTS: • Fourteen putative DHA1 transporters are encoded in the Candida auris genome. • Deletion of the CauMDR1 gene does not lead to major changes in drug resistance. • CauMdr1 recognizes and effluxes numerous xenobiotics, including prominent azoles.

Mortality implications and factors associated with nonengagement in a public epilepsy care initiative in a transient population.

BACKGROUND: Community-based, public care programs are a requisite to close the epilepsy treatment gap in disadvantaged communities in low- and middle-income countries (LMICs). Potential beneficiaries may, however, choose not to engage in these programs. AIMS: The aim of the study was to describe factors associated with and mortality consequences of nonacceptance of a public epilepsy care initiative. METHODS: In this cross-sectional study, we contacted 207 (36%) people out of 575 who screened positive for epilepsy during a population-based survey of 59,509 people. They were invited for neurological evaluation and care provision (including antiseizure medications (ASMs)) but chose not to engage. Structured questionnaires and qualitative interviews were conducted to determine reason for their nonengagement. Factors associated with nonengagement were evaluated by univariate and multivariate analysis. We conducted verbal autopsies for those who had died. RESULTS: Ten (5%) of the 207 individuals died since the initial screening; six with epilepsy-related causes. Of those who could be contacted (n = 48), 40 (19%) were confirmed to have epilepsy. Nonengaging individuals were likely to be older (odds ratio (OR): 1.02; 95% confidence interval (CI), 1.01, 1.11), locals (OR: 4.32; 95% CI, 1.55, 12.03), and earn less than US$ 78/month (OR: 3.6; 95% CI, 1.62, 8.06). Reasons for not engaging included a belief that epilepsy is inconsequential, loss of daily wages owing to healthcare facility visit and physical infirmity. CONCLUSIONS: Nonacceptance of a community-based public epilepsy care initiative is associated with high premature mortality, mostly attributed to epilepsy-related causes. Older age, ethnic status, and economic deprivation are factors associated with nonacceptance, though the underlying reasons may be varied.

Epilepsy knowledge, attitudes, and practices among primary healthcare providers in an Indian district.

INTRODUCTION: Scaling up the involvement of primary care providers in epilepsy management in low- and middle-income countries (LMICs) requires an understanding of their epilepsy knowledge, attitudes, and practices (KAP). AIM: The aim of the study was to document levels of knowledge about, attitudes towards, and practices regarding epilepsy among different ranks of primary healthcare providers in a North-Western Indian district. METHODS: The survey included government medical officers (MOs), auxiliary nurse midwives (ANMs), and accredited social health activists (ASHAs). They were administered a specially designed KAP questionnaire. Responses were analyzed according to rank. RESULTS: The survey showed that nearly 10% of ANMs and almost a fifth of ASHAs had never heard about epilepsy. A quarter of MOs and over two-thirds of ANMs and ASHAs had never provided care to someone with epilepsy. There were significant differences in the levels of knowledge between the three groups of workers. CONCLUSIONS: Closing the huge gaps in KAP by educating primary care and community health workers about epilepsy should be a priority before engaging them in the epilepsy care delivery.

Association of oxidative stress and inflammatory markers with chronic stress in patients with newly diagnosed type 2 diabetes.

AIMS: Chronic stress is associated with increased risk of type 2 diabetes. Oxidative stress and inflammation are potential mediators of this risk. This study was conducted to investigate the association of oxidative stress and inflammatory markers with chronic stress and newly diagnosed type 2 diabetes. METHODS: Oxidative stress/antioxidant status (malondialdehyde [MDA], reduce glutathione [GSH], glutathione reductase [GR], glutathione peroxidase [GPx], catalase [CAT], superoxide dismutase [SOD]), inflammatory markers (highly sensitive C-reactive protein [hsCRP], adiponectin, leptin), chronic stress levels as assessed by stress scales-presumptive stressful life events scale (PSLES), perceived stress scale (PSS), sense of coherence (SOC) and stress biomarker-salivary cortisol in 125 subjects with newly detected diabetes mellitus (NDDM) were compared with an equal number of age and sex matched subjects with normal glucose tolerance (NGT). RESULTS: NDDM subjects as compared with NGT had significantly increased MDA (P < 0.001), hsCRP (P < 0.001), and leptin (P = 0.014) levels and increased GR (P = 0.043) and SOD (P < 0.001) activity along with decreased GSH (P < 0.001) and adiponectin (P < 0.001) levels. They also had significantly higher PSLES-LT and PSS and lower SOC scores along with elevated levels of 10:00 pm salivary cortisol and post dexamethasone salivary cortisol as compared with NGT. In stepwise logistic regression analysis, variables GSH (OR: 0.805), SOD (OR: 1.004), and adiponectin (OR: 0.771) along with PSLES-LT (OR: 1.007), PSS (OR: 1.147), SOC (OR: 0.667), salivary cortisol 10:00 pm (OR: 1.382), WC (OR: 1.087), and HOMA-IR (OR: 2.721) emerged as significant predictors of NDDM. CONCLUSION: The findings of this study indicate that chronic psychological stress and stress responses are associated significantly with inflammation and oxidative stress, which could act as mediating stress related risk factors for type 2 diabetes.

Estimation of nuclear DNA content and its variation among Indian Tea accessions by flow cytometry.

Nuclear DNA content and genome size variation among 36 Indian tea accessions were analyzed by flow cytometry. Initial standardization of protocols for isolation of nuclei, DNA staining and selection of an internal standard for tea accessions which have significantly high amount of phenolic secondary metabolites in their cytosol was carried out. Results obtained revealed that 2C DNA content of Indian tea is 7.46 pg which corresponds to 1C genome size of 3673 Mb. Inter accession variation in 2C DNA content was also observed among 35 diploid taxa ranging from 7.23 to 7.73 pg which was significant at 1% probability level. The 2C DNA content of triploid (UPASI 3) was observed to be 11.47 pg which is concurrent with the expected value. Results obtained showed that Assam and Cambod type tea accession have higher 2C DNA content of 7.73 pg whereas Assam Cambod hybrids and Assam China hybrids have reduction in DNA content with 2C amounts, 7.23 and 7.32 pg DNA respectively. The present study suggests that the species involved in origin of Indian tea must have differed in their genome sizes owing to significant inter accession variation in nuclear DNA content.

Dyslipidaemia & oxidative stress in patients of psoriasis: Emerging cardiovascular risk factors.

BACKGROUND & OBJECTIVES: Psoriasis is a recurrent hyper-proliferative skin disease which is often associated with free radical generation, abnormal lipid metabolism and increased inflammatory secretion that induce cardiovascular risk in these patients. The present study was intended to evaluate serum lipids, lipoprotein and oxidants-antioxidants status and to establish their relationship with atherogenic risk markers [oxidized low-density lipoprotein (oxLDL) and high-sensitivity C-reactive protein (hsCRP)] in patients with psoriasis. METHODS: The study was conducted on 150 psoriasis patients and 150 age- and sex-matched healthy controls. Overnight fasting blood samples were obtained for lipids, lipoproteins, lipid oxidation and peroxidation products [oxLDL, malondialdehyde (MDA)], antioxidant enzymes [reduced glutathione (GSH) and total antioxidant status] levels and hsCRP estimations. RESULTS: The mean levels of atherogenic lipids [total cholesterol (P<0.001), triacylglycerol (P<0.01)], lipid peroxidation products (P<0.001) and oxLDL and hsCRP (P<0.001) levels in patients with psoriasis were found to be significantly higher than those of healthy controls. On the other hand, ferric-reducing ability of plasma (FRAP, P<0.001) and antioxidant enzyme activities (reduced GSH, P<0.01) were significantly lower when compared to healthy controls. The plasma oxLDL was positively correlated to LDL cholesterol (P<0.001) and MDA (P<0.001) and negatively associated with antioxidant status in these patients. Serum MDA, FRAP and oxLDL were correlated with risk of atherosclerosis in the patients with psoriasis; however, no significant association was found between reduced GSH and hsCRP. INTERPRETATION & CONCLUSIONS: The study results suggest that LDL oxidation and reactive oxygen species in addition to inflammatory markers may play a pivotal role in inducing atherosclerosis in patients of psoriasis.

Assessment of prophylactic effect of Senna auriculata (L.) Roxb. leaves on alcohol-induced pancreatitis in rat model.

Aqueous leaf extract of Senna auriculata (L.) Roxb. syn. Cassia auriculata (SLEx) is known to possess potential antidiabetic and antioxidant properties. Based on the known correlation between exocrine pancreatic function and endocrine secretary capacity, here, we studied the prophylactic effect of the SLEx on alcohol induced pancreatitis in rats. To induce chronic pancreatitis, the rats were fed with unsaturated fat i.e. corn oil (2.5 mL/kg) along with high dose of ethanol (10.2 g/kg) for 4 wk, and was increased 0.6 g/kg after every 2 days for 1 wk and then 0.6 g/kg after every 4 days for a period of 4 wk. SLEx was orally administered to rats at dose of 400 mg/kg/day for 4 wk. At the end of 4th wk, pancreatic enzymes i.e., α-amylase, lipase, serum and pancreatic MDA levels were estimated. Pancreatic histopathological studies were also performed. The SLEx significantly reduced the serum levels of α-amylase and lipase along with significant suppression in serum and pancreatic tissue lipid peroxidation. Histomorphological studies did not show any fatty vacoules in acinar cells of SLEx-treated rats. However, vacoulation was seen in acini of pathogenic control rats. With the results, we conclude that Senna auriculata aqueous leaf extract has potential to reduce the ethanol-induced pathogenecity, and it possesses prophylactic effect on alcohol-induced pancreatitis. However, a long term trial is needed to ascertain its therapeutic potential for pancreatitis.

Terminalia arjuna (Roxb.) Wight & Arn. augments cardioprotection via antioxidant and antiapoptotic cascade in isoproterenol induced cardiotoxicity in rats.

Worldwide, Ischemic heart disease (IHD) affects a large population. Implication of myocardial infarction (MI) and its multiple pathophysiology in cardiac function is well known. Further, isoproterenol (ISP) is known to induce MI. Today, there is an urgent need for effective drug that could limit the myocardial injury. Therapeutic intervention with antioxidants has been shown useful in preventing the deleterious changes produced by ISP. Here, we investigated the protective effects of oral pre-treatment of hydroalcoholic extract of bark of Terminalia arjuna (HETA) on biochemical and apoptotic changes during cardiotoxicity induced by isoproterenol (ISP) in rats. HETA was orally administered at a dose of 100, 200 and 400 mg/kg body wt., for 30 days with concurrent administration of ISP (85 mg/kg body wt.) on days 28th and 29th at an interval of 24 h. ISP caused deleterious changes in the myocardium and significantly increased (P < 0.05) malondialdehyde, serum glutamate oxaloacitate transaminase, creatine kinase-MB, lactate dehydrogenase and troponin-I. However, it significantly decreased (P < 0.05) glutathione and superoxide dismutase compared to healthy control. Oral pre-treatment of HETA for 30 days significantly decreased (P < 0.05) the biochemical parameters of oxidative stress and cardiac markers as compared to ISP control. Histopathological findings also revealed that architecture of the myocardium was restored towards normal in HETA pre-treated group. Overall, the present study has shown that the hydroalcoholic extract of bark of T. arjuna (HETA) attenuates oxidative stress, apoptosis and improves antioxidant status in ISP-induced cardiotoxicity in rats.

ß-Adrenoreceptor Agonist Isoproterenol Alters Oxidative Status, Inflammatory Signaling, Injury Markers and Apoptotic Cell Death in Myocardium of Rats.

Sustained high levels of circulating catecholamines are reported to induce cardiotoxicity. Isoproterenol (ISP), a synthetic catecholamine has been widely employed to induce myocardial injury, though the role of inflammation and apoptosis is not well established. This study was designed to investigate the underlying mechanism of oxidative damage, inflammatory signaling, cell death in ISP induced myocardial infarction in rats. Wistar albino rats were divided in two groups: group I (sham control) and group II (ischemic control). ISP (85 mg/kg, s.c.) was administered at an interval of 24 h to group II for two consecutive days. On day third, after 48 h of the first injection of ISP, blood was collected from retro orbital plexus of rat eyes to estimate the biochemical parameters. Glutathione (GSH) and superoxide dismutase (SOD) were measured for antioxidant status. Similarly, malondialdehyde (MDA) was measured as an index of lipid peroxidation. Cardiac markers (SGOT, CK-MB, TropI and LDH) and pro-inflammatory cytokines (IL-6, CRP and TNF-α) were also estimated in ISP-induced rats. At the end of experiments animals were sacrificed for histopathological studies. GSH and SOD showed significant decrease after ISP challenge as compared to sham (control) group (p < 0.01) while MDA level, increased significantly (p < 0.01). ISP, also increased the level of cardiac markers and markers of inflammation significantly (p < 0.01), which was further verified by histopathological studies of the heart tissues. The study confirmed that ISP causes detrimental changes in the myocardium by altering cardiac and inflammatory markers, which leads to severe necrosis. The deleterious effects produced by ISP substantiate its suitability as a novel animal model for evaluation of cardioprotective agents/drugs.

Association of carotid intima-media thickness with leptin and apoliprotein b/apoliprotein a-I ratio reveals imminent predictors of subclinical atherosclerosis in psoriasis patients.

Psoriasis patients are often susceptible to cardiovascular diseases (CVD), including atherosclerosis. Traditional markers (biochemical and inflammatory) and diagnostic tools could detect occlusive but not subclinical atherosclerosis. Carotid intima-media thickness (CIMT), has recently been recognised as a non invasive diagnostic tool for identification of premature atherosclerosis. Therefore we evaluated 80 psoriasis patients and 80 age sex matched healthy controls for serum leptin levels and apolipoprotein B/apolipoprotein A-I ratio (apoB/apoA-I ratio) in relation with CIMT of carotid artery. Carotid intima-media thickness and carotid plaques were simultaneously measured by carotid sonography. Serum concentration of leptin and apolipoprotein were measured using enzyme-linked immuno sorbent assay (ELISA) and nephelometry respectively. Raised CIMT correlated to age of onset of the disease, serum leptin and apoB/apoA-I ratio in psoriasis patients. Taking into account, values that were above the 75 percentile of the three markers (leptin, apoB/apoA-I ratio and CIMT) the odds ratio was 4.26 (2.06-8.80 CI). Leptin and apoB/apoA-I ratio showed significant cumulative association with CIMT. Results of predictive analysis supports measurement of CIMT along with estimation of serum leptin and apoB/apoA-I ratio for prediction of premature atherosclerosis in psoriasis patients.

Tensile strength of conventional glass ionomer cement and silver reinforced glass ionomer cement.

A comparative analysis and assessment of the compressive strength (CS) and diametral tensile strength (DTS) between conventional glass ionomer cement (C-GIC) and a silver-reinforced GIC (S-GIC) variant is of interest. Ten specimens of both C-GIC (GC Fuji II, Japan) and S-GIC (Riva Silver, SDI, Australia) were fabricated for the evaluation of compressive strength, and an identical number of samples were created for the examination of tensile strength. These specimens were then tested using a universal testing apparatus. The results exhibited that both the compressive and diametral tensile strengths were significantly greater for the S-GIC cement in comparison to the C-GIC, with a notable p-value of 0.001. The findings suggest that S-GIC may be considered a viable alternative to conventional GIC.

Diagnosis of abdominal tuberculosis: Detection of mycobacterial CFP-10 and HspX proteins by gold nanoparticle-PCR amplified immunoassay.

Attempts were made to improve the efficacy of PCR amplified immunoassay (I-PCR) for diagnosing abdominal TB cases by utilizing the gold nanoparticle (AuNP)-based I-PCR, where AuNPs were functionalized with detection antibodies/oligonucleotides that exhibited 84.3% sensitivity and 95.1% specificity. This assay would improve the ongoing algorithms used in abdominal TB diagnosis.

Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques.

Treatment nonadherence is a pressing issue in people living with HIV (PLWH), as they require lifelong therapy to maintain viral suppression. Poor adherence leads to antiretroviral (ARV) resistance, transmission to others, AIDS progression, and increased morbidity and mortality. Long-acting (LA) ARV therapy is a promising strategy to combat the clinical drawback of user-dependent dosing. Islatravir (ISL) is a promising candidate for HIV treatment given its long half-life and high potency. Here we show constant ISL release from a subdermal LA nanofluidic implant achieves viral load reduction in SHIV-infected macaques. Specifically, a mean delivery dosage of 0.21 ± 0.07 mg/kg/day yielded a mean viral load reduction of -2.30 ± 0.53 log10 copies/mL at week 2, compared to baseline. The antiviral potency of the ISL delivered from the nanofluidic implant was higher than oral ISL dosed either daily or weekly. At week 3, viral resistance to ISL emerged in 2 out of 8 macaques, attributable to M184V mutation, supporting the need of combining ISL with other ARV for HIV treatment. The ISL implant produced moderate reactivity in the surrounding tissue, indicating tolerability. Overall, we present the ISL subdermal implant as a promising approach for LA ARV treatment in PLWH.

Assessment of serum cholinesterase in rural punjabi sprayers exposed to a mixture of pesticides.

Serum cholinesterase (SChE) activity is considered as a biomarker and is also taken as an exposure index to assess the low level, chronic residue exposures among sprayers. Thus, cholinesterase activity was studied in the professional rural Punjabi sprayers of Bathinda district in Punjab. This study was made to estimate the irregularities in the level of cholinesterase according to multiple pesticides used by sprayers, exposure periods, age, and body mass index (BMI) of the sprayers. The data generated was statistically analyzed by applying Student's 't' test and one-way analysis of variance. A positive correlation was found between SChE activity and years of exposure and a significant reduction in SChE activity was observed in younger population. Again, a positive correlation was seen between BMI and SChE inhibition.

Evaluation of oxidative stress and genotoxicity in battery manufacturing workers occupationally exposed to lead.

Battery manufacturing workers are occupationally exposed to lead (Pb), which is a highly toxic heavy metal. The aim of this study was to investigate the blood lead levels (BLL) of 30 battery manufacturing workers and find the correlation between BLL, micronucleated cell (MNC) frequency, binucleated cell (BNC) frequency in buccal mucosal cells and malondialdehyde concentrations in serum. 30 subjects of the BMW group, exposed to lead, and 30 control subjects, matched with the exposed subjects with respect to age, socio-economic status, sex, diet, smoking and drinking habits, were monitored for this study. BLL was found to have highly significant difference between both the groups (P < 0.001). The serum MDA levels were observed at significantly higher levels (6.76 ± 3.26) for the exposed group as compared to the control group (2.10 ± 1.02; P < 0.001). Buccal micronucleus test showed that both MNC and BNC frequencies were higher among the workers, in comparison to the control subjects. A positive correlation has been found between BLL and all the parameters. Our results indicate an increased health associated risk for workers occupationally exposed to lead.

Modulation of glucose metabolism-related genes in diabetic rats treated with herbal synthetic anti-diabetic compound (α-HSA): insights from transcriptomic profiling.

OBJECTIVES: Eugenia jambolana is a medicinal plant traditionally used for treating diabetes. The bioactive compound FIIc, which is derived from the fruit pulp of E. jambolana, has been identified and purified as α-HSA. Previous studies have demonstrated that administration of α-HSA for 6 weeks improved glycemic index and dyslipidemia in rats with T2D. This study investigated the molecular mechanism underlying the potential therapeutic effects of α-HSA in experimentally induced diabetic rats. METHODS: Male Wistar rats were divided into four groups: diabetic control, diabetic treated with FIIc, diabetic treated with α-HSA, and diabetic treated with glibenclamide. Over a 6-week experimental period, transcriptomic analysis was conducted on liver, skeletal, and pancreatic tissue samples collected from the rats. RESULTS: The study findings revealed significant upregulation of genes associated with glucose metabolism and insulin signaling in the groups treated with FIIc and α-HSA, compared to the diabetic control group. Moreover, pro-inflammatory genes were downregulated in these treatment groups. These results indicate that α-HSA has the potential to modulate key metabolic pathways, improve glucose homeostasis, enhance insulin sensitivity, and alleviate inflammation. CONCLUSIONS: This study provides compelling scientific evidence supporting the potential of α-HSA as a therapeutic agent for diabetes treatment. The observed upregulation of genes related to glucose metabolism and insulin signaling, along with the downregulation of pro-inflammatory genes, aligns with the pharmacological activity of α-HSA in controlling glucose homeostasis and improving insulin sensitivity. These findings suggest that α-HSA holds promise as a novel therapeutic approach for managing diabetes and its associated complications.

Effect of Succinamic Acid Derivative on the Growth Kinetics and Induction of Apoptosis in a Cancer Cell Line.

Introduction Head and neck cancers are heterogeneous malignancies associated with significant morbidity. Oral cancers are related to the use of tobacco products. Smokeless tobacco usage is a health problem worldwide, and its carcinogenic mechanism is largely unknown. Despite advances in conventional treatments, side effects and drug resistance remain unsolved. Therefore, novel therapeutic agents with minimal side effects using plant derivatives should be explored. An active antihyperglycemic and antioxidant compound known as FIIc was isolated from the fruit pulp of Eugenia jambolana (US Patent No.: 2,30,753). Although E. jambolana is reported to have anticancer activity, no study has been reported on its growth kinetics and apoptotic potential in the human head and neck cancer cell line (SCC4). The present study evaluated the effect of an herbal compound isolated from the fruit pulp of E. jambolana and chemically synthesized the same compound, α-hydroxy succinamic acid (α-HSA), on SCC4 proliferation and apoptotic gene expression. Methods The SCC4 cell line was cultured in Dulbecco's Modified Eagle Medium (DMEM). The dosages of smokeless tobacco extract (STE), herbal compound, and synthetic compound were determined by cell viability assay, and their effect on mRNA expression of apoptotic genes was measured by real-time polymerase chain reaction. Results The present study observed significant therapeutic effects of the natural and synthetic compounds from the fruit pulp of E. jambolana at the concentration range of 100-200 µg/mL on the SCC4 cell line. α-HSA had antiproliferative action; upregulated apoptotic genes like p53, p21, and Bax; and downregulated anti-apoptotic genes like survivin in the SCC4 cell line. Conclusion The therapeutic potential of α-HSA and the putative mechanisms involved may be explored to provide the basis for future therapeutic interventions in oral cancer mediated by smokeless tobacco.