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Background Beryllium and its compounds are carcinogenicity, but the mechanisms through which this occurs have yet to be clarified. Accumulating evidence exists that long noncoding RNAs (lncRNAs) play an important role in occurrence and development of cancer. Aims and Methods To explore the carcinogenic mechanism of beryllium, human bronchial epithelial cells (16HBE) were treated with 50 μM beryllium sulfate (BeSO4) for 45 passages (~23 weeks). The expression levels of lncRNA SNHG7, SNHG11, SNHG15, MIR22HG, GMPS, and SIK1 were detected at passage 0 (P0), 15 (P15), 25 (P25), 35 (P35), and 45 (P45). Results The results indicated that enhanced cell proliferation, extensive clones in soft agar, protein expressions of up-regulated matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 2 (MMP2), proliferating cell nuclear antigen (PCNA), cyclin D1, and down-regulated p53 were all observed at the 45th passage in 16HBE cells. Thus, BeSO4-transformed 16HBE cells (T-16HBE) were established. Meanwhile, the study found that the expression of lncRNA SNHG11 was elevated during malignant transformation. Knockdown of SNHG11 in T-16HBE cells blocked cell proliferation, invasion, and migration, and decreased the protein levels of MMP9, MMP2, PCNA, cyclin D1, but increased p53. Conclusions The studies revealed that SNHG11 acts as an oncogene in the malignant transformation of 16HBE cells induced by BeSO4, which signifies progress in the study of the carcinogenic mechanism of beryllium.

Cypermethrin (CP) exhibits anti-androgenic effects through antagonism on androgen receptor (AR) activation. This study was to identify whether AR-mediated disabled 2 interacting protein (DAB2IP)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was involved in CP-induced mouse Sertoli cells (TM4) proliferation disorder. Real-Time Cell Analysis-iCELLigence system was to measure cell proliferation. Bioinformatic analyses were performed to identify AR-regulated genes. Quantitative Real-Time PCR and western blot were to detect the genes and proteins levels in AR-mediated DAB2IP/PI3K/AKT pathway. Results showed CP suppressed TM4 proliferation and the expression of AR. Activation of AR restored the inhibition efficacy of CP on TM4 proliferation. AR regulated DAB2IP expression and phosphorylation levels of PI3K and AKT in CP-exposed TM4 cells. In addition, knockdown of DAB2IP alleviated the inhibition efficacy of CP on cell proliferation and phosphorylation of PI3K and AKT. Taken together, AR was a modulator in CP-induced inhibition of Sertoli cells proliferation by negatively regulating DAB2IP/PI3K/AKT signaling pathway. The study may provide a new insight for the mechanisms of male reproductive toxicity induced by CP.

Aldicarb, a carbamate pesticide banned in France since 2008, represents a persistent risk of human poisoning. There is no up-to-date picture of aldicarb intentional poisonings associated to detailed diagnosis and clinical management of cases to evaluate the effect of its ban on intoxication risk reduction, including suicide. This retrospective epidemiological study describes cases of suicidal intoxication from the Hauts-de-France region between 2012 and 2021 and illustrates this situation through one analytically documented case. 60 cases were collected, mostly presenting a pathognomonic symptomatology. Thirty-five victims presented a muscarinic syndrome (58.3%), 14 a nicotinic syndrome (23.3%), and 37 a central nervous system impairment (61.7%). Hospitalization was necessary for 44 cases (73.3%), with 2 fatal evolutions. Diagnosis was based on the blood cholinesterase activities. Among the 25 cases with toxicology results, 45.8% presented a moderate decrease of acetylcholinesterase activity, whereas 87.5% presented a strong decrease of butyrylcholinesterase activity. Blood or urine detection of aldicarb and its metabolites may be considered in therapeutic management, although their quantification is unlikely to change the emergency medical care. Our study updates epidemiology of aldicarb poisoning at a regional level, highlighting a persisting health threatening situation with banned pesticides. More than 65% of national cases occurred in this agricultural area, aldicarb remaining available from storage of previously purchased products. Robust evidence is presented that acute poisoning is an ongoing major global public health challenge. There is a need for continued international efforts in risk reduction, knowledge, and information strategies.

Dezocine, a dual agonist and antagonist of the μ-opioid receptor and κ-opioid receptor, is widely used as an analgesic in China. At present, there are few studies on anti-tumor effects of dezocine, most of which are used to treat cancer pain. However, it has recently been reported that dezocine can induce apoptosis of triple negative breast cancer cells. Dezocine may have some anti-tumor activity, but the effect and potential mechanism of dezocine in the treatment of other types of cancer remain to be fully studied. The purpose of the present study was to investigate the effect of dezocine on human Hela cervical carcinoma cells, and to elucidate the underlying molecular mechanisms. We performed CCK-8 assays, clone formation assays, xenograft, flow cytometry analysis, western blot and RNA-seq analysis to evaluate the effects of dezocine on Hela cells. In addition, the role of endoplasmic reticulum (ER) stress in dezocine-induced apoptosis was investigated using qPCR and western blot analysis. Dezocine inhibited Hela cell viability in dose-dependent and time-dependent manners, and notably did not achieve this effect by targeting the opioid receptors. Further mechanistic studies demonstrated that dezocine activated ER stress by upregulating the expression of GRP78, IRE1 and p-JNK, and that dezocine-induced apoptosis was attenuated when the ER stress pathway was blocked. Our results provide a foundation to support the redefinition of dezocine as a novel, adjuvant treatment for patients with cervical cancer, although further research will be required to support its application in clinical practice.

Background Mitochondrial dynamics is essential for the maintenance of healthy mitochondrial network. Emerging evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of hepatic fibrogenesis following chronic liver injury. However, the role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in the context of liver fibrosis remains unclear. Methods and Results In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, mitochondrial fission intervention experiments were achieved by the mitochondrial division inhibitor 1 (Mdivi-1). The results demonstrated that chronic CCl4 exposure resulted in severe hepatic fibrogenesis and mitochondrial damage. By contrast, pharmacological inhibition of mitochondrial division by Mdivi-1 substantially reduced the changes of mitochondrial dynamics and finally prevented the deposition of extracellular matrix proteins. Mechanistically, excessive mitochondrial fission may activate hepatic stellate cells through RIPK1-MLKL-dependent hepatocyte death, which ultimately promotes liver fibrosis. Conclusion Our study imply that inhibiting Drp1-mediated mitochondrial fission attenuates CCl4-induced liver fibrosis and may serve as a therapeutic target for retarding progression of chronic liver disease.

The cardiotoxicity induced by arsenic trioxide (ATO) limits its clinical application in acute promyelocytic leukemia treatment. Sacubitril/valsartan (LCZ696) is an effective drug for the treatment of heart failure. In this study, we aimed to investigate the protective effect and mechanisms of LCZ696 against the ATO-induced cardiotoxicity in mice and H9c2 cells. We found that LCZ696 could alleviate the decrease of ejection fraction and fractional shortening induced by ATO, thereby improving mouse cardiac contractile function. LCZ696 could also reduce the myocardial enzyme, resist oxidative stress, mitigate myocardial fibrosis, and ameliorate myocardial structure, thereby alleviating myocardial damage caused by ATO. In addition, LCZ696 could significantly increase the cell viability and reduce the accumulation of reactive oxygen species in ATO-treated H9c2 cells. Besides, in vivo and in vitro studies have been found that LCZ696 could restore the expression of Bcl-2 and reduce Bax and Caspase-3 levels, inhibiting ATO-induced apoptosis. Meanwhile, LCZ696 decreased the levels of IL-1, IL-6, and TNF-α, alleviating the inflammatory injury caused by ATO. Furthermore, LCZ696 prevented NF-κB upregulation induced by ATO. Our findings revealed that LCZ696 has a considerable effect on preventing cardiotoxicity induced by ATO, which attributes to its capability to suppress oxidative stress, inflammation, and apoptosis.

Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. It is of great interest to us that dimethyl fumarate (DMF) has been shown to have anti-inflammatory effects. The aim of this study was to investigate whether DMF could alleviate lipopolysaccharide(LPS)-induced ALI, and to explore its mechanism of action. Materials and methods We established a mice model of ALI with intratracheal instillation of LPS and intraperitoneal injection of DMF to treat ALI. The pathological damage and inflammatory response of lung tissues were observed by hematoxylin and eosin (H&E) staining, ELISA assay and western blot. ATP plus LPS was used for the establishment of ALI in vitro model, the therapeutic effects of DMF was explored by ELISA assay, RT-qPCR, western blot, and flow cytometry, and the therapeutic mechanisms of DMF was explored by administration of Brusatol (BT), a nuclear factor erythroid-2-related factor 2 (Nrf2) inhibitor. Results We found that intraperitoneal injection of DMF significantly reduced LPS-induced the pulmonary injury, pulmonary edema, and infiltration of inflammatory mediators. In LPS-induced ALI, NLRP3 inflammasome-mediated pyroptosis was markedly activated, followed by cleavage of caspase-1 and GSDMD. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and ATP plus LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nrf2, leading to inactivation of NLRP3 inflammasome and reduced pyroptosis in vivo and in vitro. Conversely, BT reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI. Conclusions DMF could improve LPS-induced ALI via inhibiting NLRP3 inflammasome and pyroptosis, and that these effects were mediated by triggering Nrf2 expression, suggesting a therapeutic potential of DMF as an anti-inflammatory agent for ALI/ARDS treatment.

Objective The central objective of this study was to investigate the cumulative effects restraint stress and sodium arsenite on reproductive health in male rats. Methods Healthy male Wistar rats were allocated into 4 groups (n = 8). Animals in group 1 served as controls and did not subjected to any stress. Rats in groups 2, 3, and 4 were subjected to either restraint stress (5 h/day) or maintained on arsenic (25 ppm) via drinking water or both for 65 days. After completion of the experimental period, all the rats were analyzed for selected reproductive endpoints. Results Restraint stress or sodium arsenite treatment increased serum corticosterone levels, reduced testicular daily sperm count, epididymal sperm viability, motility, membrane integrity, and decreased testicular steroidogenic enzymes such as 3β- and 17β-hydroxysteroid dehydrogenases associated with reduced serum testosterone levels, deteriorated testicular architecture, and reduced activity levels of testicular superoxide dismutase and catalase accompanied by elevated lipid peroxidation levels. In rats subjected to restraint stress and sodium arsenite, a significant decrease in selected sperm qualitative and quantitative parameters, serum testosterone levels were observed as compared with rats subjected to sodium arsenite alone. A significant increase in the levels of lipid peroxidation with a concomitant decrease in the activities of antioxidant enzymes was observed in the testis of rats subjected to both restraint stress and sodium arsenite treatment as compared with sodium arsenite alone intoxicated rats. Surprisingly, serum corticosterone levels were significantly elevated in rats following both stressors as compared with arsenic alone treated rats. Analysis of atomic absorption spectroscopy revealed that the accumulation of arsenic in the testis of arsenic-treated and arsenic plus immobilization stress groups was significant as compared with controls. Conclusions Based on the findings, it can be concluded that deterioration of male reproductive health could be accelerated in arsenic intoxicated rats following restraint stress.

Acute lung injury has been reported following various chemotherapeutic agents administration. Several pathways for lung injury have been speculated however, the exact mechanism of the lung injury induced by methotrexate (MTX) is yet to be defined. The potential protective effect of Ginkgo biloba extract (GB), a Chinese herbal medicine, against MTX-induced lung injury is still not reported. Therefore, this study was performed to examine the possible implication of NLRP3 inflammasome and miRNA-21 in the pathogenesis of the MTX-induced lung injury as well as the protective role of GB in ameliorating the induced lung injury. Rats received GB (100 mg/kg/day, orally) for 10 days and MTX (20 mg/kg single dose, intraperitoneally) on the fifth day. MTX-induced lung injury was manifested by lung histopathology. MTX exhibited a marked increase in lung malondialdehyde beside a notable decrease in lung reduced glutathione. Moreover, MTX injection activated the lung NLRP3 inflammasome by significant upregulation of the NLRP3, ASC, caspase-1 lung mRNA expressions and protein levels in addition to lung NF-kBp65 protein expression, and miRNA-21 expression when compared with the normal control group. However, GB administration mitigated lung injury and inhibited the NLRP3 activation. This study is the first report to reveal the involvement of NLRP3 inflammasome in the pathogenesis of MTX-induced lung injury and also to show that the administration of GB alleviates the lung injury induced by MTX via suppressing the oxidative stress, restoring the antioxidant activity, blocking the NLRP3/ASC/Caspase-1 signaling and downregulating the NF-kBp65 protein expression ae well as miRNA-21 expression in lung tissue.

Drug-induced nephrotoxicity is a common problem in clinical medicine and the frequency of drug-related acute and chronic kidney dysfunction worldwide. One of them is anti-tuberculosis (TB) drugs that cause renal function impairment during TB treatment. Medicinal plants contain bioactive compounds that are capable for treating drug or toxin-induced renal disorders. The aim of the present study was to assess the protective effect of the ethanolic extract of Nigella sativa seeds (NS) against anti-TB drugs (ATDs) induced nephrotoxicity in Wistar albino rats. Rats were treated with ATDs for 12weeks (3 alternative days in a week). Supplementation with 125mg NS/kg, p.o. was administered to the experimental rats for 12weeks (3 alternative days in a week considering next day of ATDs treatment). The results demonstrated that NS treatment protected against renal damage induced by ATDs, as evidenced by the reduction in serum urea, creatinine, uric acid, urea nitrogen levels, pro-inflammatory markers (TNF-α and IL-6), whereas improvement in histological tubular and glomerular damage. In addition, NS enhanced the antioxidant enzyme activity (superoxide dismutase and catalase) and decreased the lipid peroxidation and glutathione level in the kidney. In conclusion, NS could reduce chronic nephritis in ATDs treated group through suppressing inflammation and oxidative stress. It suggests that NS can be used as supplementary preventive and protective drug against kidney injury during anti-TB treatment.

Nitroglycerin (NTG)—a nitric oxide–donating drug—is traditionally administered via the sublingual route to treat acute myocardial angina attacks. NTG also increases tumor blood flow and, consequently, cancer drug delivery to tumor cells. In the homologous recombination pathway, radiation-sensitive 52 (Rad52) plays a crucial role in DNA repair by promoting the annealing of complementary single-stranded DNA and stimulating radiation-sensitive 51 (Rad51) recombinase activity. Pemetrexed—a multitargeted antifolate agent—exhibits satisfactory clinical activity in wild-type nonsquamous non-small-cell lung cancer (NSCLC) cells. However, the synergistic activity of combination therapy with NTG and pemetrexed against NSCLC cells has not yet been clarified. In 2 NSCLC cell lines (i.e. lung squamous cell carcinoma H520 and lung adenocarcinoma H1975 cells), NTG reduced Rad52 expression; in addition, decreased phospho-AKT and phospho-ERK1/2 protein levels were observed. Enhancement of AKT or ERK1/2 activity through transfection with a constitutively active AKT (AKT-CA) vector or constitutively active mitogen-activated protein kinase kinase 1 (MKK1-CA) vector increased the Rad52 protein level and cell survival, which were suppressed by NTG. The knockdown of Rad52 expression by using small interfering RNA or by inhibiting AKT and ERK1/2 activity enhanced the cytotoxicity and cell growth inhibition induced by NTG. Moreover, NTG synergistically enhanced the cytotoxicity and cell growth inhibition induced by pemetrexed in NSCLC cells; these effects were associated with AKT and ERK1/2 inactivation and, consequently, Rad52 downregulation in H520 and H1975 cells. The results provide a rationale for combining NTG and pemetrexed in lung cancer treatment to improve lung cancer control.

Acute liver failure (ALF), characterized by the quick occurrence of disorder in liver, is a serious liver injury with extremely high mortality. Therefore, we investigated whether diallyl trisulfide (DATS), a natural product from garlic, protected against ALF in mice and studied underlying mechanisms. In the present study, lipopolysaccharide (LPS) (10 μg·kg−1)/D-galactosamine (D-gal) (500 mg·kg−1) was intraperitoneally injected to ICR mice to induce ALF. The mice were orally administered 20-, 40-, or 80-mg·kg−1 DATS) 1 h before LPS/D-gal exposure. Serum biochemical analyses and pathological study found that DATS pretreatment effectively prevented the ALF in LPS/D-gal-treated mice. Mechanistically, pretreatment of DATS inhibited the increase of the numbers of CD11b+ Kupffer cells and other macrophages in the liver, the release of tumor necrosis factor-α into the blood, and Caspase-1 activation induced by LPS/D-gal treatment in mice. Furthermore, DATS inhibited the activation of Caspase-3, downregulation of Bcl-2/Bax ratio, and increase of TUNEL positive staining. Altogether, our findings suggest that DATS exhibits hepatoprotective effects against ALF elicited by LPS/D-gal challenge, which probably associated with anti-inflammation and anti-apoptosis.

A new and valid method was developed for the quantitative voltammetric analysis of midodrine hydrochloride (MID) in pharmaceutical tablets (Midodrine) and biological samples. The method is based on electro-oxidation of MID supported by both disposable pencil electrode (PE) and glassy carbon electrode (GCE). The analysis was carried out using cyclic voltammetry, differential pulse voltammetry (DPV), and square wave voltammetry (SWV) techniques. The proposed analytical method was validated according to ICH guidelines. MID was successively assayed at concentration ranges of 1.15–6.55 and 0.58–3.05 μg mL−1 at PE. Also, MID was successively assayed at concentration ranges of 1.15–5.28 and 2.86–27.6 μg mL−1 at GCE for DPV and SWV methods, respectively. The proposed method was successfully used for the analysis of MID in its dosage form and human urine with good recoveries of 99.66 ± 0.33, 99.8 ± 0.45 at PE and 99.8 ± 0.25, 98.7 ± 1.27 at GCE for the DPV and SWV methods, respectively. The suggested method could be applied to the studied drug in the quality control lab as well as in its pharmacokinetic studies.

Gibberellic acid (GA3), a widely known plant growth regulator, has been mostly used in agriculture. Little is known regarding its toxicity or the impact of its metabolic mechanism on human health. The current study examined the protective impact of chrysin against GA3-induced liver and kidney dysfunctions at biochemical, molecular, and histopathological levels. Forty male albino rats were allocated into 4 groups. The control group received saline; the chrysin group received 50 mg/kg/BW orally daily for 4 weeks; the GA3 group received 55 mg/kg/BW GA3 via daily oral gavage for 4 weeks, and the protective group (chrysin + GA3) was administered both chrysin and GA3 at the same dosage given in chrysin and GA3 groups. Chrysin was administered 1 h earlier than GA3. The GA3 induced liver and kidney injuries as proven by the elevation of hepatic and renal markers with a significant increase in malondialdehyde levels. Furthermore, a decrease of catalase and glutathione was reported in the GA3-administered rats. Pre-administration of chrysin significantly protected the hepatorenal tissue against the deleterious effects of GA3. Chrysin restored the hepatorenal functions and their antioxidant ability to normal levels. Moreover, chrysin modulated the hepatorenal toxic effects of GA3 at the molecular level via the upregulation of the antiapoptotic genes, interleukin-10 (IL-10), hemoxygenase-1, and nuclear factor erythroid 2-related factor 2 expressions; the downregulation of the kidney injury molecule-1 and caspase-3 mRNA expressions; and a decrease in IL-1β and tumor necrosis factor-α secretions. Additionally, the pre-administration of chrysin effectively attenuated the GA3-induced hepatorenal histopathological changes by regulating the immunoexpression of cytochrome P450 2E1 (CYP2E1) and pregnane X receptor, resulting in normal values at the cellular level. In conclusion, chrysin attenuated GA3-induced oxidative hepatorenal injury by inhibiting free-radical production and cytokine expression as well as by modulating the antioxidant, apoptotic, and antiapoptotic activities. Chrysin is a potent hepatorenal protective agent to antagonize oxidative stress induced by GA3.

Contemporary exposure to PM2.5 has been reported to disrupt spermatogenesis. However, the subsequent toxicological responses and the mechanisms of male reproductive damage in offspring induced by maternal exposure to PM2.5 remain largely unknown. For the first time, this study aimed to explore the apoptotic response in spermatogenesis of male offspring following maternal exposure to PM2.5 and its mechanisms. The C57BL/6 mice with vaginal plugs were randomly divided into four groups. Mice in the PM2.5 groups were intratracheally exposed to PM2.5 (4.8 mg/kg body weight, 43.2 mg/kg body weight) during pregnancy (every 3 days, six times in total). The mice in the membrane control group were treated similarly to the PM2.5 groups, applying only PM2.5 sampling membrane, while mice in the control group were kept untreated. The results showed that maternal exposure to PM2.5 during pregnancy resulted in structural lesions of the testis, reduced numbers of primary spermatocytes and spermatids, decreased sperm count and quality, shortened diameter of seminiferous tubules, and reduced testosterone and ABP in the offspring testes. Furthermore, cell apoptosis was increased and protein expression of IRE-1/P-JNK/cleaved caspase-12/cleaved caspase-3 was activated. These findings suggested that maternal exposure to PM2.5 may affect spermatogenesis by increasing apoptosis through activation of UPR-mediated JNK apoptotic pathway in offspring testicles and by reducing testosterone secretion.

Acrylamide is a well-known neurotoxicant and carcinogen. Apart from industrial exposure, acrylamide is also found in different food products. The present study deals with in vivo experiment to test the protective effect of rutin against acrylamide induced toxicity in rats. The study was carried out on female rats with exposure of acrylamide at the dose of 38.27 mg/kg body weight, orally for 10 days followed by the therapy of rutin (05, 10, 20 and 40 mg/kg orally), for three consecutive days. All animals were sacrificed after 24 h of last treatment and various biochemical parameters in blood and tissue were investigated. Histopathology of liver, kidney and brain was also done. On administration of acrylamide for 10 days, neurotoxicity was observed in terms of decreased acetylcholinesterase activity and oxidative stress was observed in terms of increased lipid peroxidation, declined level of reduced glutathione, antioxidant enzymes (superoxide dismutase and catalase) in liver, kidney and brain. Acrylamide exposure increased the activities of serum transaminases, lipid profile, bilirubin, urea, uric acid and creatinine in serum indicating damage. Our experimental results conclude that rutin showed remarkable protection against oxidative DNA damage induced by acrylamide, which may be due to its antioxidant potential.

Neratinib is a pan-HER tyrosine kinase inhibitor newly approved by FDA in 2017 to treat HER2-positive breast cancer, but the phase III trial of neratinib showed that 96% of the patients taking neratinib experienced diarrhea. So far very few mechanistic studies explore neratinib-induced gastrointestinal (GI) toxicity. Hereby, we performed toxicity studies in mice to characterize the potential mechanism underlying this adverse effect. C57BL/6 J mice were separated into three groups A, B, C. Group A received vehicle; group B was orally dosed with 100 mg/kg neratinib once daily for 18 days. Group C was dosed with 100 mg/kg neratinib for 12 days and switched to vehicle for 6 days. Intestine and liver were collected for further analysis. Human intestine-derived cells were treated with neratinib in vitro. Our results showed that 12 days treatment of neratinib caused persistent histological damage in mouse GI tract. Both gene expression and activity of Cyp3a11, the major enzyme metabolizing neratinib in mice was reduced in small intestine. The gene expression of proinflammatory cytokines increased throughout the GI tract. Such damages were not recovered after 6 days without neratinib treatment. In addition, in vitro data showed that neratinib was potent in killing human intestine-derived cell lines. Based on such findings, we hypothesized that neratinib downregulates intestinal CYP3A enzyme to cause excessive drug disposition, eventually leading to gut injury.

Ayurvedic formulations are widely used and perceived as safer medicine and subjected to be self-prescribed. However, recent reports have demonstrated adulterating these drugs with toxic quantities of heavy metals. To study the magnitude of the problem in Indian-manufactured Ayurvedic medications, we randomly collected common over-the-counter Ayurvedic preparations from the licensed Ayurvedic shops in the local markets of Chandigarh in 2017. The samples were analyzed to identify and quantify eight metal ions, including mercury, arsenic, lead, cadmium, zinc, iron, copper, and chromium, using inductively coupled plasma mass spectrometry in Postgraduate Institute of Medical Education and Research, Chandigarh. The permissible limit set by the Food and Agriculture Organization/World Health Organization (FAO/WHO) for herbal medicines was followed to define the high metal concentrations. Out of 43 Ayurvedic preparations, 42 were analyzed. Heavy metals were detected in all formulations. The median (range) concentrations (in μg/g or mg/kg) of the metals were quantified as follows- mercury, 13.52 (0.00–61 095.99); arsenic, 0.00 (0.00–1038.83); lead, 1.40 (0.00–57.09); zinc, 84.2200 (26.48–22 519.03); iron, 1356.21 (128.24–136 835.25); copper, 17.1450 (0.00–12 756.86) and chromium, 20.9050 (0.00–2717.58). The metal contents above the FAO/WHO-mandated limit for zinc, mercury, arsenic, and lead were detected in 35, 29, 6, and 2 formulations, respectively. All medications contained detectable quantities of zinc and iron. Copper was detected in all except one. Cadmium was not found in any sample. Ayurvedic medications have a high prevalence of heavy metals. An evaluation of the sources of contamination and the necessary drug safety regulations are required.

Silicosis is a chronic irreversible pulmonary disease caused by the inhalation of silica crystals in occupational settings in most cases. Persistent inflammation in the alveolar space is considered to be the major reason for tissue damage and lung fibrogenesis. The mechanisms by which silica exposure activates immune cells are not well understood. Here, we employed an in vivo silicosis disease model by intratracheal instillation of a large dose of silica suspension in rats and explored the involvement of inflammasome activation. Marked leukocyte infiltration and edema were observed 3 days following silica exposure in treated animals compared to controls. Using this model, we compared the expression of inflammasome sensors (AIM2 and NLRP3) and effector protein (caspase-1) by western blot and immunohistochemical staining using the lung homogenates and lung tissue sections. Our results demonstrated that following acute silica exposure, AIM2, NLRP3 and caspase-1 expressions were increased in macrophages or/and lung epithelial cells compared to control animals. We also analyzed interleukin 1β expression using lung homogenates, and significant increase in interleukin 1β was observed in 3-day silica-exposed rats. The activation of inflammasome sensors AIM2 and NLRP3 suggested to us that blocking these activators may attenuate silica-associated tissue damage and inflammation.

The amyloid beta precursor protein (APP) plays a pathophysiological role in the development of Alzheimer’s disease as well as a physiological role in neuronal growth and synaptogenesis. The aryl hydrocarbon receptor (AhR)/WNT/Catenin Beta 1 (CTNNB1)/Notch signaling pathways stamp in many functions, including development and growth of neurons. However, the regulatory role of AhR-/WNT-/CTNNB1-/Notch-induced APP expression and its influence on hippocampal-dependent learning and memory deficits is not clear. Male BALB/C mice received 6-formylindolo[3,2-b]carbazole (an AhR agonist), CH223191(an AhR antagonist), DAPT (an inhibitor of Notch signaling), and XAV-939 (a WNT pathway inhibitor) at a single dose of 100 μg/kg, 1, 5 , and 5 mg/kg of body weight, respectively, via intraperitoneal injection alone or in combination. Gene expression analyses and protein assay were performed on the 7th and 29th days. To assess the hippocampal-dependent memory, all six mice also underwent contextual fear conditioning on the 28th day after treatments. Our results showed that endogenous ligand of AhR has a regulatory effect on APP gene. Also, the interaction of AhR/WNT/CTNNB1 has a positive regulatory effect, but Notch has a negative regulatory effect on the mRNA and protein expression of APP, which have a correlation with mice’s learning skills and memory.

© 2021 The Author(s). Published by Oxford University Press. All rights reserved.Resveratrol is a chemical that attracts attention due to its antioxidative, anti-inflammatory, and estrogenic/antiestrogenic properties. In the present study, it was aimed to investigate developmental and reproductive effects (developmental periods, average numbers of offspring, sex ratios) of resveratrol in Drosophila melanogaster. Their larvae were exposed to 50, 100, and 200 μM of resveratrol. Resveratrol treatments did not affect pupation and maturation rate (P > 0.05) statistically. But the pupation and maturation times were significantly extended at all doses (P < 0.05). Also, 100 and 200 μM resveratrol treatments resulted in a significant decrease in the number of offspring (P < 0.05). The results reveal that resveratrol, which is generally known for its positive effects, may have negative effects on the development and reproduction of invertebrates. The results of this study support the idea that resveratrol may act as an endocrine disruptor, as it is a phytoestrogen.

The retina plays a key role in human vision. It is composed of cells that are essential for vision signal generation. Thus far, conventional medications have been ineffective for treating retinal diseases because of the intrinsic blood–retinal barrier. Nanoparticles (NPs) are promising effective platforms for ocular drug delivery. However, nanotoxicity in the retinal tissue has not received much attention. This study used R28 cells (a retinal precursor cell line that originated from rats) to investigate the safety of two commonly used types of NPs: silica nanoparticles (SiO2NPs, 100 nm) and titanium dioxide nanoparticles (TiO2NPs, 100 nm). Cellular viability and reactive oxygen species generation were measured after 24, 48, and 72 h of exposure to each NP. Cellular autophagy and the mTOR pathways were evaluated. The retinal toxicity of the NPs was investigated in vivo in rat models. Both types of NPs were found to induce significant dose-dependent toxicity on the R28 cells. A significant elevation of reactive oxygen species generation was also observed. Increased autophagy and decreased mTOR phosphorylation were observed after SiO2NPs and TiO2NPs exposure. The diffuse apoptosis of the retinal cellular layers was detected after intravitreal injection.

Background A sensitive method to investigate cellular stress and cytotoxicity is based on measuring mitochondrial membrane potential. Recently, JC-10, was developed to measure mitochondrial membrane potential in vitro and used as an indicator for cytotoxicity. Yet, JC-10 has never been used in vivo (whole organism). In normal cells, JC-10 concentrates in the mitochondrial matrix, where it forms red fluorescent aggregates. However, in apoptotic/necrotic cells, JC-10 diffuses out of the mitochondria, changes to monomeric form, and stains cells in green. Here, we aimed to develop and optimize a JC-10 assay to measure cytotoxicity in zebrafish embryo. We also investigated the effectiveness of JC-10 assay by comparing it to common cytotoxicity assays. Methods Zebrafish embryos were exposed to a toxic surfactant AEO-7 at no observed effect concentration (6.4 μg/L), and then cytotoxicity was measured using (i) JC-10 mitochondrial assay, (ii) acridine orange (AO), (iii) TUNEL assay, and (iv) measuring the level of Hsp70 by western blotting. Results As compared to the negative control, embryos treated with NOEC of AEO-7 did not show significant cytotoxicity when assessed by AO, TUNEL or western blotting. However, when JC-10 was used under the same experimental conditions, a significant increase of green:red fluorescent ratio signal was detected in the AEO-7 treated embryos, indicating mitochondrial damage and cellular cytotoxicity. Noteworthy, the observed green: red ratio increase was dose dependent, suggesting specificity of the JC-10 assay. Conclusion JC-10 is a sensitive in vivo method, thus, can be used as surrogate assay to measure cytotoxicity in whole zebrafish embryos.

Widespread application of hexaconazole for agriculture purpose poses a threat to human health by disrupting normal endocrine homeostasis. To avoid adverse health effects on human, it is crucial to identify the effects of hexaconazole on key enzymes responsible for steroidal hormone synthesis. In view of this, present study was conducted to investigate the interaction mechanisms of hexaconazole with key enzymes in comparison with their food drug administration (FDA) approved inhibitor by molecular docking and molecular dynamics simulations. Results indicate that hexaconazole contacts with the active site of the key enzymes required for steroidal hormonal synthesis. Results pertaining to root-mean-square deviation, root-mean-square calculation, radius of gyration, hydrogen bonding and solvent accessible surface area exhibited that the interaction pattern and stability of interaction of hexaconazole was similar to enzyme specific inhibitor. In addition, ligand and enzyme complex interaction energy of hexaconazole was almost similar to key enzyme and FDA-approved enzyme specific inhibitor complex. This study offers a molecular level of understanding of hexaconazole with different enzymes required for steroidal hormonal synthesis. Findings of the study clearly suggest that hexaconazole has efficacy to stably interact with various enzyme required to progress the pathway of hormonal synthesis. If incessant exposure of hexaconazole occurs during agricultural work it may lead to ravage hormonal synthesis or potent endocrine disruption. The result of binding energy and complex interaction energy is depicted in the graphical abstract.

Laghu vishagarbha taila (LVT) is a medicated oil preparation used in the Ayurvedic system of medicine and applied topically for the treatment of painful musculoskeletal and inflammatory disorders. It contains some mildly poisonous phytoconstituents which may show untoward effects upon application. The present study evaluated the toxicity of LVT in the acute, subacute, and subchronic dermal toxicity study in Wistar rats. LVT was tested for its compliance using physicochemical and analytical parameters as per standard methods prescribed in Ayurvedic Pharmacopoeia of India, while acute, subacute, and subchronic toxicity studies were carried out as per OECD 402, 410, and 411 guidelines, respectively. In the acute dermal toxicity study, a single dose of LVT (2000 mg/kg) was applied topically to rats, while in subacute and subchronic dermal toxicity study, the rats were topically applied LVT (1000 mg/kg) up to 28 and 90 days, respectively. LVT did not cause any alterations in clinical signs and no mortality or moribund stage was observed. The change in weekly body weight was insignificant compared with the vehicle control group. In subacute and subchronic dermal toxicity study, there were no significant changes in behavior, body weight, feed consumption, biochemical and hematological parameters, organ weight, and histological parameters compared with vehicle control rats. Topical application of single and repeated doses of LVT in rats did not exhibit adverse effects and suggests that the LD50 of LVT is more than 2000 mg/kg in the acute dose and NOAEL is more than 1000 mg/kg/day in repeated dose application.

Natural antioxidant products play a vital role in the treatment and prevention of cancer disease because they have no side effects. This study aimed to compare the chemoprotective effect of Spirulina platensis (SP) and garlic against hepatocellular carcinoma (HCC) in rats. This study was being done by using 60 male Wistar rats and divided into four groups. Group (I): normal group. Group (II): HCC group induced by injection of a single dose of DEN (200 mg/kg/I.P) and after 14 days injected CCl4 (1 mg/kg/I.P) 3 times/week/six weeks. Group (III): HCC group received SP orally at a dose (500 mg/kg). Group (IV): HCC group received garlic (250 mg/kg) orally. The results revealed that the Spirulina and garlic treatment have a significant decrease in Glutamate pyruvate transaminase, Glutamate oxaloacetate transaminase, GGT, LDH, and the Malondialdehyde (MDA) activity, and furthermore, a significant increase in the total protein level, the superoxide dismutase (SOD), and Catalase (CAT) activity nearly to normal activity. Furthermore, the hepatic expression of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase, transforming growth factor-beta (TGF-β1), Heat Shock Protein glycoprotein 96 (HSPgp96), and Glypican 3 (GP3) were down regulated by the Spirulina and garlic treatment in comparison with those in HCC group. All findings reported that the chemoprotective of both Spirulina and garlic that have nearly the same effect may be due to antioxidant activity and inhibition of lipid peroxidation, amelioration of pro-inflammatory cytokine, HSPgp96, and GP3.

In present study, diverse Litchi chinensis-mediated nanostructures in combination with 5-fluorouracil drug were fabricated viz. Au, Se, Ag, Ag–Se, Ag–Au, 5-FU Ag–Se and 5-FU Ag–Au with subsequent characterization and scrutinization of their anticarcinogenic capabilities. UV–Visible spectroscopic analysis confirmed the state transition for each precursor salt. XRD and transmission electron microscopy analysis revealed spherical/quasispherical nanostructures with monoclinic crystalline organization ranged between 18 nm and 38 nm. FTIR analysis revealed fabricated nanoparticles to be capped with various phytoconstituents. DLS and Zeta potential analysis of unloaded and drug-loaded bielemental nanoparticles (BNPs) showed comparatively large hydrodynamic particle size distribution and sufficient stability of nanoparticles. BNPs showed promising lethality concentrations for brine shrimp (LC50

Xylitol has reported to decrease gingival inflammation and nasopharyngeal pneumonia, which indicated that xylitol may have potential application in respiratory diseases. Although some studies have reported the inhalation toxicity of xylitol, however, the longest period tested was only for 14 days. The inhalation toxicity of xylitol is insufficient. This work investigated the potential subacute toxicity of xylitol according to the OECD TG 412. Rats were randomly divided into a control group and different dosage groups (2 g/m3, 3 g/m3, 5 g/m3), and exposed for 6 hours/day, 5 days/week for 28 days. At the end of the exposure or recovery period, clinical signs, mortality, body weight, food consumption, hematology, blood biochemistry, gross pathology, organ weight, and histopathology were examined. Compared with the control group, rats of both sexes in the exposure groups exhibited no significant changes in body weight, organ mass, and food uptake. After the xylitol exposure, aspartate aminotransferase activity in the xylitol group (3 g/m3) was significantly higher than that in the control group, while other blood indicators and pathological changes of liver and the analysis of the recovery group showed no changes, suggesting that xylitol exerted no observable toxic effect on the liver. Finally, other observations including the histopathology of target organs and hematology also showed no alterations. These results indicated that xylitol had no significant inhalation toxicity at doses up to 5 g/m3. These subacute inhalation toxicity results of xylitol showed that its no-observed-adverse-effect concentration (NOAEC) in rats was determined to 5 g/m3.

Tramadol (TR) is a centrally acting analgesic drug that is used to relieve pain. The therapeutic (0.1–0.8 mg/l), toxic (1–2 mg/l) and lethal (>2 mg/l) ranges were reported for TR. The present study was designed to evaluate which doses of TR can induce liver mitochondrial toxicity. Mitochondria were isolated from the five rats’ liver and were incubated with therapeutic to lethal concentrations (1.7–600 μM) of TR. Biomarkers of oxidative stress including: reactive oxygen species (ROS), lipid peroxidation (LPO), protein carbonyl content, glutathione (GSH) content, mitochondrial function, mitochondrial membrane potential (MMP) and mitochondrial swelling were assessed. Our results showed that ROS and LPO at 100 μM and protein carbonylation at 600 μM concentrations of TR were significantly increased. GSH was decreased specifically at 600 μM concentration. Mitochondrial function, MMP and mitochondrial swelling decreased in isolated rat liver mitochondria after exposure to 100 and 300 μM, respectively. This study suggested that TR at therapeutic and toxic levels by single exposure could not induce mitochondrial toxicity. But, in lethal concentration (≥100 μM), TR induced oxidative damage and mitochondria dysfunction. This study suggested that ROS overproduction by increasing of TR concentration induced mitochondrial dysfunction and caused mitochondrial damage via Complex II and membrane permeability transition pores disorders, MMP collapse and mitochondria swelling.

Cancer is one of the leading causes of death in the world. It is very important to find drugs with high efficiency, low toxicity, and low side effects for the treatment of cancer. Flavonoids and their derivatives with broad biological functions have been recognized as anti-tumor chemicals. 8-Formylophiopogonanone B (8-FOB), a naturally existed homoisoflavonoids with rarely known biological functions, needs pharmacological evaluation. In order to explore the possible anti-tumor action of 8-FOB, we used six types of tumor cells to evaluate in vitro effects of this agent on cell viability and tested the effects on clone formation ability, scratching wound-healing, and apoptosis. In an attempt to elucidate the mechanism of pharmacological action, we examined 8-FOB-induced intracellular oxidative stress and -disrupted mitochondrial function. Results suggested that 8-FOB could suppress tumor cell viability, inhibit cell migration and invasion, induce apoptosis, and elicit intracellular ROS production. Among these six types of tumor cells, the nasopharyngeal carcinoma CNE-1 cells were the most sensitive cancer cells to 8-FOB treatment. Intracellular ROS production played a pivotal role in the anti-tumor action of 8-FOB. Our present study is the first to document that 8-FOB has anti-tumor activity in vitro and increases intracellular ROS production, which might be responsible for its anti-tumor action. The anti-tumor pharmacological effect of 8-FOB is worthy of further investigation.

Chloropropanols such as 3-monochloropropane-1,2-diol (3-MCPD) and 1,3-dichloro-2-propanol (1,3-DCP) have drawn increasing attention due to their release from food contact paper and their potential carcinogenic effects. In this study, the effects were investigated of water extraction conditions on release of chloropropanols from food contact paper, and the extraction efficiencies of chloropropanols by water extract and migration method were compared. Cold water was found to be more severe than hot water for extraction of chloropropanols, with the highest water extraction value obtained at 23°C. Two hours of extraction was sufficient as the chloropropanols can be fully extracted from food contact paper within a short period of time. Increase of temperature in the range of 10°C-60°C had little impact on release of chloropropanols, however, the extraction of chloropropanols decreased when high temperatures (80°C or above) were applied due to volatilisation losses. Hence, attention should be paid when choosing extract conditions representing the worst-case scenario. The water extraction value using EN 645 method gives higher results compared to migration test described in GB 31604.1 and GB 5009.156, suggesting that the water extract method was probably more severe. For migration test, aqueous-based simulants were found to be more conservative than oil-based simulants, suggesting the conventional experiment conditions applicable for compliance test of chloropropanols migration can be simplified and optimised.

Pentachlorophenol (PCP) is a broad spectrum biocide that has many domestic and industrial applications. PCP enters the environment due to its wide use, especially as a wood preservative. Human exposure to PCP is through contaminated water and adulterated food products. PCP is highly toxic and is classified as class 2B or probable human carcinogen. In this study, we explored the effect of PCP on rat intestine. Adult rats were orally given different doses of PCP (25–150-mg/kg body weight/day) in corn oil for 5 days, whereas controls were given similar amount of corn oil. The rats were sacrificed 24 h after the last treatment. A marked increase in lipid peroxidation, carbonyl content, and hydrogen peroxide level was seen. The glutathione and sulfhydryl group content was decreased in all PCP treated groups. This strongly suggests the generation of reactive oxygen species (ROS) in the intestine. PCP administration suppressed carbohydrate metabolism, inhibited enzymes of brush border membrane (BBM), and antioxidant defense system. It also led to increase in DNA damage, which was evident from comet assay, DNA-protein cross-linking, and DNA fragmentation. Histological studies supported the biochemical results showing marked dose-dependent tissue damage in intestines from PCP treated animals. This study reports for the first time that oral administration of PCP induces ROS, impairs the antioxidant system, damages DNA, and alters the enzyme activities of BBM and metabolic pathways in rat intestine.

Background Automobile repair workshops contribute immensely to the generation of soil and water contamination. This study was conducted to compare the soil microbial load, heavy metals, and consequent toxicological effects, in three (3) automobile mechanic sites. Method Soil samples were randomly collected from 3 different auto mechanic workshop in Abeokuta town of Ogun-State, Nigeria. Bacterial and fungal counts were done via standard procedures. High-performance liquid chromatography was employed for the aflatoxin quantification. Also, 24 Wistar rats were divided into 4 groups (n = 6), group 1—Control animals: orally administered distilled water, Group 2—administered soil sample solution from Ita Oshin mechanic site (I M), Group 3—administered soil sample solution from Ajebo mechanic site (A M), while Group 4—administered soil sample solution from Laderin mechanic site (L M), for two (2) weeks. Conventional methods were used to determine some physical and biochemical parameters in the rat’s serum and tissues. Results Eight bacterial and fungal genera were identified from the soil samples with Bacillus subtilis and Aspergillus niger occurring most frequently. The levels of heavy metals (lead, zinc, chromium, and cadmium) analyzed were higher than the WHO permissible heavy metal limits in all samples. The activity of liver function enzymes ALP, AST, and ALT was significantly increased in the serum of animals exposed to the 3 soil solution samples when compared with the control group, with the highest recorded at Site II. Conclusion High level of heavy metals and aflatoxins could predispose to several health-related hazards when humans are exposed to contaminated soil solutions around and within automobile mechanic areas.

The health and environmental impacts of the increasing commercial use of silver nanoparticles (AgNPs) are a growing concern. Methyl mercury (MeHg) is a potent toxin that biotransforms from mercury or inorganic mercury compounds in waterways and causes dangerous environmental contamination. However, the potential interactions and combined effects of AgNPs and MeHg are yet to be established. In the current study, we showed that low/non-embryotoxic doses of AgNPs and MeHg interact synergistically to induce embryotoxicity and further explored the underlying mechanisms affecting mouse embryo development. Notably, co-treatment with noncytotoxic concentrations of AgNPs (10 μM) and MeHg (0.1 μM) triggered apoptotic processes and embryotoxicity in mouse blastocysts and evoked intracellular reactive oxygen species (ROS) generation, which was effectively blocked by preincubation with 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), a classic antioxidant. Further experiments demonstrated that ROS serve as a key upstream inducer of endoplasmic reticulum (ER) stress and mitochondria-dependent apoptotic processes in AgNP/MeHg-induced injury of mouse embryo implantation and pre- and postimplantation development. Our results collectively indicate that AgNP and MeHg at non-embryotoxic concentrations can synergistically evoke ROS, ultimately causing embryotoxicity through promotion of ER stress and mitochondria-dependent apoptotic signaling cascades.

Nonylphenol (NP) is an endocrine disrupting chemical, which widely exists in environment and can result in multiple system dysfunction. Pancreas as one of the most important organs is sensitive to NP, while the detail toxic effect is still less studied. Previously, we unveiled nonylphenol causes pancreatic damage in rats, herein, we further explore the potential mechanism and seek protection strategy in vitro. Insulinoma (INS-1) cells exposed to NP were observed to suffer oxidative stress and mitochondrial dysfunction, as reflected by the abnormal levels of reactive oxygen species, malonic dialdehyde, superoxide dismutase, Ca2+, and mitochondrial membrane potential. Melatonin (MT) was found to alleviate NP-induced mitochondrial dysfunction and oxidative stress, further inhibit apoptosis and restore pancreas function. Mechanically, MT induced the MDM2-P53-P21 signaling, which upregulated the Nrf2 signaling pathway. In summary, our study clarified NP-induced INS-1 cells mitochondrial dysfunction and oxidative stress, which could be ameliorated by MT through MDM2-P53-P21 axis.

This study aimed to evaluate the possible protective effects of quercetin, a natural flavonoid, against nephrotoxicity induced by Di (2-ethylhexyl) phthalate (DEHP) in kidney tissue of rats and human embryonic kidney (HEK) 293 cell line. The HEK-293 cells were treated with different concentrations of quercetin 24 h before treatment with monoethylhexyl phthalate (MEHP). Male rats were treated with 200-mg/kg DEHP, 200-mg/kg DEHP plus quercetin (50 and 100 mg/kg), and 200-mg/kg DEHP plus vitamin E (20 mg/kg) for 45 days by gavage. Quercetin treatment reduced cytotoxicity and oxidative damage inducing by MEHP in HEK-293 cells. The in vivo findings showed that 100-mg/kg quercetin significantly suppressed DEHP-induced kidney damage. For exploring the involved mechanisms, the expressions of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) genes were determined via real-time Polymerase chain reaction (PCR) assay. High dose of quercetin significantly decreased the gene expressions of NF-κB and TNFα, whereas the alternations of Nrf2 and HO-1 gene expressions were not significant in quercetin groups in compared with DEHP group. These findings suggested that the suppression of DEHP-induced nephrotoxicity via quercetin is correlated, at least in part, with its potential to regulate NF-κB signaling pathway.

The cytogenetic study using hospital effluent was carried out engaging three cytogenetic end points—chromosomal aberration (CA) assay, mitotic indices (MIs), and micronucleus (MN) Analysis. These bioassays were performed in hematopoietic bone marrow cells of Mus musculus. The experiment commenced with the collection of hospital effluent from the final outlet when wastewater gets collected after undergoing treatment by a multistep process. The pure treated sample water was collected at different times between March 2019 to January 2020 and was given ad libitum to mice at its low (90% dilution) and high (pure form), i.e. 100% concentration for 3 different durations i.e. 7, 15, and 30 days, respectively. The results indicated a significant (P

This study examined if wheat germ oil (WGO) has gastroprotective impacts against ethanol-induced gastric ulcer in rats. Rats were assigned into control, WGO, ethanol, omeprazole + ethanol, and WGO + ethanol. WGO prevented gastric ulceration and damage induced by ethanol, the same effect induced by omeprazole, a widely known medication used for gastric ulcer treatment. WGO reduced gastric ulcer index, nitric oxide, and malondialdehyde levels in the stomach. WGO boosted the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Bcl2, and the antioxidants. WGO showed inflammatory and anti-inflammatory impacts through the control of interleukin (IL)-1β, Tumor necrosis factor alpha (TNF-α), and IL-10 that were altered in ethanol-administered rats. Ethanol up-regulated caspase-3 and nuclear factor-kappa B (NF-kB) expression and showed histopathological changes such as necrosis and mucosal degeneration that were mitigated by pre-administration of WGO. Moreover, WGO decreased gastric immunoreactivity of NF-kB and increased transforming growth factor beta-1 (TGF-β1) that were associated with upregulation of Nrf2, heme oxygenase-1 (HO-1), and antioxidant expression and production. In conclusion, WGO reduced ethanol-induced stomach toxicity by regulating genes involved in oxidative stress, inflammation, and apoptotic/antiapoptotic pathways.

One of the main antineoplastic chemotherapy medications is cisplatin, of which nephropathy is a major side effect. In this current study, we aim to investigate the molecular protective effect of Spirulina platensis (SP) on cisplatin-induced nephrotoxicity. In total, 48 healthy male albino rats were allocated into 4 groups. Group 1 received saline intraperitoneally (IP) twice per week (normal rats). Group 2 received SP (100 mg/kg BW orally). Group 3 were injected with cisplatin (1.5 mg/kg IP) twice per week. Group 4 received SP and on the 4th day received cisplatin (1.5 mg/kg IP) for 21 days. After 3 weeks of experiment, blood and renal tissues were taken for serum analysis, gene expression using qRT-polymerase chain reaction, and renal histopathology. As per our findings, it was found that SP significantly ameliorated the alterations in body weight, relative kidney weight, and the disturbance in examined renal markers. Furthermore, SP recovered and restored cisplatin-induced oxidative stress biomarkers (MDA and NO) and antioxidant activity (SOD and GSH) and cisplatin-induced upregulation in the gene expression of TNF-α, inducible nitric oxide synthase, TGF1-β, IL-1β, and IL-6. Interestingly, these gene expressions were ameliorated by the SP pre-administration. Furthermore, cisplatin upregulated pro-apoptotic gene Bax, whereas it downregulated anti-apoptotic gene Bcl2. Interestingly, SP mitigated this alteration in apoptosis and anti-apoptotic associated genes. Renal histopathology revealed the protective impacts of SP against cisplatin-induced severe glomerular congestion, hemorrhage, inflammatory cell infiltration, degeneration, and severe necrosis in renal glomeruli and tubules. In conclusion, SP has a protective effect against cisplatin-induced renal damage through modulating oxidative stress and anti-inflammatory, anti-necrotic, and anti-apoptotic-associated genes.

Background Cadmium (Cd) is a highly toxic heavy metal that adversely affects both human and animal health. Chronic cadmium exposure causes serious kidney damage. The current study investigated the protective role of cerium oxide nanoparticles (CeO2NPs) against cadmium chloride (CdCl2)-induced renal injury. Method One hundred and twenty male albino rats were divided into 6 equal groups. Group (C): considered as control group which was given distilled water orally. Group (NC.1 and NC.5): rats were injected i.p. with nanoceria at a dose of (0.1 and 0.5 mg/kg b.wt), respectively, twice a week for 2 weeks starting at the 15th day of the study. Group (Cd): rats were received CdCl2 orally (10 mg/kg b.wt) daily for 28 days. Groups (Cd + NC.1 and Cd + NC.5): rats were given CdCl2 orally (10 mg/kg b.wt) for 28 days and CeO2NPs by i.p. injection at a dose of (0.1 and 0.5 mg/kg b.wt), respectively, twice a week for 2 weeks started at the 15th day of the experiment. Results The Cd group exhibited a significant increase in the serum levels of IL-1β, KIM-1, Cys-C, and β2-MG, downregulation of the antioxidant initiator genes such as Nrf-2, and up-regulation of apoptosis markers such as nibrin gene (NBN). Urine examination showed a high level of microalbuminuria, abnormal physical, chemical, and microscopical changes in comparison with control groups. Conculsion Remarkably, posttreatment with CeO2NPs showed significant improvement in kidney histopathological picture and relieved the alterations in kidney biomarkers, inflammatory markers, urine abnormalities, and expressions of different genes as Nrf-2 and NBN.

Zoletil® (ZOL) is a combination drug of tiletamine, a dissociative anesthetic and zolazepam, a minor tranquilize, which has been used to induce short-term anesthesia in various animals. Depending on the administered dose, the effects of ZOL can range from sedation to anesthesia. Here, we aimed to determine the neurotoxicity of ZOL and elucidate its mechanism of action using BV-2 microglial cells. The results of MTT reduction assay and TUNEL staining revealed that ZOL induced neuronal toxicity and apoptosis in BV-2 cells. ZOL caused apoptosis via phosphorylation of c-Jun N-terminal kinase, increased ratio of Bax to Bcl-2, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase. Furthermore, reactive oxygen species were involved in ZOL-induced neuronal cell death as assessed by 2′,7′-dichlorofluorescein diacetate staining. Moreover, BV-2 cells treated with ZOL exhibited increased expression of inflammatory enzymes, such as inducible nitric oxide synthase and cyclooxygenase-2, along with subsequent production of nitric oxide and prostaglandin E2. ZOL upregulated the expression of interleukin-1β, a proinflammatory cytokine. With respect to its molecular mechanism, ZOL increased the nuclear translocation and DNA binding of redox-sensitive transcription factor NF-κB, which seemed to be mediated by activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. These findings suggest that ZOL leads to apoptosis in BV-2 cells by inducing oxidative stress and inflammatory responses.

Di-(2-ethylhexyl) phthalate (DEHP) is one of the ubiquitous pollutants worldwide. This study aimed to clarify the potential thyroid disrupting effect of DEHP and explore the probable ameliorative effects of selenium nanoparticles (Se-NPs) and curcumin nanoparticles (CUR-NPs). Forty-two male albino rats were divided into seven groups (n = 6): Group I (negative control); group (II) orally received DEHP (500 mg/kg BW, dissolved in corn oil); Group (III) orally received Se-NPs (.2 mg/kg BW) in combination with DEHP; Group (IV) orally received CUR-NPs (15 mg/kg BW) alongside with DEHP; Group V (corn oil); Group VI (Se-NPs) and Group VII (CUR-NPs). The duration of the experiment was 30 days. DEHP administration significantly decreased serum free T4 and significantly increased serum free T3 as compared to control group, whereas thyroid-stimulating hormone showed no significant change. DEHP disrupted redox status leading to accumulation of malondialdehyde and depletion of reduced glutathione. Histologically, the effect of DEHP on thyroid follicles was confirmed by light and electron microscopic examination and morphometric analysis. Se-NPs slightly improved thyroid parameters as well as redox status. CUR-NPS reinstated the values of all studied thyroid parameters to nearly control levels. This research provides Se-NPs and CUR-NPs as novel protective agents against DEHP-thyroid disrupting effects.

To investigate the effect of nonylphenol (NP) exposure on the colonic mucosa in rats, and the protective effects of Guizhou zinc-selenium tea (Zn-Se tea) on the damage induced by NP, sixty Sprague–Dawley rats were randomly divided into 6 groups (n = 10 in each group): control group (corn oil), and rats gavaged with NP at the doses of 0.4 mg/kg/d (Low NP group), 4 mg/kg/d (Medium NP group), 40 mg/kg/d (High NP group), and 40 mg/kg NP combined with green tea group at the doses of 0.2 g/ml (NP + GT group) and 0.2 g/ml Zn-Se tea group (NP + ZST group). NP at 40 mg/kg/d was administered to the tea groups for 3 months, followed by NP + green tea and NP + Zn-Se tea for 4 months, and the rest of the groups were gavaged for 7 months. With the increase of NP concentration, NP accumulation in colon gradually increased (P

Kefiran is a polysaccharide present in kefir grains that have been widely explored due to its potential health benefits. The objective of this work was to characterize and quantify the components present in the ethanolic extract of milk kefir grains; to study its pharmacokinetic and toxicological properties in silico and evaluate the acute toxicity of the kefiran in zebrafish. The prediction of pharmacokinetic properties was performed by QikProp software. In silico toxicity assessment was performed using the DEREK (deductive estimate of risk from existing knowledge) software. In the chromatographic, kefiran was identified as the major component. Results showed that the kefiran had low human oral absorption and intestinal absorption its due poor solubility profile; low logP value, indicating its lipophilicity and the low MDCK and Caco-2 cells permability, and unable to cross the blood–brain barrier. Kefiran did not present any structural warning for in silico toxicity. In zebrafish, the dose of 2,000 mg/kg of kefiran produced nonsignificant alterations in the analyzed organs. It can be said then that kefiran has an acceptable degree of safety for use in the development of drugs or functional foods. Further research such as in vivo testing to confirm its pharmacological potential is currently underway.

NaAsO2-induced liver damage leads to autophagy, which plays an important role in cell quality control. Mitophagy plays an important role in hepatocyte damage, and PINK1 and Parkin constitute an important pathway in mitophagy. PINK1 selectively degrades abnormal mitochondria, and Parkin can recognize damaged mitochondria. However, the mechanism underlying the involvement of PINK1/Parkin in NaAsO2-induced mitophagy is unclear. Transfection plasmids containing dsRNA were used to interfere with the expression of Parkin in the following groups: the empty plasmid group was established by add the empty plasmid only, the PINK1-knockdown (KD) group was established by adding 5 μg of PINK1 dsRNA and then by adding 10 mM NaAsO2, and the Parkin-KD group was established by adding 5 μg of Parkin dsRNA and then by adding 10 mM NaAsO2. The expression of PINK1 and Parkin in autophagy was detected by western blotting and immunofluorescence staining. The ultrastructures of autophagosomes and mitochondria were observed by transmission electron microscopy. The successful KD of PINK1 and Parkin aggravated the NaAsO2-induced damage to mitophagy. The degeneration of mitochondrial vacuoles and the appearance of autophagosomes were detected in the NaAsO2, NaAsO2 + PINK1-KD and NaAsO2 + Parkin-KD groups. NaAsO2 can induce mitophagy in rat hepatocytes, and the silencing of PINK1 and Parkin can aggravate mitochondrial damage during this process. This study explored the mechanism of NaAsO2-induced mitophagy in BRL-3A cells after PINK1 and Parkin gene silencing.

Silicosis is a devastating disease that, without effective treatment, endangers the health of miners. Therefore, studies exploring the pathogenesis of SiO2-induced pulmonary fibrosis are necessary to develop treatments for silicosis. Although macrophages are known to play a pivotal role in SiO2-induced pulmonary fibrosis, the underlying mechanism remains unknown. Here, we explored whether ferroptosis was involved in SiO2-induced pulmonary fibrosis. To this end, C57BL/6 mice and mouse macrophage (RAW264.7) cells and mouse lung fibroblast (MLF) cells were subjected to iron content, cell viability, enzyme-linked immunosorbent assay, immunofluorescence staining, histological, western blotting, quantitative reverse transcription-PCR, reactive oxygen species, and lipid peroxidation analysis. In vivo, SiO2 was found to damage the lung alveolar structure, cause infiltration of inflammatory cells, and facilitate fibrosis. Additionally, it increased the iron concentration and lipid peroxidation as well as altered the expression of ferroptosis-related genes and the mitochondrial morphology in macrophages. In vitro, ferroptosis occurred in SiO2-treated RAW264.7 cells, which showed iron overload, lipid peroxidation, and gene alterations. Furthermore, ferrostatin-1 (Fer-1) attenuated ferroptosis in SiO2-treated RAW264.7 cells by inhibiting lipid peroxidation and cell death and regulating ferroptosis-related genes expression, in addition to attenuating the secretion of pro-fibrotic cytokines and fibrosis. Collectively, SiO2 induces ferroptosis in macrophages, which leads to the secretion of pro-fibrotic cytokines and fibrosis.

Alternariol (AOH) and ochratoxin A (OTA), two mycotoxins found in many foods worldwide, exhibit cytotoxicity and embryotoxicity, triggering apoptosis and cell cycle arrest in several mammalian cells and mouse embryos. The absorption rate of AOH from dietary foodstuff is low, meaning that the amount of AOH obtained from the diet rarely approaches the cytotoxic threshold. Thus, the potential harm of dietary consumption of AOH is generally neglected. However, previous findings from our group and others led us to question whether a low dosage of AOH could aggravate the cytotoxicity of other mycotoxins. In the present study, we examined how low dosages of AOH affected OTA-triggered apoptosis and embryotoxicity and investigated the underlying regulatory mechanism in mouse blastocysts. Our results revealed that non-cytotoxic concentrations of AOH (1 and 2 μM) could enhance OTA (8 μM)-triggered apoptotic processes and embryotoxicity in mouse blastocysts. We also found that AOH can enhance OTA-evoked intracellular reactive oxygen species (ROS) generation and that this could be prevented by pretreatment with the potent ROS scavenger, N-acetylcysteine. Finally, we observed that this ROS generation acts as a key inducer of caspase-dependent apoptotic processes and subsequent impairments of embryo implantation and pre- and post-implantation embryonic development. In sum, our results show that non-cytotoxic dosages of AOH can aggravate OTA-triggered apoptosis and embryotoxicity through ROS- and caspase-dependent signaling pathways.

High-fat diet (HFD) is the primary cause of metabolic syndrome associated chronic kidney disease. This study aimed to investigate the pathogenesis of HFD-induced kidney injury. ApoE−/− mice were fed with HFD and kidney damage was examined. In addition, HK-2 human renal proximal tubular epithelial cells were treated with fructose and receptor of advanced glycation end products (RAGE) siRNA. The results showed that HFD increased body weight, blood glucose and insulin resistance in ApoE−/− mice. The kidney damage was associated with increased oxidative stress and strong staining of RAGE and NF-κB in kidney tissues, as well as high serum levels of TNF-α, IL-1β and IL-6. Western-blot analysis showed that HFD increased the levels of RAGE, p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9 but decreased the levels of Bcl-2 in kidney tissues. In HK-2 cells, fructose promoted the secretion of TNF-α, IL-1β and IL-6 and increased the levels of RAGE, p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9, but decreased the levels of Bcl-2. Moreover, RAGE siRNA could attenuate increased levels of p-IκBα, p-NF-κB, bax, caspase-3 and caspase-9 while restore decreased levels of Bcl-2 in fructose-treated HK-2 cells. In conclusion, HFD causes kidney injury by promoting oxidative stress, inflammation and apoptosis possibly through the activation of RAGE/NF-κB pathway.

Deuteration is a chemical modification strategy that has recently gained traction in drug development. The replacement of one or more hydrogen atom(s) in a drug molecule with its heavier stable isotope deuterium can enhance its metabolic stability and pharmacokinetic properties. However, it remains uninterrogated if rational deuteration at bioactivation “hot-spots” could attenuate its associated toxicological consequences. Here, our preliminary screening with benzofuran antiarrhythmic agents first revealed that dronedarone and its major metabolite N-desbutyldronedarone elicited a greater loss of viability and cytotoxicity in human hepatoma G2 (HepG2) cells as compared with amiodarone and its corresponding metabolite N-desethylamiodarone. A comparison of dronedarone and its in-house synthesized deuterated analogue (termed poyendarone) demonstrated that deuteration could attenuate its in vitro toxicity in HepG2 cells by modulating the extent of mitochondrial dysfunction, reducing the dissipation of mitochondrial membrane potential, and evoking a distinct apoptotic kinetic signature. Furthermore, although pretreatment with the CYP3A inducer rifampicin or the substitution of glucose with galactose in the growth media significantly augmented the loss of cell viability elicited by dronedarone and poyendarone, a lower loss of cell viability was consistently observed in poyendarone across all concentrations. Taken together, our preliminary investigations suggested that the rational deuteration of dronedarone at its benzofuran ring reduces aberrant cytochrome P450 3A4/5-mediated bioactivation, which attenuated its mitochondrial toxicity in human hepatic HepG2 cells.

Sensory irritation is an acute adverse effect leading to temporary disability posed by riot control agents in various deployable forms are utilized by defense personal in violent mob attacks but their irreversible toxic effects and risk assessment have been a matter of concern. These intimidating risks of available riot control agents have led to exploring the pulmonary toxicity profile of the oil in water emulsion formulation developed for vicious crowd controls containing an irritant oleoresin capsicum, a malodorant (skatole), and a commercial dye, followed by characterization using standard methods. Nonlethal riot control combinational formulation (NCF) has been aimed to be the best possible low-lethal alternative for riot control measures. In this study, 30 min of acute inhalation exposure of NCF was given to Wistar rats and various respiratory parameters like lung dynamics, bronchoalveolar lavage fluid (BALF) cytological assays, pro-inflammatory cytokines estimation, antioxidant activity, collagen accumulation, cytotoxicity, in vivo lung imaging, western blot, histology of lung tissue, etc. were investigated to validate its potentiality and rate of irritation reversibility as nonlethal agents. An exaggerated physiological change like sensory irritation, changes in lung functional variables, increased pro-inflammatory cytokines, etc. were noticed initially without airway obstruction as the expression of nociceptive TRPV1 protein did not alter the physiological regulation of protective proteins like Nrf2 and HO-1 and also no abnormality was found in lung tissue architecture. In conclusion, it can be stated that this formulation can be explored as a nonlethal riot control agent intending to generate discomfort but with early reversibility of sensory irritation and no recurrence of toxicity.