Melatonin counteracts polyethylene microplastics induced adreno-cortical damage in male albino rats.

There are various substances that can disrupt the homeostatic mechanisms of the body, defined as endocrine-disrupting chemicals (EDCs). The persistent nature of microplastics (MPs) is a cause for concern due to their ability to accumulate in food chains and widespread use, making their toxic effects particularly alarming. The potential of MPs for disrupting the endocrine system was observed in multiple tissues. Moreover, the adrenal gland is known to be extremely sensitive to EDCs, while with the effect of MPs on the adrenal gland has not previously been studied. This study aimed to highlight the potential polyethylene microplastics (PE-MPs) induced adreno-toxic effects rather than exploring the implicated mechanisms and concluding if melatonin (Mel) can afford protection against PE-MPs induced adreno-toxicity. To fulfill the goal, six groups of rats were used; control, Mel, PE-MPs (3.75 mg/kg), PE-MPs (15 mg/kg), PE-MPs (3.75 mg/kg) +Mel, and PE-MPs (15 mg/kg) +Mel. PE-MPs induced toxic changes in the adrenal cortex, which was evident by increased adrenal weight, histopathological examination, and ultrastructural changes detected by electron microscope. A reduction in serum cortisol and an increase in serum adrenocorticotropic hormone resulted from the adreno-toxic effects of PE-MPs. Mechanisms may include the reduction of steroidogenesis-related genes, as PE-MPs drastically reduce mRNA levels of StAR, Nr0b1, Cyp11A1, as well as Cyp11B1. Also, oxidative stress that results from PE-MPs is associated with higher rates of lipid peroxidation and decreased superoxide dismutase and glutathione. PE-MPs inflammatory effect was illustrated by elevated expression of IL-1ß and NF-kB, detected by immunohistochemical staining, in addition to increased expression of caspase-3 and mRNA of Bax, markers of proapoptotic activity. The impacts of PE-MPs were relatively dose-related, with the higher dose showing more significant toxicity than the lower one. Mel treatment was associated with a substantial amelioration of PE-MPs-induced toxic changes. Collectively, this study fills the knowledge gap about the MPs-induced adrenal cortex and elucidates various related toxic mechanisms. It also supports Mel's potential protective activity through antioxidant, anti-inflammatory, anti-apoptotic, and gene transcription regulatory effects.

Pentoxifylline and thiamine ameliorate rhabdomyolysis-induced acute kidney injury in rats via suppressing TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis.

Acute kidney injury (AKI) is a common complication of rhabdomyolysis (RM), a syndrome characterized by skeletal muscle damage resulting in renal tubular oxidative stress, inflammation, and activated toll like receptor-4 (TLR-4) and NOD-like receptor protein-3 (NLRP-3) inflammasome. Pyroptosis is a programmed cell death mediated by NLRP-3 leading to the activation of caspase-1 and gasdermin D (GSDMD), the hallmark of pyroptosis. This study aims to investigate the renoprotective effects of two antioxidants; pentoxifylline (PTX) and thiamine (TM) via targeting the aforementioned pathways. RM-AKI was induced in male Albino Wistar rats by intramuscular injection of glycerol (50% v/v, 10 ml/kg). PTX (100 mg/kg, oral) and TM (25 mg/kg, i.p) were administered for 12 days prior glycerol injection and continued for 3 days following induction of RM-AKI. Serum creatinine, blood urea nitrogen (BUN), creatin kinase, lipid peroxides, total antioxidant activity, inflammatory markers (tumor necrosis factor-α, interleukin-1ß, and nuclear factor kappa B), TLR4, NLRP-3, caspase-1, GSDMD and c-myc (an apoptotic marker) were estimated. Compared to AKI model, co-administered drugs revealed a significant improvement in renal function and pathology as indicated by the reduction in serum creatinine, BUN and protein cast accumulation. The elevations of oxidative stress, and inflammatory markers as well as the over-expression of c-myc were alleviated. Protein levels of TLR4, NLRP3, cleaved caspase-1, and GSDMD were significantly elevated in RM-AKI model, and this elevation was attenuated by the tested drugs. In conclusion, PTX and TM could be a potential renoprotective approach for patients with RM through targeting TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis pathways.

Poly(ADP-ribose) polymerase inhibitors in the treatment landscape of triple-negative breast cancer (TNBC).

OBJECTIVE: Chemotherapy is the mainstay for triple-negative breast cancer (TNBC) patients. Over the years, the use of chemotherapy for these patients has demonstrated many adversities, including toxicity and resistance, which suggested the need to develop novel alternative therapeutic options, such as poly(ADP-ribose) polymerase inhibitors (PARPi). Herein, we provide an overview on PARPi, mechanisms of action and the role of biomarkers in PARPi sensitivity trials, clinical advances in PARPi therapy for TNBC patients based on the most recent studies and findings of clinical trials, and challenges that prevent PARP inhibitors from achieving high efficacy such as resistance and overlapping toxicities with other chemotherapies. DATA SOURCES: Searching for relevant articles was done using PubMed and Cochrane Library databases by using the keywords including TNBC; chemotherapy; PARPi; BRCA; homologous recombination repair (HRR). Studies had to be published in full-text in English in order to be considered. DATA SUMMARY: Although PARPi have been used in the treatment of local/metastatic breast malignancies that are HER2 negative and has a germline BRCA mutation, several questions are still to be answered in order to maximize the clinical benefit of PARP inhibitors in TNBC treatment, such as questions related to the optimal use in the neoadjuvant and metastatic settings as well as the best combinations with various chemotherapies. CONCLUSIONS: PARPi are emerging treatment options for patients with gBRCA1/2 mutations. Determining patients that are most likely to benefit from PARPi and identifying the optimal treatment combinations with high efficacy and fewer side effects are currently ongoing.

Thymol ameliorates 5-fluorouracil-induced intestinal mucositis: Evidence of down-regulatory effect on TGF-ß/MAPK pathways through NF-κB.

5-Fluorouracil (5-FU) is a front-line cytotoxic therapy. However, intestinal mucositis is a well-known adverse event of 5-FU, which limits its therapeutic use. Indeed, thymol, which is a monoterpene component of the essential oil derived from thymus, has a potential anti-inflammatory and immunomodulatory activity. Therefore, this study aimed to investigate the potential chemoprotective effect of thymol against 5-FU-induced intestinal mucositis. Rats were either exposed to two doses of 5-FU (150 mg/kg, ip) and/or treated with thymol (60 or 120 mg/kg). Oxidative stress and inflammatory markers, as well as pathological changes, were assessed. 5-FU-induced severe intestinal damages as were evidenced by histopathological changes as well as oxidative and inflammatory responses. Thymol pretreatment inhibited 5-FU-induced oxidative stress by reducing lipid peroxidation and increasing intestinal levels of antioxidant systems. Moreover, inflammatory response markers, such as interleukin-6, prostaglandin E2, and COX-2 were also improved. The immunoblotting analysis also showed that thymol significantly inhibited the 5-FU-induced expression of nuclear factor-κB, tumor necrosis factor-α, and transforming growth factor ß-1 (TGF-ß1), in addition to the suppression of p38 and phosphorylated c-Jun N-terminal kinases (p-JNK) mitogen-activated protein kinase proteins' expressions. Our study is the first to demonstrate the promising protective effect of thymol against 5-FU-induced intestinal mucositis through inhibition of oxidative, inflammatory pathways, and suppression of TGF-ß/p38/p-JNK signaling.

Thymoquinone attenuates isoproterenol-induced myocardial infarction by inhibiting cytochrome C and matrix metalloproteinase-9 expression.

Thymoquinone (TQ) is the main active constituent of Nigella sativa. The present study aimed to investigate the effect of TQ on apoptotic parameters and MMP-9 expression in isoproterenol (ISP)-induced myocardial infarction (MI). TQ was given once daily for 7 days at doses of 10 and 20 mg/kg orally with ISP (86 mg/kg; s.c.) administered on the sixth and seventh days. TQ pre-treatment protected against ISP-induced MI as approved by normalisation of electrocardiogram (ECG) and b (CK)-MB, minimal histopathological changes, and reduction of the infarction size. Effects of TQ could be supported by its antioxidant activity, evidenced by the increase of cardiac reduced glutathione and total serum antioxidant capacity, and the inhibition of ISO-induced lipid peroxidation. TQ anti-inflammatory activity was associated with reduced expression of NF-κB and TNF-α. TQ ameliorated cardiomyocytes, apoptotic pathways by inhibiting both the intrinsic pathway, via reducing cytoplasmic cytochrome C, and the extrinsic pathway, by inhibiting TNF-α and caspases, and the effect of TQ was dose-dependent. Moreover, TQ reduced the expression of metalloproteinase (MMP)-9, which is considered as a prognostic marker of ventricular remodelling, recommending that TQ can be used as a possible supplement to minimise post-MI changes. So, we conclude that TQ antiapoptotic activity and the inhibitory modulation of MMP-9 expression contribute to TQ protective effects in MI. To our knowledge, this is the first study reporting the effect of TQ on cytochrome c activity and MMP-9 expression in MI.

The beneficial effects of antioxidants combination on cardiac injury induced by tetrachloromethane.

The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in combination with α-tocopherol (α-TOCO) and/or turmeric (TUMR) against tetrachloromethane (TCM)-induced cardiomyocyte injury in rats. Administration of CAR either alone or in combination with α-TOCO and/or TUMR post-TCM injection, significantly mitigated the increases in serum troponin T, creatine kinase-MB (CK-MB) as well as interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP). They also decline the elevation of caspase-3, vascular endothelial growth factor (VEGF) protein expression as well as DNA damage in cardiac tissues induced by TCM. The biochemical results were confirmed by histopathological investigation. Conclusion: The combination of the three antioxidants showed greater cardioprotective potential, compared to individual drugs. Therefore, this combination may be recommended as a complementary therapy to antagonize cardiac injury induced by different insults.

Rifaximin Protects against Malathion-Induced Rat Testicular Toxicity: A Possible Clue on Modulating Gut Microbiome and Inhibition of Oxidative Stress by Mitophagy.

Testicular dysfunction is caused by chronic exposure to environmental pollution, such as malathion, which causes oxidative stress, promoting cell damage. Autophagy is a key cellular process for eliminating malfunctioning organelles, such as the mitochondria (mitophagy), an eminent source of reactive oxygen species (ROS). Autophagy is crucial for protection against testicular damage. Rifaximin (RFX) is a non-absorbable antibiotic that can reshape the gut microbiome, making it effective in different gastrointestinal disorders. Interestingly, the gut microbiome produces short chain fatty acids (SCFAs) in the circulation, which act as signal molecules to regulate the autophagy. In this study, we investigated the regulatory effects of RFX on gut microbiota and its circulating metabolites SCFA and linked them with the autophagy in testicular tissues in response to malathion administration. Moreover, we divided the groups of rats that used malathion and RFX into a two-week group to investigate the mitophagy process and a four-week group to study mitochondriogenesis. The current study revealed that after two weeks of cotreatment with RFX, apoptosis was inhibited, oxidative stress was improved, and autophagy was induced. More specifically, PINK1 was overexpressed, identifying mitophagy activation. After four weeks of cotreatment with RFX, there was an increase in acetate and propionate-producing microflora, as well as the circulating levels of SCFAs. In accordance with this, the expression of PGC-1α, a downstream to SCFAs action on their receptors, was activated. PGC-1α is an upstream activator of mitophagy and mitochondriogenesis. In this sense, the protein expression of TFAM, which regulates the mitochondrial genome, was upregulated along with a significant decrease in apoptosis and oxidative stress. Conclusion: we found that RFX has a positive regulatory effect on mitophagy and mitochondria biogenesis, which could explain the novel role played by RFX in preventing the adverse effects of malathion on testicular tissue.

Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats.

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.

Comparative study of the ciliary body and iris morphology in the anterior eye chamber of five different vertebrate classes.

One crucial component of the optical system is the ciliary body (CB). This body secretes the aqueous humour, which is essential to maintain the internal eye pressure as well as the clearness of the lens and cornea. The histological study was designed to provide the morphological differences of CB and iris in the anterior eye chambers of the following vertebrate classes: fish (grass carp), amphibians (Arabian toad), reptiles (semiaquatic turtle, fan-footed gecko, ocellated skink, Egyptian spiny-tailed lizard, Arabian horned viper), birds (common pigeon, common quail, common kestrel), and mammals (BALB/c mouse, rabbit, golden hamster, desert hedgehog, lesser Egyptian jerboa, Egyptian fruit bat). The results showed distinct morphological appearances of the CB and iris in each species, ranging from fish to mammals. The present comparative study concluded that the morphological structure of the CB and iris is the adaptation of species to either their lifestyle or survival in specific habitats.

Dibenzazepine, a γ-Secretase Enzyme Inhibitor, Protects Against Doxorubicin-Induced Cardiotoxicity by Suppressing NF-κB, iNOS, and Hes1/Hey1 Expression.

Doxorubicin (DOX) is an effective chemotherapeutic drug; however, its cardiotoxicity and resistance compromise its therapeutic index. The Notch pathway was reported to contribute to DOX cancer resistance. The role of Notch pathway in DOX cardiotoxicity has not been identified yet. Notch receptors are characterized by their extracellular (NECD) and intracellular (NICD) domains (NICD). The γ-secretase enzyme helps in the release of NICD. Dibenzazepine (DBZ) is a γ-secretase inhibitor. The present study investigated the effect of Notch pathway inhibition on DOX cardiotoxicity. Twenty-four male Wistar rats were divided into four groups: control group, DOX group, acute cardiotoxicity was induced by a single dose of DOX (20 mg/kg) i.p., DOX (20 mg/kg) plus DBZ group, and DBZ group. The third and fourth groups received i.p. injection of DBZ daily for 14 days at 2 mg/kg dose. DOX cardiotoxicity increased the level of serum creatine kinase-MB and cardiac troponin I, and it was confirmed by the histopathological examination. Moreover, the antioxidants glutathione peroxidase and superoxide dismutase levels were markedly decreased, and the inflammatory markers, inducible nitric oxide synthase, nuclear factor-kB, and tumor necrosis factor-α were markedly increased. Furthermore, DOX increased BAX protein and downregulated BCL-2. In addition, DOX upregulated Notch pathway-related parameters: Hes1 and Hey1 mRNA levels, and increased Hes1 protein levels. DBZ ameliorated DOX-induced cardiotoxicity, evidenced by reducing the cardiac injury biomarkers, improving cardiac histopathological changes, correcting antioxidant levels, and reducing inflammatory and apoptotic proteins. Our study indicates the protective effect of Notch inhibitor against DOX-induced cardiotoxicity.

Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3ß Pathway in In Vivo and In Silico Experimental Models.

BACKGROUND: 5-fluorouracil (5-FU) is a widely used, highly effective chemotherapeutic agent. However, its therapeutic efficacy is often limited by associated adverse effects, with hepatotoxicity being frequently reported with 5-FU therapy. Thymol is a monoterpene found in thyme (Thymus vulgaris L., Lamiaceae) and is known for its antioxidant, anti-apoptotic, and anticancer activities. This study aimed to explore the hepatoprotective activity of thymol against 5-FU-induced liver injury. METHODS: Rats received two intraperitoneal doses of 5-FU (150 mg/kg) either alone or in combination with thymol at doses of 60 mg/kg or 120 mg/kg. Liver enzymes, oxidative stress, and apoptotic markers, in addition to histopathological changes, were assessed. RESULTS: 5-FU induced marked liver injuries as evidenced by elevated liver enzymes and histopathological changes, in addition to abnormalities of oxidative and apoptotic markers. The administration of thymol ameliorated the 5-FU-induced oxidative damage through increasing hepatic antioxidants and lowering lipid peroxidation. Apoptotic response markers such as Bax, Bcl-2, Bax/Bcl-2 ratio, and PARP were also improved. Furthermore, Western blotting analysis showed that thymol modulated the 5-FU-induced changes in the expression of Akt/GSK-3ß and p44/42 MAPK (ERK1/2) signaling pathways. CONCLUSIONS: Our research is the first to shed light on thymol's potential protective effect against 5-FU- induced hepatotoxicity by inhibiting oxidative and apoptotic pathways and modulating the Akt/ GSK-3ß as well as p44/42 MAPK (ERK1/2) signaling pathways.

The Protective Effects of Vitamin B Complex on Diclofenac Sodium-Induced Nephrotoxicity: The Role of NOX4/RhoA/ROCK.

Diclofenac sodium (DIC) is a widely used non-steroidal anti-inflammatory drug. Unfortunately, its prolonged use is associated with nephrotoxicity due to oxidative stress, inflammation, and fibrosis. We aimed to investigate the nephroprotective effects of vitamin B complex (B1, B6, B12) against DIC-induced nephrotoxicity and its impact on NOX4/RhoA/ROCK, a pathway that plays a vital role in renal pathophysiology. Thirty-two Wistar rats were divided into four groups: (1) normal control; (2) vitamin B complex (16 mg/kg B1, 16 mg/kg B6, 0.16 mg/kg B12, intraperitoneal); (3) DIC (10 mg/kg, intramuscular); and (4) DIC plus vitamin B complex group. After 14 days, the following were assayed: serum renal biomarkers (creatinine, blood urea nitrogen, kidney injury molecule-1), oxidative stress, inflammatory (tumor necrosis factor-α, interleukin-6), and fibrotic (transforming growth factor-ß) markers as well as the protein levels of NOX4, RhoA, and ROCK. Structural changes, inflammatory cell infiltration, and fibrosis were detected using hematoxylin and eosin and Masson trichrome stains. Compared to DIC, vitamin B complex significantly decreased the renal function biomarkers, markers of oxidative stress and inflammation, and fibrotic cytokines. Glomerular and tubular damage, inflammatory infiltration, and excessive collagen accumulation were also reduced. Protein levels of NOX4, RhoA, and ROCK were significantly elevated by DIC, and this elevation was ameliorated by vitamin B complex. In conclusion, vitamin B complex administration could be a renoprotective approach during treatment with DIC via, at least in part, suppressing the NOX4/RhoA/ROCK pathway.

Sleep and Daytime Function in People with Spinal Cord Injury.

Study Design: Cross-sectional cohort study. Objectives: To determine the role of sleep-disordered breathing (SDB), insomnia symptoms and sleep quality in the daytime function and quality of life of veterans with spinal cord injury (SCI). Setting: A Veterans Administration (VA) medical center in the Midwestern US. Methods: Thirty-eight male veterans with SCI (22 cervical, 16 thoracic; mean [SD] age = 62.9[9.5] years) completed baseline assessments within a larger clinical trial. Measures assessed sleep apnea severity (apnea-hypopnea index, AHI), insomnia symptoms (Insomnia Severity Index, ISI), self-reported sleep quality (Pittsburg Sleep Quality Index, PSQI), daytime sleepiness (Epworth Sleepiness Scale, ESS), fatigue (Flinders Fatigue Scale, FFS), depression (Patient Health Questionnaire-9 item, PHQ-9 excluding sleep item), functioning (Spinal Cord Independence Measure, SCIM), and quality of life (World Health Organization Quality of Life, WHOQOL-BREF). Bivariate correlations (alpha p<.05) were used to assess relationships between sleep (AHI, ISI, PSQI, ESS) and function (FFS, PHQ-9, SCIM, WHOQOL-BREF). Results: Mean AHI was 29.9(26.6), mean ISI was 9.38(6.2), mean PSQI was 9.0(4.6), and mean ESS was 7.0(5.2). There were no significant relationships between AHI and function measures. Significant relationships emerged between ISI and PHQ-9, some WHOQOL-BREF subscales, and SCIM as well as between PSQI and FFS, PHQ-9, and some WHOQOL-BREF subscales. Conclusions: Among Veterans with SCI, insomnia symptom severity and poor sleep quality were associated with worse functioning, whereas SDB severity was not. Insomnia and poor sleep quality represent modifiable contributors to poor daytime function. Research evaluating the impact of evidence-based insomnia treatments among individuals living with SCI is warranted.

Podocin, mTOR, and CHOP dysregulation contributes to nephrotoxicity induced of lipopolysaccharide/diclofenac combination in rats: Curcumin and silymarin could afford protective effect.

AIM: Sepsis is a common cause of acute kidney injury (AKI). Lipopolysaccharides (LPS) are the main gram-negative bacterial cell wall component with a well-documented inflammatory impact. Diclofenac (DIC) is a non-steroidal anti-inflammatory drug with a potential nephrotoxic effect. Curcumin (CUR) and silymarin (SY) are natural products with a wide range of pharmacological activities, including antioxidant and anti-inflammatory ones. The objective of this study was to examine the protective impact of CUR and SY against kidney damage induced by LPS/DIC co-exposure. MATERIALS AND METHODS: Four groups of rats were used; control; LPS/DIC, LPS/DIC + CUR, and LPS/DIC + SY group. LPS/DIC combination induced renal injury at an LPS dose much lower than a nephrotoxic one. KEY FINDING: Nephrotoxicity was confirmed by histopathological examination and significant elevation of renal function markers. LPS/DIC induced oxidative stress in renal tissues, evidenced by decreasing reduced glutathione and superoxide dismutase, and increasing lipid peroxidation. Inflammatory response of LPS/DIC was associated with a significant increase of renal IL-1ß and TNF-α. Treatment with either CUR or SY shifted measured parameters to the opposite side. Moreover, LPS/DIC exposure was associated with upregulation of mTOR and endoplasmic reticulum stress protein (CHOP) and downregulation of podocin These effects were accompanied by reduced gene expression of cystatin C and KIM-1. CUR and SY ameliorated LPS/DIC effect on the aforementioned genes and protein significantly. SIGNIFICANCE: This study confirms the potential nephrotoxicity; mechanisms include upregulation of mTOR, CHOP, cystatin C, and KIM-1 and downregulation of podocin. Moreover, both CUR and SY are promising nephroprotective products against LPS/DIC co-exposure.

Radioprotective Effects of Carvacrol and/or Thymol against Gamma Irradiation-Induced Acute Nephropathy: In Silico and In Vivo Evidence of the Involvement of Insulin-like Growth Factor-1 (IGF-1) and Calcitonin Gene-Related Peptide.

Radiotherapy (RT) is an effective curative cancer treatment. However, RT can seriously damage kidney tissues resulting in radiotherapy nephropathy (RN) where oxidative stress, inflammation, and apoptosis are among the common pathomechanisms. Carvacrol and thymol are known for their antioxidative, anti-inflammatory, and radioprotective activities. Therefore, this study investigated the nephroprotective potentials of carvacrol and/or thymol against gamma (γ) irradiation-induced nephrotoxicity in rats along with the nephroprotection mechanisms, particularly the involvement of insulin-like growth factor-1 (IGF-1) and calcitonin gene-related peptide (CGRP). Methods: Male rats were injected with carvacrol and/or thymol (80 and 50 mg/kg BW in the vehicle, respectively) for five days and exposed to a single dose of irradiation (6 Gy). Then, nephrotoxicity indices, oxidative stress, inflammatory, apoptotic biomarkers, and the histopathological examination were assessed. Also, IGF-1 and CGRP renal expressions were measured. Results: Carvacrol and/or thymol protected kidneys against γ-irradiation-induced acute RN which might be attributed to their antioxidative, anti-inflammatory, and antiapoptotic activities. Moreover, both reserved the γ -irradiation-induced downregulation of CGRP- TNF-α loop in acute RN that might be involved in the pathomechanisms of acute RN. Additionally, in Silico molecular docking simulation of carvacrol and thymol demonstrated promising fitting and binding with CGRP, IGF-1, TNF-α and NF-κB through the formation of hydrogen, hydrophobic and alkyl bonds with binding sites of target proteins which supports the reno-protective properties of carvacrol and thymol. Collectively, our findings open a new avenue for using carvacrol and/or thymol to improve the therapeutic index of γ-irradiation.

In vivo and In silico evidence of the protective properties of carvacrol against experimentally-induced gastric ulcer: Implication of antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Gastric ulcer is a serious disease that affects millions of individuals worldwide. Alcohol consumption is a major contributor to the disease pathogenesis and ethanol-induced ulcer in rats closely recapitulates the clinical pathology of ulcer. In this study, rats were pretreated with carvacrol (CAR,50 and 100 mg/kg, orally) 1 h before absolute ethanol administration to induce gastric ulcer. CAR prevented ethanol-induced increases in gastric volume and acidity while restored mucin content. The gastro-protective activity of CAR, particularly the higher dose (100 mg/kg), was further supported by histopathological examination, as manifested by reduced gastric lesions. Interestingly, oxidative stress is linked to early stages of ulcer development and progression. In this study, ethanol administration upregulated the levels of ROS-producing enzymes, NADPH oxidase homologs 1 and 4 (Nox1 and Nox4) and lipid peroxides while depleting the antioxidant defense mechanisms, including GSH, Glutathione Peroxidase (GPX) and catalase. Interestingly, these alterations were significantly ameliorated by CAR pretreatment. Additionally, CAR possesses anti-inflammatory and anti-apoptotic activities. Pretreatment with CAR blunted ethanol-induced increases in inflammatory cytokines (NF-κB and TNF-α) and rectified the apoptosis regulator (Bax/Bcl2 ratio) in gastric tissue. Moreover, the docking simulation of CAR illustrated good fitting and interactions with GPX, Nox1 and TNF-α through the formation of hydrogen and hydrophobic (pi-H) bonds with conservative amino acids, thus, further supporting the anti-inflammatory and antioxidant effects underlying the gastroprotective effects of CAR. In conclusion, this study elucidates, using in silico and in vivo models, that the gastroprotective activity of CAR is attributed, at least in part, to its mucin-secretagogue, antioxidative, anti-inflammatory, and anti-apoptotic mechanisms.

TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity.

BACKGROUND: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA. METHODS: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection. RESULTS: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-κB and TNF-α) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1ß) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes. CONCLUSIONS: This study emphasizes that inhibition of TLR4/NLPR3/IL-1ß/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.

Targeting Store-Operated Calcium Entry Regulates the Inflammation-Induced Proliferation and Migration of Breast Cancer Cells.

Persistent challenges complicating the treatment of breast cancer remain, despite some recent undeniable successes. Sufficient evidence currently exists demonstrating the crucial role of inflammation, characterized by the enhanced activation of Toll-like receptor 4 (TLR4) and the COX-2/PGE2 pathway, in the migration and proliferation of breast cancer cells. Interestingly, the store-operated calcium entry (SOCE) pathway was shown to be essential for the TLR4 activity and COX-2 expression in immune cells such as macrophages and microglia. However, whether SOCE influences inflammatory signaling and the inflammation-induced proliferation and migration of breast cancer cells is still unknown. Thus, the current study intended to delineate the role of SOCE in the TLR4-induced inflammation, migration, and proliferation of breast cancer cells. To this end, MDA-MB-231 breast cancer cells were treated with lipopolysaccharide (LPS) to activate TLR4, BTP2 to inhibit SOCE, and Thapsigargin to induce SOCE. Following these treatments, several experiments were conducted to evaluate the proliferation and migration rates of the MDA-MB-231 cells and the expression of several inflammatory and oncogenic genes, including COX-2, PGE2, IL-6, IL-8, and VEGF. Different techniques were used to achieve the aims of this study, including qRT-PCR, Western blotting, ELISA, MTT, and wound healing assays. This study shows that SOCE inhibition using BTP2 suppressed the LPS-induced migration and proliferation of breast cancer cells. Additionally, treatment with LPS caused approximately six- and three-fold increases in COX-2 mRNA and protein expression, respectively, compared to the controls. The LPS-induced elevations in the COX-2 mRNA and protein levels were suppressed by BTP2 to the control levels. In addition to its effect on COX-2, BTP2 also suppressed the LPS-induced productions of PGE2, IL-6, IL-8, and VEGF. Conversely, SOCE induction using Thapsigargin enhanced the LPS-induced inflammation, migration, and proliferation of breast cancer cells. Collectively, these results provide evidence for the potentially important role of SOCE in inflammation-induced breast cancer progression processes. Thus, we argue that the current study may provide novel targets for designing new therapeutic approaches for the treatment of breast cancer.

Hematological consequences of polyethylene microplastics toxicity in male rats: Oxidative stress, genetic, and epigenetic links.

Microplastics (MPs) pollution is a newly emerging environmental issue. MPs can accumulate within animals and humans, which can pose a serious health threat. Petroleum-based polyethylene (PE) is one of the most popular plastics. Accordingly, its exposure rates have steadily increased over the years. This study aimed to analyze the effects of PE-MPs on the hematological system of albino rats and the epigenetic effect. Five groups of adult male eight-weeks-old rats received either distilled water, corn oil, 3.75 mg/kg PE-MPs, 15 mg/kg PE-MPs, or 60 mg/kg of PE-MPs, daily by oral gavage for 35 days. PE-MPs significantly increased the body weights of the rats and lipid peroxidation, with concomitant reduction of superoxide dismutase activity and depletion of reduced glutathione, thus adversely affecting oxidants/antioxidants balance. Moreover, PE-MPs increased the % of abnormal RBCs, irregular cells, tear drop cells, Schistocyte cells, and folded cells. The genotoxic effects on DNA were evident by increased DNA damage, confirmed by the comet assay, in addition to increased DNA methylation. The effects of PE-MPs have been shown to be dose correlated. In conclusion, this study provides evidence of dose-related PE-MPs-induced hematological, genotoxic, and epigenetic effects in mammals, and thus emphasizes the potentially hazardous health effects of environmental PE-MPs.

The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1/Nrf2/NF-κB Signaling Pathway and Microbiota Modulation.

Amoxicillin/clavulanate (Co-Amox), a commonly used antibiotic for the treatment of bacterial infections, has been associated with drug-induced liver damage. Quercetin (QR), a naturally occurring flavonoid with pleiotropic biological activities, has poor water solubility and low bioavailability. The objective of this work was to produce a more bioavailable formulation of QR (liposomes) and to determine the effect of its intraperitoneal pretreatment on the amelioration of Co-Amox-induced liver damage in male rats. Four groups of rats were defined: control, QR liposomes (QR-lipo), Co-Amox, and Co-Amox and QR-lipo. Liver injury severity in rats was evaluated for all groups through measurement of serum liver enzymes, liver antioxidant status, proinflammatory mediators, and microbiota modulation. The results revealed that QR-lipo reduced the severity of Co-Amox-induced hepatic damage in rats, as indicated by a reduction in serum liver enzymes and total liver antioxidant capacity. In addition, QR-lipo upregulated antioxidant transcription factors SIRT1 and Nrf2 and downregulated liver proinflammatory signatures, including IL-6, IL-1ß, TNF-α, NF-κB, and iNOS, with upregulation in the anti-inflammatory one, IL10. QR-lipo also prevented Co-Amox-induced gut dysbiosis by favoring the colonization of Lactobacillus, Bifidobacterium, and Bacteroides over Clostridium and Enterobacteriaceae. These results suggested that QR-lipo ameliorates Co-Amox-induced liver damage by targeting SIRT1/Nrf2/NF-κB and modulating the microbiota.