Role of IRE1α/XBP1/CHOP/NLRP3 Signalling Pathway in Neonicotinoid Imidacloprid-Induced Pancreatic Dysfunction in Rats and Antagonism of Lycopene: In Vivo and Molecular Docking Simulation Approaches.

Imidacloprid (IMI) is a commonly used new-generation pesticide that has numerous harmful effects on non-targeted organisms, including animals. This study analysed both the adverse effects on the pancreas following oral consumption of imidacloprid neonicotinoids (45 mg/kg daily for 30 days) and the potential protective effects of lycopene (LYC) administration (10 mg/kg/day for 30 days) with IMI exposure in male Sprague-Dawley rats. The apoptotic, pyroptotic, inflammatory, oxidative stress, and endoplasmic reticulum stress biomarkers were evaluated, along with the histopathological alterations. Upon IMI administration, noticeable changes were observed in pancreatic histopathology. Additionally, elevated oxidative/endoplasmic reticulum-associated stress biomarkers, inflammatory, pyroptotic, and apoptotic biomarkers were also observed following IMI administration. LYC effectively reversed these alterations by reducing oxidative stress markers (e.g., MDA) and enhancing antioxidant enzymes (SOD, CAT). It downregulated ER stress markers (IRE1α, XBP1, CHOP), decreased pro-inflammatory cytokines (TNF-α, IL-1ß), and suppressed pyroptotic (NLRP3, caspase-1) along with apoptotic markers (Bax, cleaved caspase-3). It also improved the histopathological and ultrastructure alterations brought on by IMI toxicity.

The protective role of sesame oil against Parkinson's-like disease induced by manganese in rats.

Chronic exposure to manganese (Mn) results in motor dysfunction, biochemical and pathological alterations in the brain. Oxidative stress, inflammation, and dysfunction of dopaminergic and GABAergic systems stimulate activating transcription factor-6 (ATF-6) and protein kinase RNA-like ER kinase (PERK) leading to apoptosis. This study aimed to investigate the protective effect of sesame oil (SO) against Mn-induced neurotoxicity. Rats received 25 mg/kg MnCl2 and were concomitantly treated with 2.5, 5, or 8 ml/kg of SO for 5 weeks. Mn-induced motor dysfunction was indicated by significant decreases in the time taken by rats to fall during the rotarod test and in the number of movements observed during the open field test. Also, Mn resulted in neuronal degeneration as observed by histological staining. The striatal levels of lipid peroxides and reduced glutathione (oxidative stress markers), interleukin-6 and tumor necrosis factor-α (inflammatory markers) were significantly elevated. Mn significantly reduced the levels of dopamine and Bcl-2, while GABA, PERK, ATF-6, Bax, and caspase-3 were increased. Interestingly, all SO doses, especially at 8 ml/kg, significantly improved locomotor activity, biochemical deviations and reduced neuronal degeneration. In conclusion, SO may provide potential therapeutic benefits in enhancing motor performance and promoting neuronal survival in individuals highly exposed to Mn.

MAP kinase inhibitor PD98059 regulates Th1, Th9, Th17, and natural T regulatory cells in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

Experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS), provides significant insights into the mechanisms that initiate and drive autoimmunity. MS is a chronic autoimmune disease of the central nervous system, characterized by inflammatory infiltration associated with demyelination. T lymphocyte cells play a crucial role in MS, whereas natural T regulatory (nTreg) cells prevent autoimmune inflammation by suppressing lymphocyte activity. This study sought to investigate the role of PD98059, a selective MAP kinase inhibitor, in Th1, Th9, Th17, and nTreg cells using the SJL/J mouse model of EAE. Following EAE development, the mice were intraperitoneally administered PD98059 (5 mg/kg for two weeks) daily. We evaluated the effects of PD98059 on Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγT), and nTreg (FoxP3 and Helios) cells in the spleen using flow cytometry. Moreover, we explored the effects of PD98059 on the IFN-γ, T-bet, IL-9, IRF4, IL-17A, RORγT, FoxP3, and Helios mRNA and protein levels in brain tissues using qRT-PCR and Western blot analyses. PD98059 treatment significantly decreased the proportion of CD4+IFN-γ+, CD4+T-bet+, CD4+IL-9+, CD4+IRF4+, CD4+IL-17A+, CD4+RORγT+, CD4+IL-17A+, and CD4+RORγT+ cells while increasing that of CD4+FoxP3+ and CD4+Helios+ cells. In addition, PD98059 administration decreased the mRNA and protein levels of IFN-γ, T-bet, IL-9, IRF4, IL-17A, and RORγT but increased those of FoxP3 and Helios in the brain tissue of EAE mice. Our findings suggest that PD98059 corrects immune dysfunction in EAE mice, which is concurrent with the modulation of multiple signaling pathways.

Histamine H4 Receptor Antagonist Ameliorates the Progression of Experimental Autoimmune Encephalomyelitis via Regulation of T-Cell Imbalance.

Multiple sclerosis (MS) is a degenerative condition characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. The histamine H4 receptor (H4R) is mainly expressed in cellular populations and plays a vital role in inflammation and immunological responses. The role of H4R in neurons of the CNS has recently been revealed. However, the precise role of H4R in neuronal function remains inadequately understood. The objective of this work was to investigate the impact of JNJ 10191584 (JNJ), a highly effective and specific H4R antagonist, on the development of experimental autoimmune encephalomyelitis (EAE) and to gain insight into the underlying mechanism involved. In this study, we examined the potential impact of JNJ therapy on the course of EAE in SJL/J mice. EAE mice were administered an oral dose of JNJ at a concentration of 6 mg/kg once a day, starting from day 10 and continuing until day 42. Afterward, the mice's clinical scores were assessed. In this study, we conducted additional research to examine the impact of JNJ on several types of immune cells, specifically Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγt), and regulatory T (Tregs; Foxp3 and TGF-ß1) cells in the spleen. In this study, we further investigated the impact of JNJ on the mRNA expression levels of IFN-γ, T-bet, IL-9, IRF4, IL-17A, RORγt, Foxp3, and TGF-ß1 in the brain. Daily treatment of JNJ effectively reduced the development of EAE in mice. The percentages of CD4+IFN-γ+, CD4+T-bet+, CD4+IL-9+, CD4+IRF4+, CD4+IL-17A+, and CD4+RORγt+ cells were shown to decrease, whereas the percentages of CD4+TGF-ß1+ and CD4+Foxp3+ cells were observed to increase in EAE mice treated with JNJ. Therefore, the HR4 antagonist positively affected the course of EAE by modulating the signaling of transcription factors. The identified results include possible ramifications in the context of MS treatment.

Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing.

Introduction: Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity. Methods: In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity. Results: The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2 g every 24 h is lower than the accumulation of 1 g every 12 h dosing regimen. Discussion: In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment.

Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model.

We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage, and neurodegeneration. Over the past decade, pharmacological research into the H4R has gained significance in immune and inflammatory disorders. For this study, Swiss Jim Lambert EAE mice were treated with 4-MeH (30 mg/kg/day) via intraperitoneal administration from days 14 to 42, and the control group was treated with a vehicle. Subsequently, we evaluated the clinical scores. In addition, flow cytometry was employed to estimate the impact of 4-Methylhistamine (4-MeH) on NF-κB p65, GM-CSF, MCP-1, IL-6, and TNF-α within CD19+ and CXCR5+ spleen B cells. Additionally, we investigated the effect of 4-MeH on the mRNA expression levels of Nf-κB p65, Gmcsf, Mcp1, Il6, and Tnfα in the brain of mice using RT-PCR. Notably, the clinical scores of EAE mice treated with 4-MeH showed a significant increase compared with those treated with the vehicle. The percentage of cells expressing CD19+NF-κB p65+, CXCR5+NF-κB p65+, CD19+GM-CSF+, CXCR5+GM-CSF+, CD19+MCP-1+, CXCR5+MCP-1+, CD19+IL-6+, CXCR5+IL-6+, CD19+TNF-α+, and CXCR5+TNF-α+ exhibited was more pronounced in 4-MeH-treated EAE mice when compared to vehicle-treated EAE mice. Moreover, the administration of 4-MeH led to increased expression of NfκB p65, Gmcsf, Mcp1, Il6, and Tnfα mRNA in the brains of EAE mice. This means that the H4R agonist promotes pro-inflammatory mediators aggravating EAE symptoms. Our results indicate the harmful role of H4R agonists in the pathogenesis of MS in an EAE mouse model.

Rituximab exerts its anti-arthritic effects via inhibiting NF-κB/GM-CSF/iNOS signaling in B cells in a mouse model of collagen-induced arthritis.

Rheumatoidarthritis (RA) is an autoimmune disease characterized by uncontrolled joint inflammation and damage to bone and cartilage. B cells are known to play a crucial role in the pathogenesis and development of arthritis. Previous studies have found that B cells may be a potential target for treating RA. Rituximab, a monoclonal antibody targeting B cells, has induced long-term clinical responses in RA. Collagen-induced arthritis (CIA) mouse model is a widely studied autoimmune model of RA. CIA mouse model was used to investigate the effect of rituximab on the RA severity in the mice. Following induction of CIA, animals were treated with rituximab (250 mg/kg/week) intraperitoneally on the days 28, 35, 42, 49, 56, and 63 after collagen induction. We investigated the effect of rituximab on NF-κB p65, IκBα, GM-CSF, MCP-1, iNOS, TNF-α, and IL-6 cells in splenic CD19+ and CD45R+ B cells using flow cytometry. We also assessed the effect of rituximab on NF-κB p65, GM-CSF, IκBα, MCP-1, iNOS, TNF-α, and IL-6 at mRNA levels using RT-PCR analyses of knee tissues. Rituximab treatment significantly decreased CD19+NF-κB p65+, CD45R+NF-κB p65+, CD19+GM-CSF+, CD45R+GM-CSF+, CD19+MCP-1+, CD45R+MCP-1+, CD19+TNF-α+, CD45R+TNF-α+, CD19+iNOS+, CD45R+iNOS+, CD19+IL-6+, and CD45R+IL-6+, and increased CD45R+IκBα+ in spleen cells of CIA mice. We further observed that rituximab treatment downregulated NF-κB p65, GM-CSF, MCP-1, iNOS, TNF-α, and IL-6, whereas it upregulated IκBα, mRNA level. All these findings suggest that rituximab may be a novel therapeutic target for the treatment of RA.

CXCR3 antagonist NBI-74330 mitigates joint inflammation in Collagen-Induced arthritis model in DBA/1J mice.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. We used the CXCR3-specific antagonist NBI-74330 to block T-cell-mediated signaling in a DBA/1J mouse model of collagen-induced arthritis (CIA). After CIA induction, DBA/1J mice were treated with NBI-74330 (100 mg/kg) daily from day 21 until day 34 and evaluated for arthritic score and histopathological changes. Furthermore, using flow cytometry, we investigated the effects of NBI-74330 on Th1 (IFN-γ, TNF-α, T-bet, STAT4, Notch-3, and RANKL), Th17 (IL-21, IL-17A, STAT3, and RORγt), and Th22 (IL-22) cells in splenic CD4+ and CXCR3+T-cells. We also used RT-PCR to assess the effect of mRNA levels of IFN-γ, TNF-α, T-bet, RANKL, IL-17A, RORγt, and IL-22 in knee tissues. The IFN-γ, TNF-α, and IL-17A serum protein levels were measured using ELISA. Compared to vehicle-treated CIA mice, the severity of arthritic scores and histological severity of inflammation decreased significantly in NBI-74330-treated CIA mice. Moreover, compared to vehicle-treated CIA mice, the percentages of CD4+IFN-γ+, CD4+TNF-α+, CD4+T-bet+, CD4+STAT4+, CD4+Notch-3+, CXCR3+IFN-γ+, CXCR3+TNF-α+, CXCR3+T-bet+, CXCR3+STAT4+, CXCR3+Notch-3+, CD4+RANKL+, CD4+IL-21+, CD4+IL-17A+, CD4+STAT3+, CD4+RORγt+, and CD4+IL-22+ cells decreased in NBI-74330-treated CIA mice. Furthermore, NBI-74330-treatment downregulated IFN-γ, TNF-α, T-bet, RANKL, STAT3, IL-17A, RORγt, and IL-22 mRNA levels. Serum IFN-γ, TNF-α, and IL-17A levels were significantly lower in NBI-74330-treated CIA mice than in vehicle-treated CIA mice. This study demonstrates the antiarthritic effects of NBI-74330 in CIA mice. Therefore, these data suggest that NBI-74330 could be considered a potential RA treatment.

S3I-201, a selective stat3 inhibitor, ameliorates clinical symptoms in a mouse model of experimental autoimmune encephalomyelitis through the regulation of multiple intracellular signalling in Th1, Th17, and treg cells.

CD4+ T cells, specifically Th cells (Th1 and Th17) and regulatory T cells (Tregs), play a pivotal role in the pathogenesis of multiple sclerosis (MS), a demyelinating autoimmune disease of the CNS. STAT3 inhibitors are potential therapeutic targets for several immune disorders. In this study, we investigated the role of a well-known STAT3 inhibitor, S3I-201, in experimental autoimmune encephalomyelitis (EAE), a model of MS. Following induction of EAE, mice were intraperitoneally administered S3I-201 (10 mg/kg) each day, beginning on day 14 and continuing till day 35 and were evaluated for clinical signs. Flow cytometry was used to investigate further the effect of S3I-201 on Th1 (IFN-γ, STAT1, pSTAT1, and T-bet), Th17 (IL-17A, STAT3, pSTAT3, and RORγt), and regulatory T cells (Treg, IL-10, TGF-ß1, and FoxP3) expressed in splenic CD4+ T cells. Moreover, we analyzed the effects of S3I-201 on mRNA and protein expression of IFN-γ, T-bet, IL-17A, STAT1, STAT3, pSTAT1, pSTAT3, RORγ, IL-10, TGF-ß1, and FoxP3 in the brains of EAE mice. The severity of clinical scores decreased in S3I-201-treated EAE mice compared to vehicle-treated EAE mice. S3I-201 treatment significantly decreased CD4+IFN-γ+, CD4+STAT1+, CD4+pSTAT1+, CD4+T-bet+, CD4+IL-17A+, CD4+STAT3+, CD4+pSTAT3+, and CD4+RORγt+ and increased CD4+IL-10+, CD4+TGF-ß1+, and CD4+FoxP3+ in the spleens of EAE mice. Additionally, S3I-201 administration in EAE mice significantly decreased the mRNA and protein expression of Th1 and Th17 and increased those of Treg. These results suggest that S3I-201 may have novel therapeutic potential against MS.

A potent and selective CXCR2 antagonist improves neuroimmune dysregulation through the inhibition of NF-κB and notch inflammatory signaling in the BTBR mouse model of autism.

Autism comprises a broad range of neurodevelopmental disorders characterized by social communication deficits and repetitive and stereotyped behaviors. Chemokine receptor CXCR2 is expressed on neurons and is upregulated in neurological disorders. BTBR T+ Itpr3tf/J (BTBR) mice, a model for autism that shows the core features of ASD. Here, we studied the anti-inflammatory effect of a potent and selective CXCR2 antagonist SB332235 in the BTBR mice. The CXCR2 antagonist represents a promising therapeutic agent for several neuroinflammatory disorders. In this study, we investigated the effects of SB332235 administration on NF-κB-, Notch-1-, Notch-3-, GM-CSF-, MCP-1-, IL-6-, and IL-2- and TGF-ß1-expressing CD40+ cells in BTBR and C57BL/6 (C57) mice in the spleen cells by flow cytometry. We further assessed the effect of SB332235 treatment on NF-κB, Notch-1, GM-CSF, MCP-1, IL-6, and IL-2 mRNA expression levels in the brain tissue by RT-PCR. We also explored the effect of SB332235 administration on NF-κB, GM-CSF, IL-6, and TGF-ß1 protein expression levels in the brain tissue by western blotting. The SB332235-treated BTBR mice significantly decreases in CD40 + NF-κB+, CD40 + Notch-1+, CD40 + Notch-3+, CD40 + GM-CSF+, CD40 + MCP-1+, CD40 + IL-6+, and CD40 + IL-2+, and increases in CD40 + TGF-ß1+ in the spleen cells. Our results further demonstrated that BTBR mice treated with SB332235 effectively decreased NF-κB, Notch-1, GM-CSF, MCP-1, IL-6, and IL-2, increasing TGF-ß1 mRNA and protein expression levels in the brain tissue. In conclusion, these results indicate that SB332235 elicits an anti-inflammatory response by downregulating the inflammatory mediators and NF-κB/Notch inflammatory signaling in BTBR mice. This could represent a promising novel therapeutic target for autism treatment.

Anti-Heliobacter pylori and Anti-Inflammatory Potential of Salvia officinalis Metabolites: In Vitro and In Silico Studies.

Due to its rising antibiotic resistance and associated inflammations, Helicobacter pylori poses a challenge in modern medicine. Salvia officinalis, a member of the Lamiaceae family, is a promising medicinal herb. In this regard, a phytochemical screening followed by GC-MS and LC-MS was done to evaluate the chemical profile of the total ethanolic extract (TES) and the essential oil, respectively. The anti-H. pylori and the anti-inflammatory activities were evaluated by a micro-well dilution technique and COX-2 inhibition assay. Potential anti-H. pylori inhibitors were determined by an in silico study. The results revealed that the main metabolites were flavonoids, sterols, volatile oil, saponins, and carbohydrates. The LC-MS negative ionization mode demonstrated 12 compounds, while GC-MS showed 21 compounds. Carnosic acid (37.66%), epirosmanol (20.65%), carnosol1 (3.3%), and 12-O-methyl carnosol (6.15%) were predominated, while eucalyptol (50.04%) and camphor (17.75%) were dominant in LC-MS and GC-MS, respectively. TES exhibited the strongest anti-H. pylori activity (3.9 µg/mL) asymptotic to clarithromycin (0.43 µg/mL), followed by the oil (15.63 µg/mL). Carnosic acid has the best-fitting energy to inhibit H. pylori (-46.6769 Kcal/mol). TES showed the highest reduction in Cox-2 expression approaching celecoxib with IC50 = 1.7 ± 0.27 µg/mL, followed by the oil with IC50 = 5.3 ± 0.62 µg/mL. Our findings suggest that S. officinalis metabolites with anti-inflammatory capabilities could be useful in H. pylori management. Further in vivo studies are required to evaluate and assess its promising activity.

Mitogen-activated protein kinase inhibitor PD98059 improves neuroimmune dysfunction in experimental autoimmune encephalomyelitis in SJL/J mice through the inhibition of nuclear factor-kappa B signaling in B cells.

Multiple sclerosis (MS) is a severe autoimmune disease leading to demyelination, followed by consequent axonal degeneration, causing sensory, motor, cognitive, and visual symptoms. Experimental autoimmune encephalomyelitis (EAE) is the most well-studied animal model of MS. Most current MS treatments are not completely effective, and severe side effects remain a great challenge. In this study, we report the therapeutic efficacy of PD98059, a potent mitogen-activated protein kinase inhibitor, on proteolipid protein (PLP)139-151-induced EAE in SJL/J mice. Following the induction of EAE, mice were intraperitoneally treated with PD98059 (5 mg/kg for 14 days) daily from day 14 to day 28. This study investigated the effects of PD98059 on C-C motif chemokine receptor 6 (CCR6), CD14, NF-κB p65, IκBα, GM-CSF, iNOS, IL-6, TNF-α in CD45R+ B lymphocytes using flow cytometry. Furthermore, we analyzed the effect of PD98059 on CCR6, CD14, NF-κB p65, GM-CSF, iNOS, IL-6, and TNF-α mRNA and protein expression levels using qRT-PCR analysis in brain tissues. Mechanistic investigations revealed that PD98059-treated in mice with EAE had reduced CD45R+CCR6+, CD45R+CD14+, CD45R+NF-κB p65+, CD45R+GM-CSF+, CD45R+iNOS+, CD45R+IL-6+, and CD45R+TNF-α+ cells and increased CD45R+IκBα+ cells compared with vehicle-treated control mice in the spleen. Moreover, downregulation of CCR6, CD14, NF-κB p65, GM-CSF, iNOS, IL-6, and TNF-α mRNA expression level was observed in PD98059-treated mice with EAE compared with vehicle-treated control mice in the brain tissue. The results of this study demonstrate that PD98059 modulates inflammatory mediators through multiple cellular mechanisms. The results of this study suggest that PD98059 may be pursued as a therapeutic agent for the treatment of MS.

Cross-Regulation between Autophagy and Apoptosis Induced by Vitamin E and Lactobacillus Plantarum through Beclin-1 Network.

Autophagy and apoptosis are two important regulatory mechanisms for how the body can respond to diseases. This study was designed to investigate the protective actions of vitamin E (Vit-E) and lactobacillus plantarum (Lac-B) against mercuric chloride (HgCl2)-induced kidney injury. Thirty albino rats were divided into five groups: group 1 served as the normal group; rats in group 2 received high doses of HgCl2; rats in groups 3, 4 and 5 were given Vit-E, Lac-B and the combination of Vit-E and Lac-B, respectively along with HgCl2 for two weeks. HgCl2 provoked renal injury, manifested by elevation in serum urea, urea nitrogen and creatinine. Kidney levels of oxidative stress and inflammation were markedly increased post HgCl2 administration. Moreover, HgCl2 significantly elevated the gene expression levels of VCAM-1 and cystatin C, while podocin was downregulated. Additionally, it markedly decreased the protein expression of Beclin-1 and Bcl-2. Histopathological examination revealed massive degeneration with congested blood vessels following HgCl2 administration. Treatment with Vit-E or/and Lac-B restored the normal levels of the previously mentioned parameters, as well as improved the morphology of kidney tissues. Both Vit-E and Lac-B provided a protective effect against HgCl2-induced kidney damage by regulating autophagy and apoptosis.

GC-MS Profiling, Anti-Helicobacter pylori, and Anti-Inflammatory Activities of Three Apiaceous Fruits' Essential Oils.

Eradication of Helicobacter pylori is a challenge due to rising antibiotic resistance and GIT-related disorders. Cuminum cyminum, Pimpinella anisum, and Carum carvi are fruits belonging to the Apiaceae family. Their essential oils were extracted, analyzed using GC-MS, tested for anti-H. pylori activity by a micro-well dilution technique, identified for potential anti-H. pylori inhibitors by an in-silico study, and investigated for anti-inflammatory activity using a COX-2 inhibition assay. Results showed that the main components of C. cyminum, P. anisum, and C. carvi were cumaldehyde (41.26%), anethole (92.41%), and carvone (51.38%), respectively. Essential oil of C. cyminum exhibited the greatest anti-H. pylori activity (3.9 µg/mL) followed by P. anisum (15.63 µg/mL), while C. carvi showed the lowest activity (62.5 µg/mL). The in-silico study showed that cumaldehyde in C. cyminum has the best fitting energy to inhibit H. pylori.C. cyminum essential oil showed the maximum ability to reduce the production of Cox-2 expression approaching celecoxib with IC50 = 1.8 ± 0.41 µg/mL, followed by the C. carvi oil IC50 = 7.3 ± 0.35 µg/mL and then oil of P. anisum IC50 = 10.7±0.63 µg/mL. The investigated phytochemicals in this study can be used as potential adjunct therapies with conventional antibiotics against H. pylori.

Nano-Curcumin Prevents Copper Reproductive Toxicity by Attenuating Oxidative Stress and Inflammation and Improving Nrf2/HO-1 Signaling and Pituitary-Gonadal Axis in Male Rats.

Copper is essential for several cellular processes and is an important catalytic factor for many proteins. However, excess copper can provoke oxidative stress and reproductive toxicity. This study evaluated the effect of liposomal nano-curcumin (N-CUR) and CUR on testicular oxidative injury, inflammation, and apoptosis, and altered steroidogenesis and Nrf2/HO-1 signaling induced by copper sulfate (CuSO4). Rats received CuSO4 and N-CUR or CUR via oral gavage for 7 days. CuSO4 induced histopathological changes and altered pituitary-gonadal axis manifested by decreased serum gonadotropins and testosterone. Testicular steroidogenesis genes (StAR, 3ß-HSD, CYP17A1, and 17ß-HSD) and androgen receptor (AR) were downregulated in rats that received CuSO4. N-CUR and CUR prevented testicular tissue injury, increased circulating FSH, LH, and testosterone, and upregulated testicular steroidogenesis genes and AR. Additionally, N-CUR and CUR decreased testicular MDA, NO, NF-κB, iNOS, TNF-α, Bax, and caspase-3 while enhanced Bcl-2, Nrf2, and the antioxidants GSH, HO-1, SOD, and catalase. In conclusion, N-CUR and CUR prevented CuSO4-induced reproductive toxicity in male rats by suppressing oxidative injury and inflammatory response and boosting steroidogenesis, sex hormones, and Nrf2/HO-1 signaling. N-CUR was more effective in ameliorating tissue injury, oxidative stress, inflammation, and apoptosis and enhancing steroidogenesis and Nrf2/HO-1 than the native form.

Nano-Resveratrol: A Promising Candidate for the Treatment of Renal Toxicity Induced by Doxorubicin in Rats Through Modulation of Beclin-1 and mTOR.

Background: Although doxorubicin (DXR) is one of the most used anticancer drugs, it can cause life-threatening renal damage. There has been no effective treatment for DXR-induced renal damage until now. Aim: This work aims at examining the potential impact of nano-resveratrol (N-Resv), native resveratrol (Resv), and their combination with carvedilol (Card) against DXR-induced renal toxicity in rats and to investigate the mechanisms through which these antioxidants act to ameliorate DXR nephrotoxicity. Method: DXR was administered to rats (2 mg/kg, i.p.) twice weekly over 5 weeks. The antioxidants in question were taken 1 week before the DXR dose for 6 weeks. Results: DXR exhibited an elevation in serum urea, creatinine, renal lipid peroxide levels, endoglin expression, kidney injury molecule-1 (KIM-1), and beclin-1. On the other hand, renal podocin and mTOR expression and GSH levels were declined. In addition, DNA fragmentation was markedly increased in the DXR-administered group. Treatment with either Resv or N-Resv alone or in combination with Card ameliorated the previously measured parameters. Conclusion: N-Resv showed superior effectiveness relative to Resv in most of the measured parameters. Histopathological examination revealed amelioration of renal structural and cellular changes after DXR by Card and N-Resv, thus validating the previous biochemical and molecular results.

Nano-Curcumin Prevents Cardiac Injury, Oxidative Stress and Inflammation, and Modulates TLR4/NF-κB and MAPK Signaling in Copper Sulfate-Intoxicated Rats.

Copper (Cu) is essential for a plethora of biological processes; however, its high redox reactivity renders it potentially toxic. This study investigated the protective effect of curcumin (CUR) and nano-CUR (N-CUR) against Cu cardiotoxicity, emphasizing the role of oxidative stress, TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling and cell death in rats. Rats received 100 mg/kg copper sulfate (CuSO4), a pesticide used for repelling pests, and were concurrently treated with CUR or N-CUR for 7 days. Cu caused cardiac injury manifested by elevated serum cardiac troponin I (cTnI), creatine kinase (CK)-MB, and lactate dehydrogenase (LDH), as well as histopathological alterations. Cardiac malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 were increased, and reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were decreased in Cu-treated rats. CUR and N-CUR prevented cardiac tissue injury, decreased serum cTnI, CK-MB, and LDH, and cardiac MDA, NF-κB p65, TNF-α, and IL-6, and enhanced cellular antioxidants. CUR and N-CUR downregulated TLR4 and AP-1, and decreased the phosphorylation levels of p38 MAPK, JNK, and ERK1/2. In addition, CUR and N-CUR increased cardiac Bcl-2 and BAG-1, decreased Bax and caspase-3, and prevented DNA fragmentation. In conclusion, N-CUR prevents Cu cardiotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis, and modulating TLR4/NF-κB and MAPK signaling. The cardioprotective effect of N-CUR was more potent than the native form.

Curcumin and Nano-Curcumin Mitigate Copper Neurotoxicity by Modulating Oxidative Stress, Inflammation, and Akt/GSK-3ß Signaling.

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO4) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO4-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3ß. Rats received 100 mg/kg CuSO4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3ß Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3ß signaling. The neuroprotective effect of N-CUR was more potent than CUR.