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Ropinirole (ROP) is a dopamine agonist that can cross the blood-brain barrier (BBB), which is crucial for drugs targeting neurological conditions like Alzheimer's disease (AD). The rationale for the current research is to investigate the potential of ROP as an inhibitor of Microtubule affinity regulating kinase 4 (MARK4)-NFκß in neurodegenerative diseases, specifically AD. The interaction between ROP and MARK4-NFκß holds significant promise in the realm of drug discovery and therapeutic interventions for diseases like AD. Molecular docking and biophysical characterization demonstrate how ROP effectively hinders MARK4 activity, offering detailed insights into their molecular interactions. The present research also investigates the biological aspect of MARK4 shows promise in treating AD, with neuroinflammation playing a crucial role in the disease's progression. Aß42 and ROP were co-administered directly into the cells for the establishment of the AD model. We confirmed that ROP can inhibit the path of MARK4 activity, as evidenced by biophysical characterization, and can enhance the cell viability, lowers the expression of MARK4, decrease the rate of oxidative stress, and attenuate the expression of NFκß, leading to reduced neuronal apoptosis in an in vitro-induced Aß model. Overall, this research provides valuable mechanistic insights into the neuroprotective potential of ROP and its ability to target the MARK4-NFκß pathway.

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BACKGROUND: T2DM is a chronic disorder with progressive neuromuscular alterations. L-arginine (ARG) is the most common semi-essential amino acid having several metabolic functions. AIM: to investigate the impact of L-arginine in combating diabetic-induced neuromyopathy and its possible mechanisms. MATERIALS & METHODS: 24 rats were divided into CON, CON+ARG, DC, DC+ARG. Behavioral tests, Body weight (BW), fasting blood glucose (FBG), insulin, total antioxidant capacity (TAC), malondialdehyde (MDA), plasminogen activator inhibitor-1 (PAI-1), and irisin were done. Creatine kinase-MM (CK-MM), interleukin 4 (IL-4), interleukin 6 (IL-6), TAC, MDA, expression of microRNA-29a mRNA & light chain 3 protein were determined in muscle. Histological and NF-κß immunohistochemical expression in muscle and nerve were assessed. RESULTS: ARG supplementation to diabetic rats improved altered behavior, significantly increased BW, insulin, TAC, irisin and Il-4, decreased levels of glucose, microRNA-29a, NF-κß and LC3 expression, PAI-1, CK-MM and restored the normal histological appearance. CONCLUSIONS: ARG supplementation potently alleviated diabetic-induced neuromuscular alterations.

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The active ingredient in Poria cocos, a parasitic plant belonging to the family Polyporaceae, is Poria cocos polysaccharide (PCP). PCP exhibits liver protection and anti-inflammatory effects, although its effect on alcoholic liver disease (ALD) remains unstudied. This study investigated the mechanism of PCP in improving ALD by regulating the Nrf2 signaling pathway. After daily intragastric administration of high-grade liquor for 4 hours, each drug group received PCPs or the ferroptosis inhibitor ferrostatin-1. The Nrf2 inhibitor ML385 (100 mg/kg/day) group was intraperitoneally injected, after which PCP (100 mg/kg/day) was administered by gavage. Samples were collected after 6 weeks for liver function and blood lipid analysis using an automatic biochemical analyzer. In the alcoholic liver injury cell model established with 150 mM alcohol, the drug group was pretreated with PCP, Fer-1, and ML385, and subsequent results were analyzed. The results revealed that PCP intervention significantly reduced liver function and blood lipid levels in alcohol-fed rats, along with decreased lipid deposition. PCP notably enhanced Nrf2 signaling expression, regulated oxidative stress levels, inhibited NF-κß, and its downstream inflammatory signaling pathways. Furthermore, PCP upregulated FTH1 protein expression and reduced intracellular Fe2+, suggesting an improvement in ferroptosis. In vitro studies yielded similar results, indicating that PCP can reduce intracellular ferroptosis by regulating oxidative stress and improve alcoholic liver injury by inhibiting the production of inflammatory factors.

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Diabetes mellitus is a complex metabolic syndrome that involves dysfunction of spleen and other lymphoid organs. Medicinal plants, including okra (Abelmoschus esculentus (L.) Moench), were used widely for diabetes treatment. Scarce data are available about the potential anti-diabetic effects of okra, the histopathological alterations in splenic tissues and the mechanistic pathways underlying this association. The current research investigated the effects of okra pod extract on the biochemical parameters and expression of CD8+ T cells and nuclear factor kappa (NF-k) B and releasing proinflammatory cytokines in spleen in streptozotocin (STZ)-induced diabetic rat models. A total of 50 mature male Wister albino rats were divided into five isolated groups; the first served as control (untreated) animals, the second (DM group) diabetes induced by STZ (at a dose of 45 mg/kg body weight, administered intraperitoneally), the third group (DM + Insulin): diabetic rats administered insulin subcutaneously (10 units/kg bw/day) daily for 4 weeks, the fourth group was administrated 400 mg/kg okra extract daily for 4 weeks, and diabetic induced rats in the fifth group were administrated 400 mg/kg okra extract daily for 4 weeks. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity in Abelmoschus esculentus (L.) Moench was studied, and the content of phenolic compounds in okra pods was estimated using high-performance liquid chromatography. Diabetes induction led to decreased body weight, increased blood glucose levels. Capsular thickness was significantly increased, white pulp was widely dispersed, and mature lymphocytes in the periphery were also drastically decreased, with thick follicular arteries, necrosis, and depletion of lymphocytes in the germinal center. Red pulp revealed severe congestion and degenerative changes, deposition of hemosiderin granules and lymphocytic depletion. In addition, collagen fiber deposition was increased also in this group. The induction of diabetes exaggerated NF-kß expression and mediated downregulation of the expression of CD8+ T cells in spleen tissue. Interestingly, oral administration of okra extracts post diabetes induction could mitigate and reverse such adverse effects. Altogether, our study points out the potential benefits of okra in improving blood glucose levels and restoring histopathological alterations in splenic tissues through CD8+ T cells and NF-kß expression in a diabetic rat model.

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AIM: Men are more susceptible to liver fibrosis (LF) than women. However, the underlying molecular mechanism, especially the role of estrogen/estrogen receptor (ER) activation in this sexual dimorphism is unclear. Therefore, the aim of the current study was to investigate the impact and the underlying molecular mechanisms of estrogen/ER activation on diethyl nitrosamine (DEN)-induced LF. MAIN METHODS: Thirty ovariectomized (OVX) female rats were randomly allocated into five groups (n = 6), and received no treatment, diethyl nitrosamine (DEN), DEN/fulvestrant, DEN/silymarin or DEN/estradiol benzoate (EB). In addition, three sham groups received no treatment, DEN or DEN/fulvestrant, and one control group that neither ovariectomized nor treated. Directly after treatment, liver injury biomarkers were measured. In addition, hepatic tissue hydroxyproline, TNF- α, TGF- ß, and IL-10 were evaluated. Expression of NF-kß, CD68 (a marker for macrophage infiltration), ER-ß and TLR-4 were measured. Finally, liver tissue histopathology was assessed. KEY FINDINGS: Ovariectomy aggravates DEN-induced LF, as it significantly elevated all liver tissue injury biomarkers. This effect has become even worse after blocking ER by fulvestrant, indicating a protective role of estrogen/ER activation against DEN-induced LF. Inhibition of TLR-4/NF-kß signaling pathway contributed to this protective effect, as estrogen deprivation or blocking of ER significantly activates this pathway during the onset of LF. While administration of EB or silymarin (selective ER-ß activator) improved LF indices and deactivated this pathway. SIGNIFICANCE: These results provide new insight into the pivotal role of estrogen/ER activation via modulation of TLR-4/NF-kß, in the alleviation of LF pathogenesis.

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Microgliosis and neuroinflammation are prominent features of Alzheimer's disease (AD). Disease-responsive microglia meet their increased energy demand by reprogramming metabolism, specifically, switching to favor glycolysis over oxidative phosphorylation. Thus, targeting of microglial immunometabolism might be of therapeutic benefit for treating AD, providing novel and often well understood immune pathways and their newly recognized actions in AD. We report that in the brains of 5xFAD mice and postmortem brains of AD patients, we found a significant increase in the levels of Hexokinase 2 (HK2), an enzyme that supports inflammatory responses by rapidly increasing glycolysis. Moreover, binding of HK2 to mitochondria has been reported to regulate inflammation by preventing mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that its inflammatory role extends beyond its glycolytic activity. Here we report, that HK2 antagonism selectively affects microglial phenotypes and disease progression in a gene-dose dependent manner. Paradoxically, complete loss of HK2 fails to improve AD progression by exacerbating inflammasome activity while its haploinsufficiency results in reduced pathology and improved cognition in the 5XFAD mice. We propose that the partial antagonism of HK2, is effective in slowed disease progression and inflammation through a non-metabolic mechanism associated with the modulation of NFKß signaling, through its cytosolic target IKBα. The complete loss of HK2 affects additional inflammatory mechanisms associated to mitochondrial dysfunction.

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Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC50 value of 5.32 µM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kß, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1ß, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.

Three series of curcumin-based analogs, incorporating other heterocycles, were synthesised with the intention of exploring their potential as anti-inflammatory agents.Subsequently, these analogs underwent biological assessment in macrophages induced by LPS to determine their anti-inflammatory efficacy.Among the fourteen coumarin derivatives synthesised, the most potent anti-inflammatory activity was observed in the coumarin compound 14b, which featured a 3,4-dimethoxybenzylidene hydrazinyl moiety, with an EC₅₀ value of 5.32 µM.The anti-inflammatory effects of compound 14b were achieved through the modulation of signalling pathways such as AKT/mTOR and Nrf2/HO-1, as well as the downregulation of NF-kß, resulting in decreased production of pro-inflammatory cytokines including IL-6, IL-1ß, and TNF-α.Molecular modelling studies revealed that both compound 14b and dexamethasone bind to the same binding site on TNF-α, suggesting that 14b has the potential to serve as a therapeutic agent for TNF-α and other pro-inflammatory cytokines that surpasses that of dexamethasone.

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Dopamine is a well-known neurotransmitter due to its involvement in Parkinson's disease (PD). Dopamine is not only involved in PD but also controls multiple mental and physical activities, such as the pleasure of food, friends and loved ones, music, art, mood, cognition, motivation, fear, affective disorders, addiction, attention deficit disorder, depression, and schizophrenia. Dopaminergic neurons (DOPAn) are susceptible to stressors, and inflammation is a recognized risk for neuronal malfunctioning and cell death in major neurodegenerative diseases. Less is known for non-neurodegenerative conditions. Among the endogenous defenses, bilirubin, a heme metabolite, has been shown to possess important anti-inflammatory activity and, most importantly, to prevent DOPAn demise in an ex vivo model of PD by acting on the tumor necrosis factor-alpha (TNFα). This review summarizes the evidence linking DOPAn, inflammation (when possible, specifically TNFα), and bilirubin as an anti-inflammatory in order to understand what is known, the gaps that need filling, and the hypotheses of anti-inflammatory strategies to preserve dopamine homeostasis with bilirubin included.

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Copper oxide Nanoparticles (CuONPs) are used in different agricultural applications. Large amounts of CuONPs cause organ dysfunction in animals. Our study aim to compare between the toxic effects of CuONanSphere (CuONSp) and CuONanoFlower (CuONF) as new nano-pesticides, determine a less toxic form when used in agricultural applications. To characterize CuONSp and CuONF, we used X-ray diffraction (XRD), Field emission scanning electron microscopy (SEM), and High resolution transmission electron microscopy (HRTEM) and Zeta-sizer device.18 adult male albino rats were divided into three groups (n = 6), (I) control group, (II) and (III) groups were given orally 50 mg/kg/day of CuONSp and CuONF 30 days respectively. CuONSp induced oxidant-antioxidant abnormalities, including an increase in malondialdhyde (MDA) and a decrease in glutathione (GSH) in comparison to CuONF-treated one. CuONSp induced an increase in liver enzymes activities compared to CuONF. Tumour necrosis factor-alfa (TNF-α) detected an increased in liver and lung compared to CuONF. However, histological examinations revealed changes in CuONSp group than CuONF group. Changes in immune-expressions of TNF-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kß) and tumour suppressor gene (p53) were also more identified in CuONSp group than CuONF group. Ultrastructural studies of liver and lung tissues marked alternations were observed in CuONSp group than CuONF group. In conclusion, CuONSp induced biological alternation in liver and lung more than CuONF. So, CuONF is less toxic compared to CuONSp when used as nano-pesticide in agricultural applications.

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Mucopolysaccharidosis type IV A (MPS IVA) is an inborn error of the metabolism (IEM) caused by a deficiency of the enzyme N-acetylgalactosamine 6-sulfate sulfatase (GALNS). Since 2014, enzyme replacement therapy (ERT) is the recommended treatment for these patients. It is known that the inflammatory response is closely related to antioxidant defenses and oxidative stress, and literature shows involvement of oxidative stress in the pathogenesis of IEM. The aim of this study is to investigate the mechanisms of oxidative/nitrative stress and inflammation in patients with MPS IVA under long-term ERT. In the present work we investigate parameters of oxidative/nitrative stress in plasma and urine of MPS IVA patients under long-term ERT and controls, such as plasmatic nitrate/nitrite levels using the LDH Method, urinary di-tyrosine levels by fluorometric method, plasmatic content of sulfhydryl groups, urinary oxidized guanine species by ELISA kit and the plasmatic total antioxidant status. We next evaluated the plasmatic pro and anti-inflammatory cytokines concentration (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α) and the expression of factors and enzymes Nrf-2, NF-κß and HO-1, main mediators between inflammation and oxidative stress. In concern to the oxidative/nitrative stress parameters, there was no significant difference between the groups MPS IVA patients under long-term ERT and controls, showing that there is no overproducing of RNS, no protein damage, no DNA/RNA oxidative damage and no modification in the non-enzymatic antioxidant capacity of a tissue to prevent the damage associated to free radical processes in these patients. It was also verified no significant difference between the MPS IVA patients under long-term ERT and controls groups regarding the production of proinflammatory cytokines. About anti-inflammatory cytokines, IL 10 was shown to be elevated in MPS IVA patients under long-term ERT in comparison to the control group. We next evaluated the genic expression of Nrf-2, NF-κß and HO-1and there was no significant difference between the MPS IVA patients under long-term ERT and control groups. In conclusion, MPS IVA patients under long term ERT are not in an inflammatory state and there is no alteration in genic expression in the genes analyzed which are involved in oxidative stress and inflammatory pathways. It is,however, important to consider that absence of imbalance of antioxidant defenses in MPS IVA patients under long term ERT is so far preliminary it is supported by methodologies that are not highly sensitive nor very accurate. Further experiments in future using state-of-the-art methodologies will corroborate these findings. Nevertheless, our results demonstrated the protective effect of the treatment in relation to the parameters studied and the importance of starting treatment in the early stages of the disease.

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BACKGROUND: Neuroinflammation is a significant contributor to post-ischemic neuronal death after stroke, and Toll-Like Receptors (TLRs) are one of the essential mediators in many inflammatory pathways. TLRs activate the nuclear factor kappa ß (NF-kß), which promotes the expression of various pro-inflammatory genes such as interleukin (IL-1ß) and IL-6. 1,25(OH)2D3, also known as calcitriol, is an active form of vitamin D3 that acts as a neurosteroid compound with anti-inflammatory properties. This study aimed to determine the modulatory effects of calcitriol hormone on post-ischemic immunity response. METHODS: Neurological tests and conventional blood factors were evaluated in patients with stroke symptoms upon arrival (n = 38) to confirm the stroke. A blood sample was taken from each stroke patient immediately upon admission and again after 24 h. The experimental group was given 10 µg calcitriol orally. The gene expression levels of TLR4, TLR2, NF-kß, IL-1ß, and IL-6 pro-inflammatory factors were measured using real-time PCR. The protein expression of TLR4 and NF-kß markers was assessed using the flow cytometry technique. RESULTS: TLR4, NF-kß, and pro-inflammatory factors IL-1ß and IL-6 expression increased significantly after an ischemic stroke, and calcitriol could modulate the TLR4/NF-kß signaling pathway 24 h after ischemia. CONCLUSIONS: Calcitriol may be considered a protective reagent after ischemia by reducing the TLR4/NF-kB activation cascade and probably plays a beneficial role in reducing and improving ischemic stroke patients' symptoms. TRIAL REGISTRATION: Iranian Registry of Clinical Trials identifier: IRCT2017012532174N1.

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The objective of this study was to investigate the effects of onion and apple functional ingredients in homozygous (fa/fa) obese Zucker rats. Rodents were fed three diets: standard diet [obese control (OC) group], standard diet containing 10% onion [obese onion 10% (OO) group] and standard diet containing 10% apple [obese apple 10% (OA) group] for 8 weeks. Food intake and body weight gain were higher in obese than in lean rats. Food efficiency was lower in OO and AO groups compared with OC group. Within the obese groups, total cholesterol, LDL-cholesterol, triacylglycerols, glucose, insulin and triglyceride-glucose index were lower in OO group than in OC group, and HDL-cholesterol was higher in OO group than in OC group. In general, antioxidant activity (ABTS•+ and FRAP), antioxidant enzyme activities (CAT, SOD, GPx), GSH/GSSG ratio, nitrate/nitrite and GLP-1 increased in OO and OA groups compared with OC. Oxidative stress biomarkers, namely protein carbonyls, 8-hydroxy-2'-deoxyguanosine, 8-epi-prostaglandin F2α, inflammatory and vascular injury biomarkers (PAI-1, TIMP-1, VEGF, sICAM-1, sE-Selectin, MCP-1) and leptin, were lower in OO and OA groups than in OC group. Endothelial impairment was partially reversed, and superoxide content and gene expression of NLRP3, NFKß1 and COX2 decreased, in OO and OA groups with respect to OC group. The study demonstrates that high pressure-processed onion and apple functional ingredients administration to obese Zucker rats causes beneficial effects on metabolic health, in particular through improving food efficiency ratio; exerting pronounced lipid-lowering effects; reducing glycemia, insulinemia, and biomarkers of hepatic injury (ALT, AST); improving antioxidant, oxidative stress, inflammatory and vascular injury biomarkers, metabolic hormones, and endothelial function; and decreasing proinflammatory gene expression of NLRP3, NFKß1 and COX2.

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Celiac disease (CD) is an autoimmune disease characterized by an altered immune response stimulated by gliadin peptides that are not digested and cause damage to the intestinal mucosa. The aim of this study was to investigate whether the postbiotic Lactobacillus paracasei (LP) could prevent the action of gliadin peptides on mTOR, autophagy, and the inflammatory response. Most of the experiments performed were conducted on intestinal epithelial cells Caco-2 treated with a peptic-tryptic digest of gliadin (PTG) and P31-43. Furthermore, we pretreated the Caco-2 with the postbiotic LP before treatment with the previously described stimuli. In both cases, we evaluated the levels of pmTOR, p70S6k, and p4EBP-1 for the mTOR pathway, pNFkß, and pERK for inflammation and LC 3 and p62 for autophagy. For autophagy, we also used immunofluorescence analysis. Using intestinal organoids derivate from celiac (CD) patients, we analyzed the effect of gliadin after postbiotic pretreatment with LP on inflammation marker NFkß. Through these experiments, we showed that gliadin peptides are able to induce the increase of the inflammatory response in a more complex model of intestinal epithelial cells. LP postbiotic was able to induce autophagy in Caco-2 cells and prevent gliadin effects. In conclusion, postbiotic pretreatment with LP could be considered for in vivo clinical trials.

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Diabetes mellitus is a metabolic disorder caused by an increase in insulin resistance, a decrease in insulin production, or both of them, resulting in a high level of blood glucose or hyperglycemia. An uncontrolled state of DM may cause complications, namely skin disorder. One or more skin disorders are found amongst 74% of T2DM patients, with the highest percentage is dry skin (47%), followed by infection (10%), diabetic hand (5%), hair loss and diabetic dermopathy (each 4%). In DM, the state of hyperglycemia and production of advanced glycaemic end-products (AGEs) profoundly impact skin changes. In the pathological pathway, AGEs induce oxidative stress and inflammation. Nonetheless, AGEs level is higher in T2DM patients compared to non- T2DM people. This is caused by hyperglycemia and oxidative stress. Binding between AGEs and receptor of AGEs (RAGE) promotes pathway of oxidative stress and inflammation cascade via mitogen- activated protein kinases (MAPK), nuclear factor-k-light-chain-enhancer of activated ß cells (NF-kß), interleukin- 6 (IL-6), tumor necrosis factor-α (TNF-α), expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 2 (VCAM-2) pathway which furtherly effectuates DM complication including skin disorders.

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To investigate the effect of cystic echinococcosis (CE) on liver damage, we developed a secondary experimental echinococcosis in Swiss mice by intraperitoneal inoculation of viable protoscoleces. Mice were randomly allocated into three groups: Ctrl group, PBS group, and CE group. Mice were euthanized and associated indications were investigated to evaluate inflammatory and fibrotic responses in liver. Hepatic damage and fibrotic reaction were histologically analyzed. The hepatic expression of iNOS, TNF-α, NF-κß, vimentin, Bcl-2 and CD68 was evaluated by Immunohistochemical examinations. Interestingly, a significant iNOS, TNF-α, NF-κß, vimentin, Bcl-2 and CD68 increase levels was observed in liver tissue and pericystic layer of hepatic hydatid cyst and correlate with the abundance of collagen and reticulin fibers. These observations could promote a potential target for the treatment of CE-associated hepatic injury.

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AIM: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal pain and stool irregularities. STW 5 has proven clinical efficacy in functional gastrointestinal disorders, including IBS, targeting pathways that suppress inflammation and protect the mucosa. Wnt signaling is known to modulate NF-kß-dependent inflammatory cytokine production. This sparked the idea of evaluating the impact of STW 5 on the expression of inflammatory-response and Wnt/ß catenin-target genes in an IBS-like model. MAIN METHODS: We used zebrafish and dextran sodium sulfate (DSS) treatment to model IBS-like conditions in vivo and in vitro and examined the effects of subsequent STW 5 treatment on the intestines of DSS-treated fish and primary cultured intestinal and neuronal cells. Gross gut anatomy, histology, and the expression of Wnt-signaling and cytokine genes were analyzed in treated animals and/or cells, and in controls. KEY FINDINGS: DSS treatment up-regulated the expression of interleukin-8, tumor necrosis factor-α, wnt3a, and claudin-1 in explanted zebrafish gut. Subsequent STW 5 treatment abolished both the macroscopic signs of gut inflammation, DSS-induced mucosecretory phenotype, and normalized the DSS-induced upregulated expression of il10 and Wnt signaling genes, such as wnt3a and cldn1 in explanted zebrafish gut. Under inflammatory conditions, STW 5 downregulated the expression of the pro-inflammatory cytokine genes il1ß, il6, il8, and tnfα while it upregulated the expression of the anti-inflammatory genes il10 and wnt3a in enteric neuronal cells in vitro. SIGNIFICANCE: Wnt signaling could be a novel target for the anti-inflammatory and intestinal permeability-restoring effects of STW 5, possibly explaining its clinical efficacy in IBS.

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Depression is a common mental illness leading to upset or anxiety, with a high incidence rate in the world. Depression can lead to suicidal thoughts and behavior. The present study aimed to evaluate the effect of the direct oral anticoagulant rivaroxaban (RVX), in the model of depression induced by chronic unpredicted mild stress (CUMS) in rats. Fifty-six male Wister rats were randomly divided into seven experimental groups (8 rats/group); Group 1: Control group given vehicle per oral (p.o.), Group 2: RVXL-control group (received rivaroxaban 20 mg/kg/day, p.o..), Group 3: RVXH-control group (received rivaroxaban 30 mg/kg/day, p.o.), Group 4: chronic unpredictable mild stress (CUMS) group, Group 5: FLX-treated CUMS group (received fluoxetine 10 mg/kg/day, p.o..), Group 6: RVXL-treated CUMS group (received rivaroxaban 20 mg/kg/day, p.o.), and Group 7: RVXH-treated CUMS group (received rivaroxaban 30 mg/kg/day, p.o.). The rats received the drugs from the first day of the experiment and continued till 4 weeks-the duration of the study. The following were measured: monoamine neurotransmitters, malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), superoxide dismutase (SOD), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor-A (VEGF-A). A forced swimming test (FST) was done. Furthermore, histological changes and glial fibrillary acidic protein (GFAP) immunoexpression were evaluated. CUMS showed a significant decrease in hypothalamic neurotransmitters, hippocampal GSH, SOD, BNDF, and VEGF-A with a significant increase in hippocampal MDA, NOx, NF-kß, Myd88, TLR4, TNF-α, and GFAP immunoexpression. RVX showed significant improvement in all parameters (p -value < 0.0001). In conclusion, RVX in a dose-dependent manner possesses potent ameliorative effects against depression by reducing the oxidative stress and inflammatory process, through the regulation of the TLR4/Myd88/NF-kß signaling pathway.

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BACKGROUND: The immune system can produce various inflammatory mediators to protect the body from stress and surgical trauma. However, this excessive inflammatory response will interfere with the body's immune system, causing systemic inflammatory response syndrome and multi-organ failure if allowed to continue. Lidocaine as an anti-inflammatory is used to treat surgical pain and pain arising from the disease process and treat ventricular arrhythmias. This study aims to prove the efficacy of systemic lidocaine injection as an anti-inflammatory drug in BALB/c mice with sterile musculoskeletal injuries. METHODS: This study used a prospective experimental laboratory study on experimental animals of BALB/c mice using a simple randomized design. Sixteen adult white BALB/c mice (male, healthy, 10-12 weeks old, 35-40 g body weight, and no disability) were selected and randomly divided into two groups: the group given lidocaine (2 mg/kg body weight) and a group that was given sterile distilled water. NF-kß and TNF-α protein levels were detected by ELISA, while mRNA expression of NF-kß was analyzed and determined by quantitative real-time PCR. RESULTS: Musculoskeletal injury significantly increased the expression of both mRNA and protein levels of NF-kß and TNF-α protein level. In addition, the NF-kß (protein and mRNA) and TNF-α (protein) levels in rats experiencing inflammation due to musculoskeletal injury were significantly decreased in the lidocaine group (p < 0.001). CONCLUSIONS: The administration of systemic lidocaine injection was able to inhibit the expression of mRNA NF-kß, the protein levels of NF-kß, and protein levels of TNF-α in mice with musculoskeletal injuries.

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BACKGROUND: Metastasis and drug resistance remain a persistent key clinical obstacle to the success of breast cancer treatments. Recent years have seen an increased focus on understanding the factors that influence metastasis and drug resistance. METHODS: In this study, the changes in MMPs gene expression were investigated together with their regulatory pathways-PI3K, MAPK and NFKß pathways-during the process of developing tamoxifen resistance in MCF7 cell line. Gene correlation maps and Kaplan-Meier survival plots among all breast cancer patients and patients treated with tamoxifen were evaluated. RESULTS: MMPs gene expression was found to be up regulated in MCF7 cell line treated with tamoxifen during the development of tamoxifen resistance using two approaches. Up-regulation of gene expression of AKT1 and MAPK1 started in cells treated with 10 µM tamoxifen that was followed with up-regulation of other genes in these pathways and MMPs in cells treated with 35 µM tamoxifen. MMPs and genes from PI3K, MAPK and NFKß pathways showed highly significant increase of expression at 50 µM or when cells were treated sequentially six times with 35 µM. Furthermore, increased genes expression was associated with aggressive pattern, clear morphological changes, higher growth rate, increased migration and adhesion potential and tamoxifen insensitivity. Breast cancer distant metastasis-free survival, and survival among tamoxifen treated patients had high expression levels of MAPK1, AKT1, TIMP2, MMP1, and MMP9 showed poor prognosis. CONCLUSION: Early changes of MAPK1, AKT1 gene expression upon tamoxifen treatment could possibly be used as an early marker of resistance and future poor prognosis.

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The sphingolipid de novo synthesis pathway, encompassing the sphingolipids, the enzymes and the cell membrane receptors, are being investigated for their role in diseases and as potential therapeutic targets. The intermediate sphingolipids such as dihydrosphingosine (dhSph) and sphingosine (Sph) have not been investigated due to them being thought of as precursors to other more active lipids such as ceramide (Cer) and sphingosine 1 phosphate (S1P). Here we investigated their effects in terms of collagen synthesis in primary rat neonatal cardiac fibroblasts (NCFs). Our results in NCFs showed that both dhSph and Sph did not induce collagen synthesis, whilst dhSph reduced collagen synthesis induced by transforming growth factor ß (TGFß). The mechanisms of these inhibitory effects were associated with the increased activation of the de novo synthesis pathway that led to increased dihydrosphingosine 1 phosphate (dhS1P). Subsequently, through a negative feedback mechanism that may involve substrate-enzyme receptor interactions, S1P receptor 1 expression (S1PR1) was reduced.