Acid-induced Model Research Articles

A bibliometric analysis of autism spectrum disorder signaling pathways research in the past decade.

This study employs bibliometric methods to comprehensively understand the fundamental structure of research about Autism Spectrum Disorder (ASD) Signaling Pathways by examining key indicators such as nations, institutions, journals, authors, and keywords. We utilized the WoScc database to retrieve literature relevant to ASD Signaling Pathways published between 2013 and 2023. Through visual analysis and tools like CiteSpace and VosViewer, we explored nations, institutions, journals, authors, and keywords, thereby constructing relevant networks. 26 The study encompasses 1,396 articles, revealing a consistent increase in publications. The United States, China, and Germany are leading nations in this literature. Regarding research institutions, the University of California system and Eric Klann have garnered significant attention due to their substantial contributions to the field of ASD Signaling Pathways. Most relevant research is published in the journal "Molecular Autism." Research interests are concentrated across various themes, including "elevating neuronal β-catenin levels," "Tunisian children," "Fmr1 knockout (KO) mice," "de novo mutations," "autistic children," "local translation," "propionic acid-induced mouse models," "neurosystems," "glucose metabolism," and "neuronal migration." Future research may emphasize exploring aspects such as gut microbiota, genes, stress, maternal immune activation, memory, and neurodevelopmental disorders of ASD. This study, through bibliometric analysis of key indicators such as nations, institutions, journals, authors, and keywords, provides a comprehensive overview of the current state of research on ASD Signaling Pathways. These investigations predominantly focus on molecular mechanisms, animal model studies, population-based research, and the structure and function of neurosystems. Future research directions are also clearly proposed. First, in-depth research on the genes and neurodevelopmental disorders associated with ASD will continue to reveal the genetic basis and provide support for precise treatments. At the same time, attention to the gut microbiota will help explore its association with ASD, which may provide clues for new treatments. In addition, the relationship between stress and ASD will become the focus of research to understand better the emotional and behavioral characteristics of ASD patients in stressful situations. Maternal immune activation will also be further studied to explore how environmental factors influence the risk and development of ASD. Finally, a deeper understanding of the cognitive functions of patients with ASD, especially memory and learning, will help develop individualized treatment strategies to improve patients' quality of life. These directions will work together and are expected to provide a more comprehensive understanding of Signaling Pathways research in ASD and provide new ideas and opportunities for future intervention and treatment.

Effect of the Water Extract of Phlomis umbrosa Turcz. Roots on Non-Alcoholic Fatty Liver in a Free Fatty Acid-Induced Cell Model

Effect of the Water Extract of <i>Phlomis umbrosa</i> Turcz. Roots on Non-Alcoholic Fatty Liver in a Free Fatty Acid-Induced Cell Model

CU06-1004 alleviates oxidative stress and inflammation on folic acid-induced acute kidney injury in mice

PurposeAcute kidney injury (AKI) is characterized by reduced renal function, oxidative stress, inflammation, and renal fibrosis. CU06-1004, an endothelial cell dysfunction blocker, exhibits anti-inflammatory effects by reducing vascular permeability in pathological conditions. However, the potential effects of CU06-1004 on AKI have not been investigated. We investigated the renoprotective effect of CU06-1004 against oxidative stress, inflammation, and fibrotic changes in a folic acid-induced AKI model. MethodsAKI was induced by intraperitoneal injection of high dose (250 mg/kg) folic acid in mice. CU06-1004 was orally administered a low (10 mg/kg) or high dose (20 mg/kg). ResultsCU06-1004 ameliorated folic acid-induced AKI by decreasing serum blood urea nitrogen and creatinine levels, mitigating histological abnormalities, and decreasing tubular injury markers such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in folic acid-induced AKI mice. Additionally, CU06-1004 alleviated folic acid-induced oxidative stress by reducing 4-hydroxynonenal and malondialdehyde levels. Furthermore, it attenuated macrophage infiltration and suppressed the expression of the proinflammatory factors, including tumor necrosis factor-α, intercellular adhesion molecule-1, and vascular cell adhesion protein-1. Moreover, CU06-1004 mitigated folic acid-induced tubulointerstitial fibrosis by decreasing α-smooth muscle actin and transforming growth factor-β expression. ConclusionThese findings suggest CU06-1004 as a potential therapeutic agent for folic acid-induced AKI.

Wikstroemia indica (L.) C. A. Mey. Exerts analgesic activity by inhibiting NaV1.7 channel

Ethnopharmacological relevanceWikstroemia indica (L.) C. A. Mey. is traditionally used for the treatment of gastrointestinal disorders, respiratory illnesses, skin infections, and inflammatory conditions. Despite extensive evidence of its biological potential, including antipyretic, antimicrobial, antifungal, anti-inflammatory, and diuretic properties, there are currently no reports indicating its analgesic effects. Aim of the studyCrude extracts from W. indica stems were examined for anti-nociceptive activity. Additionally, an in-depth investigation was conducted to uncover the molecular basis for the possible analgesic phenomenon. Materials and methodsW. indica stems were subjected to ethanol extraction. To evaluate the in vivo analgesic activity, both chemical and physical-induced pain models were employed. Additionally, single-cell electrophysiological recordings were performed on human embryonic kidney 293T (HEK293T) cells expressing NaV1.7 channel. ResultsCrude extracts derived from W. indica exhibited significant efficacy in mitigating the pain sensation, as evidenced by their substantial effects in both acetic acid-induced and heat-induced pain models. Further screening unveiled osthenol as a key bioactive compound responsible for mediating the analgesic properties of W. indica. Osthenol directly interacts with the pore domain of NaV1.7 channels, leading to channel inhibition. Importantly, this interaction is independent of any changes in the channel gating modifier domain. ConclusionBoth W. indica and osthenol demonstrate potential as effective anti-nociceptive agents in preclinical studies. Their analgesic effects are likely achieved by inhibiting the NaV1.7 channel, which is crucial in pain initiation, transmission, and modulation. These results elucidate the molecular basis of the W. indica as a pain-relieving medication. Additionally, osthenol holds great potential in advancing the development of anti-nociceptive drugs targeting the NaV1.7 channel.

Therapeutic Benefits of Tuna Oil by In Vitro and In Vivo Studies Using a Rat Model of Acetic Acid-Induced Ulcerative Colitis.

Ulcerative colitis (UC), an inflammation of the colon lining, represents the main form of inflammatory bowel disease IBD. Nutritional therapy is extremely important in the management of ulcerative colitis. Fish oil contains long-chain omega-3 polyunsaturated fatty acids, which have beneficial effects on health, including anti-inflammatory effects. This study aims to investigate the benefits of bluefin tuna oil extracted by the Soxhlet method in vitro by determining the anti-radical and anti-inflammatory activities and in vivo by evaluating the preventive and curative effects. The experiments were carried out using two doses of oil (100 and 260 mg/kg) and glutamine (400 and 1000 mg/kg) on the acetic acid-induced UC model. UC has been induced in Wistar rats by intrarectal administration of a single dose of 1 mL acetic acid (5% v/v in distilled water). The obtained results indicate that tuna oil and glutamine have a significant anti-free radical effect. Tuna oil has a marked anti-inflammatory power based on membrane stabilization and inhibiting protein denaturation. The reduction of various UC parameters, such as weight loss, disease activity score DAS, and colonic ulceration in rats pre-treated with tuna oil and glutamine, demonstrate that these treatments have a significant effect on UC. Total glutathione GSH, superoxide dismutase SOD, and catalase activities are significantly restored in the tuna oil and glutamine groups, while lipid peroxidation has been markedly reduced.

Krüppel-like Factor 15 Suppresses Ferroptosis by Activating an NRF2/GPX4 Signal to Protect against Folic Acid-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a common and serious disease with high morbidity and mortality, and its pathophysiological mechanisms are not fully understood. Increasing evidence suggests an important role of ferroptosis in AKI. Krüppel-like factor 15 (KLF15) is a transcription factor involved in several metabolic diseases, but its role in AKI and ferroptosis remains unclear. In this study, we explored the potential role of KLF15 using a folic acid-induced AKI model. Our study showed that KLF15 expression was reduced in kidney tissues of AKI mice, and KLF15 knockout exacerbated folic acid-induced ferroptosis and kidney injury. In vitro studies revealed that the ferroptosis inducer erastin significantly suppressed KLF15 expression in human tubular epithelial cells. Notably, the overexpression of KLF15 attenuated ferroptosis, as evidenced by a decrease in the lipid peroxidation marker of malondialdehyde and the upregulation of glutathione peroxidase 4 (GPX4), while KLF15 knockdown with shRNA exerted the opposite effect. Mechanistically, KLF15 stabilized the protein of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently increased the GPX4 level. Collectively, KLF15 plays an important role in the modulation of ferroptosis in AKI and may be a potential therapeutic target for treating AKI.

Dynamic alterations in metabolomics and transcriptomics associated with intestinal fibrosis in a 2,4,6-trinitrobenzene sulfonic acid-induced murine model.

Intestinal fibrosis is a common and severe complication of inflammatory bowel disease without clear pathogenesis. Abnormal expression of host genes and metabolic perturbations might associate with the onset of intestinal fibrosis. In this study, we aimed to investigate the relationship between the development of intestinal fibrosis and the dynamic alterations in both fecal metabolites and host gene expression. We induced intestinal fibrosis in a murine model using 2,4,6-trinitrobenzene sulfonic acid (TNBS). TNBS-treated or control mice were sacrificed after 4 and 6weeks of intervention; alterations in colonic genes and fecal metabolites were determined by transcriptomics and metabolomics, respectively. Differential, tendency, enrichment, and correlation analyses were performed to assess the relationship between host genes and fecal metabolites. RNA-sequencing analysis revealed that 679 differential genes with enduring changes were mainly enriched in immune response-related signaling pathways and metabolism-related biological processes. Among them, 15 lipid metabolism-related genes were closely related to the development of intestinal fibrosis. Moreover, the fecal metabolic profile was significantly altered during intestinal fibrosis development, especially the lipid metabolites. Particularly, dynamic perturbations in lipids were strongly associated with alterations in lipid metabolism-related genes expression. Additionally, six dynamically altered metabolites might serve as biomarkers to identify colitis-related intestinal fibrosis in the murine model. Intestinal fibrosis in colitis mice might be related to dynamic changes in gene expression and metabolites. These findings could provide new insights into the pathogenesis of intestinal fibrosis.

Krüppel-like factor 12 regulates aging ovarian granulosa cell apoptosis by repressing SPHK1 transcription and sphingosine-1-phosphate (S1P) production

Oxidative stress triggered by aging, radiation, or inflammation impairs ovarian function by inducing granulosa cell (GC) apoptosis. However, the mechanism inducing GC apoptosis has not been characterized. Here, we found that ovarian GCs from aging patients showed increased oxidative stress, enhanced reactive oxygen species activity, and significantly decreased expression of the known antiapoptotic factor sphingosine-1-phosphate/sphingosine kinase 1 (SPHK1) in GCs. Interestingly, the expression of Krüppel-like factor 12 (KLF12) was significantly increased in the ovarian GCs of aging patients. Furthermore, we determined that KLF12 was significantly upregulated in hydrogen peroxide-treated GCs and a 3-nitropropionic acid-induced invivo model of ovarian oxidative stress. This phenotype was further confirmed to result from inhibition of SPHK1 by KLF12. Interestingly, when endogenous KLF12 was knocked down, it rescued oxidative stress-induced apoptosis. Meanwhile, supplementation with SPHK1 partially reversed oxidative stress-induced apoptosis. However, this function was lost in SPHK1 with deletion of the binding region to the KLF12 promoter. SPHK1 reversed apoptosis caused by hydrogen peroxide-KLF12 overexpression, a result further confirmed in an invitro ovarian culture model and an invivo 3-nitropropionic acid-induced ovarian oxidative stress model. Overall, our study reveals that KLF12 is involved in regulating apoptosis induced by oxidative stress in aging ovarian GCs and that sphingosine-1-phosphate/SPHK1 can rescue GC apoptosis by interacting with KLF12 in negative feedback.

GKLF, a transcriptional activator of Txnip, drives microglia activation in kainic acid-induced murine models of epileptic seizures.

Neuroinflammation is a major component of epilepsy. Gut-enriched Kruppel-like factor (GKLF), a transcription factor of Kruppel-like factor family, has been reported to promote microglia activation and mediate neuroinflammation. However, the role of GKLF in epilepsy remains poorly characterized. This study focused on the function of GKLF in neuron loss and neuroinflammation in epilepsy and the molecular mechanism underlying microglia activation induced by GKLF upon lipopolysaccharides (LPS) treatment. An experimental epileptic model was induced by an intraperitoneal injection of 25mg/kg kainic acid (KA). Lentivirus vectors (Lv) carrying Gklf CDS or short hairpin RNA targeting Gklf (shGKLF) was injected into the hippocampus, resulting in Gklf overexpression or knockdown in the hippocampus. BV-2 cells were co-infected with Lv-shGKLF or/and Lv carrying thioredoxin interacting protein (Txnip) CDS for 48h and treated with 1μg/mL LPS for 24h. Results showed that GKLF enhanced KA-induced neuronal loss, pro-inflammatory cytokine secretion, activation of NOD-like receptor protein-3 (NLRP3) inflammasomes and microglia, and TXNIP expression in the hippocampus. GKLF inhibition showed negative effects on LPS-induced microglia activation, as evidenced by reduced pro-inflammatory cytokine secretion and activation of NLRP3 inflammasomes. GKLF bound to Txnip promoter and increased TXNIP expression in LPS-activated microglia. Interestingly, Txnip overexpression reversed the inhibitory effect of Gklf knockdown on microglia activation. These findings indicated that GKLF was involved in microglia activation via TXNIP. This study demonstrates the underlying mechanism of GKLF in the pathogenesis of epilepsy and uncovers that GKLF inhibition may be a therapeutic strategy for epilepsy treatment.

In-vitro and in-vivo assessment of the anti-diabetic, analgesic, and anti-inflammatory potenstials of metal-based carboxylates derivative

In the current research work, an amide based metal carboxylate chemical ([((5-((5-(2-hydroxyethyl)-4-methylthiazol-3-ium-3-yl)methyl)-2-methylpyrimidin-4-yl)amino)bis((4-((4-methoxy-2-nitrophenyl)amino)-4-oxobutanoyl)oxy)zinc]) was identified as anti-diabetic analgesic and anti-inflammatory. The identified chemical(MT-1) was tested for acute toxicity (the MT-1 was fund safe), antidiabetic analgesic, and anti-inflammatory potentials. The in-vitro study was conducted for antidiabetic enzyme inhibition (α-amylase and α-glucosidase) and the in-vivo studies included analgesic (acetic acid-induced writing and hot plate model) and anti-inflammatory (carrageenan etc induced edema) effects. The tested compound showed 88.63% (IC50 = 3.23 μg/ml) and 89.10%(IC50 = 5.10 μg/ml) againstα-amylase and α-glucosidase respectively. A significant (p < 0.001) analgesic effect was noted by MT-1 in acetic acid-induced animal models with a percent effect of 86.00, 60.,06, and 55.29 at the tested doses of 20, 1,0, and 5 mg/kg respectively. In the case of the hot plate model, the MT-1 showed a significant (p < 0.001) effect with maximum percent prolongation in latency observed after 60 min.08, 22.2,9, and 11.61) against 20, 1,0, and 5 mg/kg. The analgesic effect in the hot plate model was significantly (p < 0.01) reversed by the injection of naloxone (0.125 mg/kg). The paw edema induced by carrageenan, histamine, bradykinin, arachidonic acid, and PGE2 was significantly antagonized with percent attenuation of 34.09, 33.57, 34.60, 34.14, and 48.04 respectively. Furthermore, to predict the interactions between the MT-1 compound and COX-2 molecular docking was carried out and the result was compared with the standard compound. The docking score of MT-1 was predicted as −6.30 while that of Diclofenac was predicted as −6.82. Both compounds made several hydrogen bond interactions with the active site of the COX-2 enzyme. The docking study revealed the potent inhibitory potential of the compound MT-1 against the COX-2 receptor.

Study on Chemical Constituents of the Enriched Extracts of Erigeron multiradiatus and Anti-thrombotic Effect on Zebrafish

Background Erigeron multiradiatus (Lindl.) Benth. has been used for years to treat various diseases in Traditional Tibetan Medicine (TTM). Our previous studies have shown that E. multiradiatus extract has important pharmacological effects, such as anti-myocardial ischemia–reperfusion (I/R) injury, anti-inflammatory, and anti-diabetic effects. To date, there have been no reports on using this extract to treat thrombosis. Objectives The aim of this study was to enrich the active components of E. multiradiatus and to further investigate its anti-thrombotic activity. Materials and Methods We used D101 macroporous adsorption resin to enrich the main active substances of E. multiradiatus and performed quantitative determination using ultra-high-performance liquid chromatography with a photodiode array detector (UHPLC-PDA). Furthermore, we investigated the anti-thrombotic effects of E. multiradiatus using three models: an arachidonic acid-induced platelet aggregation thrombotic zebrafish model, a phenylhydrazine-induced red blood cell (RBC)-injuring thrombotic zebrafish model, and a ponatinib-induced vascular endothelial cell (VEC)-injuring thrombotic zebrafish model. Results The yield of active component enrichment of E. multiradiatus was 4.95% using the D101 resin. We accurately determined eight compounds in the extract. Our results showed that these extracts had significant anti-thrombotic effects in the three different zebrafish models. Conclusion The enriched extract of E. multiradiatus could be used as a natural anti-thrombotic agent. Our results will provide a reference for reasonable clinical applications of E. multiradiatus.

Rosmarinic acid ameliorates HCl-induced cystitis in rats.

Shiso (Perilla frutescens var crispa f. purprea) is a traditional medicinal herb that exerts anti-inflammatory effects and alleviates lower urinary tract symptoms. In this study, we examined the effects of rosmarinic acid, a major polyphenol in shiso, on urinary function and the bladder in a rat hydrochloric acid-induced cystitis model. Sprague-Dawley rats were administered intravesically with hydrochloric acid or saline solution (control) to induce cystitis. Afterwards, the rats were administered orally with distilled water or rosmarinic acid for three days and then the intravesical pressure was measured, a stretch stimulation test was performed using the harvested bladder, and histological and biochemical analyses were performed. In addition, we investigated the effects of rosmarinic acid on the expression of inflammation-related molecules in normal human bladder epithelial cells. Rosmarinic acid ameliorated hydrochloric acid-induced shortening of micturition interval by 49%. In hydrochloric acid-treated bladders, significantly more prostaglandin E2 was released after stretching; however, rosmarinic acid suppressed its release to control levels. Rosmarinic acid also reduced hydrochloric acid-induced epithelial thickening and the levels of inflammatory molecules in the bladder. Furthermore, rosmarinic acid suppressed interleukin 1β-induced increases in Cox2 and Il6 expression in bladder epithelial cells. These findings indicate that rosmarinic acid can ameliorate hydrochloric acid-induced cystitis in rats and that these effects are due, at least in part, to its anti-inflammatory effects on the bladder and inhibition of stretch-induced prostaglandin E2 release.

Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits

Temporal lobe epilepsy (TLE), one common type of medically refractory epilepsy, is accompanied with altered adult-born dentate granule cells (abDGCs). However, the causal role of abDGCs in recurrent seizures of TLE is not fully understood. Here, taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner, combined with Ca2+ fiber photometry, trans-synaptic viral tracing, in vivo/vitro electrophysiology approaches, we aimed to test the role of abDGCs born at different period of epileptogenic insult in later recurrent seizures in mouse TLE models. We found that abDGCs were functionally inhibited during recurrent seizures. Optogenetic activation of abDGCs significantly extended, while inhibition curtailed, the seizure duration. This seizure-modulating effect was attributed to specific abDGCs born at a critical early phase after kindled status, which experienced specific type of circuit re-organization. Further, abDGCs extended seizure duration via local excitatory circuit with early-born granule cells (ebDGCs). Repeated modulation of “abDGC-ebDGC” circuit may easily induce a change of synaptic plasticity, and achieve long-term anti-seizure effects in both kindling and kainic acid-induced TLE models. Together, we demonstrate that abDGCs born at a critical period of epileptogenic insult maintain seizure duration via local aberrant excitatory circuits, and inactivation of these aberrant circuits can long-termly alleviate severity of seizures. This provides a deeper and more comprehensive understanding of the potential pathological changes of abDGCs circuit and may be helpful for the precise treatment in TLE.

Excitatory amino acids, possible causative agents of nodding syndrome in eastern Africa

BackgroundNodding syndrome (NS) is one type of epilepsy and a progressive disease characterized by nodding symptoms with children in sub-Saharan Africa. The burden for NS children is heavy, not only mentally but financially for themselves and their families, and yet, the cause and cure of NS remain unknown. The kainic acid-induced model in experimental animals is a well-known epilepsy model that is useful for studying human diseases. In this study, we examined similarities of clinical symptoms and histological brain changes between NS patients and kainic acid-treated rats. In addition, we argued for kainic acid agonist as one of the causes of NS.MethodsClinical signs in rats were studied after kainic acid administration, and histological lesions including the expression of tau protein and gliosis, were examined at 24 h, 8 days, and 28 days after dosing.ResultsKainic acid-induced epileptic symptoms were observed in rats, including nodding accompanied by drooling and bilateral neuronal cell death in the hippocampus and piriform cortex regions. In the regions that exhibited neuronal cell death, an increase in tau protein expression and gliosis were found immunohistochemically. The symptoms and brain histology were similar in the NS and kainic acid-induced rat models.ConclusionThe results suggest that kainic acid agonist may be one of the causative substances for NS.

Qidan Tiaozhi capsule attenuates metabolic syndrome via activating AMPK/PINK1-Parkin-mediated mitophagy.

Qidan Tiaozhi capsule (QD), a traditional Chinese medicine, has been used to treat metabolic syndrome for over a decade. However, the mechanism of QD in the treatment of metabolic syndrome is still unknown. Growing studies demonstrate that impaired mitophagy is one of the important causes of metabolic syndrome. Thus, this research aims to investigate the mechanism of mitophagy in the QD treatment of metabolic syndrome. Network pharmacology and molecular docking were used to probe the mechanism of QD treatment of metabolic syndrome. In an oleic acid-induced cell model, glucose consumption and uptake capacity, triglyceride (TG), total cholesterol (TC), malonaldehyde (MDA), superoxide dismutase (SOD) and ROS levels, and mitochondrial membrane potential (MMP) were examined. mRFP-GFP-LC3 adenovirus and GFP-LC3 lentivirus were used to examine the effect of QD on mitophagy. The IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were also determined. What's more, the PINK1 gene was silenced to verify the above findings. In a high-fat diet-fed mouse model, body weight, organ indexes, OGTT, ITT, HOMA-IR, insulin sensitivity, serum MDA, SOD, TC, TG, LDL-C and HDL-C, hepatic TC, TG, LDL-C and HDL-C levels, hepatic steatosis, and IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were investigated. Results from network pharmacology and molecular docking suggested that QD might suppress oxidative stress to improve metabolic syndrome. In an oleic acid-induced cell model, compared with the model group, enhanced glucose consumption and uptake ability, inhibited intracellular lipid accumulation, TC, TG, MDA and ROS levels, and increased SOD level and MMP were found in QD groups. And mitophagy levels, IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were promoted. Interestingly, PINK1 silencing reversed the therapeutic action of QD on oleic acid-induced cells. In high-fat diet-fed mice, inhibited body weight, abdominal fat indexes, liver indexes, HOMA-IR, serum and hepatic TC, TG and LDL-C, serum MDA and hepatic steatosis, and increased insulin sensitivity, serum and hepatic HDL-C, serum SOD, and activated IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were found in QD groups. QD activates AMPK/PINK1-Parkin-mediated mitophagy to suppress oxidative stress to treat metabolic syndrome.

Shen Shuai II Recipe inhibits hypoxia-induced glycolysis by preserving mitochondrial dynamics to attenuate kidney fibrosis.

Shen Shuai II Recipe (SSR) is a traditional Chinese medicine prescription with significant clinical efficacy in chronic kidney disease (CKD) by invigorating Qi and resolving blood stasis, clearing away heat and dampness. Our previous studies demonstrated that SSR attenuated renal interstitial fibrosis (RIF) by improving hypoxia and mitochondrial dysfunction. The aim of this study was to investigate the potential mechanisms of SSR against RIF. The CKD was established by 5/6 ablation/infarction (A/I) operation. After 4 weeks, rats were gavaged with SSR or Fenofibrate for 8 weeks. Hypoxia-treated NRK-52E cells were treated with SSR and (or) glycolysis inhibitors, including GSK2837808A (GSK) and 2-Deoxy-D-glucose (2-DG). In addition, Drp1-deficient or MFP-M1-treated NRK-52E cells were treated with SSR under hypoxic conditions. The effects of SSR on fibrotic phenotype, glycolysis, mitochondrial dynamics and membrane potential in hypoxia-exposed NRK-52E cells were examined by immunoblotting, colorimetric, and fluorometric methods. Furthermore, we constructed a lactic acid-induced activation model of NRK-49F cells and a co-culture system. The activation of NRK-49F cells was evaluated by immunoblotting method. Our findings indicated that SSR significantly attenuated abnormal glycolysis in vivo and in vitro, which was correlated with its renoprotective effect. Further studies revealed that improvement of mitochondrial dynamics could be one of the mechanisms by which SSR inhibits glycolysis to achieve anti-renal fibrosis. Furthermore, treatment with SSR significantly inhibited the lactic acid-induced activation of NRK-49F cells. The co-culture results further highlighted that SSR inhibited activation of renal fibroblasts and deposition of extracellular matrix by reducing glycolysis in renal tubular cells. SSR alleviates RIF by inhibiting hypoxia-induced glycolysis through improvement of mitochondrial dynamics.

Inflachromene attenuates seizure severity in mouse epilepsy models via inhibiting HMGB1 translocation.

Epilepsy is not well controlled by current anti-seizure drugs (ASDs). High mobility group box 1 (HMGB1) is a DNA-binding protein in the nucleus regulating transcriptional activity and maintaining chromatin structure and DNA repair. In epileptic brains, HMGB1 is released by activated glia and neurons, interacting with various receptors like Toll-like receptor 4 (TLR4) and downstream glutamatergic NMDA receptor, thus enhancing neural excitability. But there is a lack of small-molecule drugs targeting the HMGB1-related pathways. In this study we evaluated the therapeutic potential of inflachromene (ICM), an HMGB-targeting small-molecule inhibitor, in mouse epilepsy models. Pentylenetetrazol-, kainic acid- and kindling-induced epilepsy models were established in mice. The mice were pre-treated with ICM (3, 10 mg/kg, i.p.). We showed that ICM pretreatment significantly reduced the severity of epileptic seizures in all the three epilepsy models. ICM (10 mg/kg) exerted the most apparent anti-seizure effect in kainic acid-induced epileptic status (SE) model. By immunohistochemical analysis of brain sections from kainic acid-induced SE mice, we found that kainic acid greatly enhanced HMGB1 translocation in the hippocampus, which was attenuated by ICM pretreatment in subregion- and cell type-dependent manners. Notably, in CA1 region, the seizure focus, ICM pretreatment mainly inhibited HMGB1 translocation in microglia. Furthermore, the anti-seizure effect of ICM was related to HMGB1 targeting, as pre-injection of anti-HMGB1 monoclonal antibody (5 mg/kg, i.p.) blocked the seizure-suppressing effect of ICM in kainic acid-induced SE model. In addition, ICM pretreatment significantly alleviated pyramidal neuronal loss and granule cell dispersion in kainic acid-induced SE model. These results demonstrate that ICM is an HMGB-targeting small molecule with anti-seizure potential, which may help develop a potential drug for treating epilepsy.

Bee Pollen and Probiotics' Potential to Protect and Treat Intestinal Permeability in Propionic Acid-Induced Rodent Model of Autism.

Rodent models may help investigations on the possible link between autism spectrum disorder (ASD) and gut microbiota since autistic patients frequently manifested gastrointestinal troubles as co-morbidities. Thirty young male rats were divided into five groups: Group 1 serves as control; Group 2, bee pollen and probiotic-treated; and Group 3, propionic acid (PPA)-induced rodent model of autism; Group 4 and Group 5, the protective and therapeutic groups were given bee pollen and probiotic combination treatment either before or after the neurotoxic dose of PPA, respectively. Serum occludin, zonulin, lipid peroxides (MDA), glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPX), catalase, and gut microbial composition were assessed in all investigated groups. Recorded data clearly indicated the marked elevation in serum occludin (1.23 ± 0.15 ng/mL) and zonulin (1.91 ± 0.13 ng/mL) levels as potent biomarkers of leaky gut in the PPA- treated rats while both were normalized to bee pollen/probiotic-treated rats. Similarly, the high significant decrease in catalase (3.55 ± 0.34 U/dL), GSH (39.68 ± 3.72 µg/mL), GST (29.85 ± 2.18 U/mL), and GPX (13.39 ± 1.54 U/mL) concomitant with a highly significant increase in MDA (3.41 ± 0.12 µmoles/mL) as a marker of oxidative stress was also observed in PPA-treated animals. Interestingly, combined bee pollen/probiotic treatments demonstrated remarkable amelioration of the five studied oxidative stress variables as well as the fecal microbial composition. Overall, our findings demonstrated a new approach to the beneficial use of bee pollen and probiotic combination as a therapeutic intervention strategy to relieve neurotoxic effects of PPA, a short-chain fatty acid linked to the pathoetiology of autism.

Amelioration of cognition impairments in the valproic acid-induced animal model of autism by ciproxifan, a histamine H3-receptor antagonist.

Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behavior. Many studies show that the number of cognitive impairmentscan be reduced by antagonists of the histamine H3 receptor (H3R). In this study, the effects of ciproxifan (CPX) (1 and 3 mg/kg, intraperitoneally) on cognitive impairments in rat pups exposed to valproic acid (VPA) (600 mg/kg, intraperitoneally) wereexamined on postnatal day 48-50 (PND 48-50) using marble-burying task (MBT), open field, novel object recognition (NOR), and Passive avoidance tasks. Famotidine (FAM) (10, 20, and 40 mg/kg, intraperitoneally) was also used to determine whether histaminergic neurotransmission exerts its procognitive effects via H2 receptors (H2Rs). Furthermore, a histological investigation was conducted to assess the degree of degeneration of hippocampal neurons. The results revealed that repetitive behaviors increased in VPA-exposed rat offspring in the MBT. In addition, VPA-exposed rat offspring exhibited more anxiety-like behaviors in the open field than saline-treated rats. It was found that VPA-exposed rat offspring showed memory deficits in NOR and Passive avoidance tasks. Our results indicated that 3 mg/kg CPX improved cognitive impairments induced by VPA, while 20 mg/kg FAM attenuated them. We concluded that 3 mg/kg CPX improved VPA-induced cognitive impairments through H3Rs. The histological assessment showed that the number of CA1 neurons decreased in the VPA-exposed rat offspring compared to the saline-exposed rat offspring, but this decrease was not significant. The histological assessment also revealed no significant differences in CA1 neurons in VPA-exposed rat offspring compared to saline-exposed rat offspring. However, CPX3 increased the number of CA1 neurons in the VPA + CPX3 group compared to the VPA + Saline group, but this increase was not significant. This study showed that rats prenatally exposed to VPA exhibit cognitive impairments in the MBT, open field, NOR, and Passive avoidance tests, which are ameliorated by CPX treatment on PND 48-50. In addition, morphological investigations showed that VPA treatment did not lead to neuronal degeneration in the CA1 subfield of the hippocampus in rat pups.

Atorvastatin Improves the Propionic Acid-Induced Autism in Rats: The Roles of Sphingosine-1-Phosphate and Anti-inflammatory Action.

Purpose The aim of this study is to investigate the benefits of atorvastatin on the propionic acid-induced autism model via increasingsphingosine-1-phosphate and anti-inflammatory actions with imaging andbrain tissue investigations. Materials and methods Twenty-five mg/kg/day/rat of propionic acid (PPA) was administered intraperitoneally to 20 male Wistar rats, and 10 male Wistar rats were fed orally. Study groups were designed as follows: Group 1: Control Group (orally fed control, n=10); Group 2 (PPA+saline, n=10); Group 3 (PPA+Atorvastatin, n=10). The brain biochemical and histopathology assessments andmagnetic resonance (MR) imaging were conducted across groups in order to compare them. Results The PPA+Atorvastatingroup was found to have significantly lowerlevels ofbrain malondialdehyde,IL-2level, IL-17, tumor necrosis factor-alpha (TNF-α),and lactate compared to the PPA+saline group.The PPA+Atorvastatingroup had higher levels of nerve growth factor and nuclear factor erythroid 2-related factor 2 (NRF-2)and sphingosine-1-phosphate. In histopathology assessments, the PPA+Atorvastatingroup was found to have significantly higher neuronal counts of CA1 andCA2 in the hippocampus, and Purkinje cells in the cerebellum. Conclusions Current findings suggest that atorvastatin increases sphingosine-1-phosphate levels and decreases inflammatory actions which characterize the autism rodent model implemented in this study.These preliminary results have to be confirmed byfurther experimental and clinical studies.