Sarcopenia and metabolic dysfunction associated steatotic liver disease: Time to address both.

Sarcopenia and metabolic dysfunction associated steatotic liver disease (MASLD) are closely intertwined. Sarcopenia, traditionally a disease of the older adult and chronic disease population, has been closely studied as one of the pathophysiologic conditions at play in the development of MASLD. They share similar risk factors of insulin resistance and physical inactivity. Given similar pathophysiology along the liver-muscle axis, sarcopenia has been studied as a risk factor for MASLD, and vice versa. Current research suggests a bidirectional relationship. Given the chronicity of MASLD as a chronic inflammatory liver disease, it can break down muscle mass and lead to sarcopenia, while sarcopenia promotes intramuscular lipid accumulation that releases cytokines that can aggravate inflammation in the liver. However, for the longest time, a lack of consensus definition for MASLD and sarcopenia made it difficult to study their relationship and outcomes. A recent nomenclature update to diagnosing MASLD has made it easier for researchers to identify cohorts for study. However, no gold standard technique to measure muscle mass or consensus sarcopenia definition has been identified yet. Future studies are needed to reach a consensus and reduce diagnostic variation. With similar pathophysiology and shared risk factors between the two diseases, future research may also identify potential therapeutic targets along the liver-muscle axis that would benefit both sarcopenia and MASLD in order to maximize their outcomes.

Importance of the gut microbiota in the gut-liver axis in normal and liver disease.

The gut microbiota is of growing interest to clinicians and researchers. This is because there is a growing understanding that the gut microbiota performs many different functions, including involvement in metabolic and immune processes that are systemic in nature. The liver, with its important role in detoxifying and metabolizing products from the gut, is at the forefront of interactions with the gut microbiota. Many details of these interactions are not yet known to clinicians and researchers, but there is growing evidence that normal gut microbiota function is important for liver health. At the same time, factors affecting the gut microbiota, including nutrition or medications, may also have an effect through the gut-liver axis.

Assessment of average femoral component rotation for balancing functionally aligned total knee replacement in varus deformity: Robotic image guidance study.

Introduction and purpose: Ensuring proper femoral component alignment post-Total Knee Arthroplasty (TKA) is crucial for normal patellofemoral (PF) kinematics. However, the customary 3° external rotation relative to the Posterior Condylar Axis (PC Axis) may not universally apply, and the expected final femoral component rotation remains unclear in functionally aligned knees. This study examines the relation between the Transepicondylar Axis (TEA) and PC axis, known as Posterior Condylar Angle (PCA) in Indian patients along with factors influencing PCA, and the feasibility of reproducing patient-specific PCA using image-guided Cuvis joint robot. Methods: Forty patients (52 Knees) with primary osteoarthritis and varus deformity were prospectively evaluated. Native PCA was determined using CT-based J planner. Pre-operative patellar shape, PF tilt, PF shift, final femoral component rotation (representing post-operative PCA), final patellar tracking, and post-operative functional and radiological assessment at 3 months were recorded. Results: Study participants averaged 64.3 years of age, with a female-to-male ratio of 23 to 17. Varus deformities varied, with IA2 being most prevalent, and sagittal plane deformities included fixed flexion (34.6 %) and hyperextension (44.2 %). The average PCA was 1.9° (range: 0°-7.3°), with most knees (41 out of 52) below 3°. The majority had Wiberg type 1 patellae, with pre-operative patellar tilt averaging 5.63°, reducing post-operatively to 4.43°. Most patients (37 out of 40) achieved excellent Knee Society functional scores at the 3-month mark. Complications included one case of delayed wound healing and one femoral array pin breakage. Notably, our study revealed a significant deviation in PCA from the commonly reported 3° in Western literature, underscoring the need for region-specific considerations in TKA planning. Conclusion: PCA of our population is statistically different from customary 3° followed with jig system. Image guided Robotics helps to identify patients specific PCA and reproducing the same was more commonly possible in patients with reducible Varus deformity.

Mendelian randomization study and mediation analysis about the relation of inflammatory bowel disease and diabetic retinopathy: the further exploration of gut-retina axis.

Background: The concept of the gut-retinal axis proposed by previous scholars primarily focused on the relationship between intestinal microbiota and retinal diseases, and few further expanded the relationship between intestinal diseases and retinal diseases. To further substantiate the concept of the gut-retinal axis, we analyzed inflammatory bowel disease (IBD) and diabetic retinopathy (DR) using Mendelian randomization (MR), and use mediation analysis to further explore the potential substances that influence this causal relationship. Methods: The genome-wide association study's (GWAS) summary statistics for genetic variations were utilized in a Mendelian randomization (MR) investigation. GWAS data on IBD (including ulcerative colitis (UC), Crohn's disease (CD), and IBD) for non-Finnish Europeans (NFE) were sourced from published articles. In contrast, data on DR (including DR and diabetic maculopathy (DMP)) were obtained from FinnGen R9. The causal relationship has been investigated using inverse variance weighted (IVW), MR-Egger, and weighted median and sensitivity analysis was applied to verify the stability of the results. In addition, we applied mediation analysis to investigate whether circulating inflammatory proteins and plasma lipids played a mediating role, and calculated its effect ratio. Results: The causal relationship between IBD and DR was discovered by employing the inverse variance weighted (IVW) method and weighted median method. In forward MR, UC was significantly associated with lower risk of DR (IVW: OR=0.874; 95%CI= 0.835-0.916; P value= 1.28E-08) (Weighted median: OR=0.893; 95%CI= 0.837-0.954; P value= 7.40E-04). In reverse MR, it was shown that DR (IVW: OR=0.870; 95%CI= 0.828-0.914; P value= 2.79E-08)(Weighted median: OR=0.857; 95%CI= 0.801-0.916; P value= 6.40E-06) and DMP (IVW: OR=0.900; 95%CI= 0.865-0.937; P value= 3.34E-07)(Weighted median: OR=0.882; 95%CI= 0.841-0.924; P value= 1.82E-07) could reduce the risk of CD. What's more, DR is associated with a lower risk of IBD according to genetic prediction (IVW: OR=0.922; 95%CI= 0.873-0.972; P value= 0.002) (Weighted median: OR=0.924; 95%CI= 0.861-0.992; P value= 0.029). Fibroblast growth factor 21 (FGF21), phosphatidylcholine (PC), and triacylglycerol (TG) serve as mediators in these relationships. Conclusions: Our research offers novel insights and sources for investigating the gut-retina axis in the genetic relationship between IBD and DR. We discover four mediators and more about the association between the intestine and retinal disorders and provide more evidence for the gut-retinal axis theory.

Hypothalamus-pituitary-adrenal axis (HPA axis) suppression with inappropriate use of steroids in recalcitrant dermatophytosis - A cross-sectional study.

Background: Improper use of over-the-counter (OTC) steroid medication has been linked to recalcitrant dermatophytosis. There is proven evidence of HPA axis suppression by the use of long-term oral steroids. This study aims to determine the prevalence and pattern of inappropriate OTC steroid use and its effects on the hypothalamus-pituitary-adrenal (HPA) axis in adults with recalcitrant dermatophytosis. Materials and Methods: This cross-sectional study of 2 months was conducted in a hospital setting and included patients of recalcitrant dermatophytosis with a history of OTC steroid use. Clinico-demographic details and basal serum cortisol levels were recorded in all and analyzed. Result: Of a total of 103 patients, 59.22% (n = 61/103) were males, and the mean duration of steroid abuse was 17.78 months. About 48.54% (n = 50/103), 3.88% (n = 4/103), and 47.57% (n = 49/103) patients reported the use of topical steroids, oral steroids, and both oral and topical steroids, respectively. Among all the topical steroid users (n = 99), clobetasol propionate 48.48% (n = 48/99), while among oral steroid users (n = 53), prednisolone 45.28% (n = 24/53) were the most commonly used agents, respectively. The morning serum cortisol levels (8-9 AM) were found to be decreased in 42.7% (n = 44/103), with a mean value of 44.28 ± 17.34 µg/dL. Conclusion: Improper OTC steroid use in recalcitrant dermatophytosis leads to HPA axis suppression. This highlights the need for intervention from apex health officials.

Huanglian Wendan Decoction Improves Insomnia in Rats by Regulating BDNF/TrkB Signaling Pathway Through Gut Microbiota-Mediated SCFAs and Affecting Microglia Polarization.

Insomnia is a typical type of sleep disorder. Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) with the effects of regulating Qi, drying dampness and resolving phlegm, calming the mind, and relieving irritation. This study aims to investigate the effect of HWD on insomnia in rats and its mechanism. Para-chlorophenylalanine (PCPA)-induced insomnia in rats was used for in vivo experiments and then treated with HWD. Behavioral tests, Western blot, real-time PCR, immunofluorescent staining, 16S rRNA sequencing were conducted. The content of SCFAs was determined by GC-MS. Acetic acid-pretreated rat hippocampal nerve cells were used for in vitro experiments. The results showed that HWD significantly improved the learning memory ability, decreased sleep latency, and prolonged sleep duration in insomniac rats. HWD reduced TNF-α and IL-6 levels and increased IL-10 and Foxp3 levels. HWD also promoted the polarization of macrophages from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. In addition, HWD increased the expression levels of BDNF and TrkB in the hippocampus. Administration of the TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) confirmed the mechanism by which HWD activates BDNF/TrkB signaling to ameliorate insomnia. Furthermore, HWD restored gut microbiota richness and diversity and promoted short-chain fatty acid (SCFA) production in insomniac rats. In vitro experiments confirmed that the acetic acid-treated SCFA group could activate the BDNF/TrkB signaling pathway in neuronal cells, further promoting neuronal cell growth. In conclusion, HWD alleviated insomnia by maintaining gut microbiota homeostasis, promoting SCFA production, reducing neuroinflammatory response and microglia activation, and activating BDNF/TrkB signaling pathway.

Fecal bacteria and short-chain fatty acids in irritable bowel syndrome: Relations to subtype.

BACKGROUND: The relationship between gut microbiota and irritable bowel syndrome (IBS) subtype is unclear. We aimed to explore whether differences in fecal bacteria composition and short-chain fatty acid (SCFA) levels were associated with subtypes and symptoms of IBS. METHODS: All participants delivered fecal samples and self-reports on IBS Symptom Severity Score (IBS-SSS), Bristol Stool Scale (BSS), and Gastrointestinal Symptom Rating Scale (GSRS). Fecal bacteria composition was assessed by the GA-map® Dysbiosis Test based on 16S rRNA sequences of bacterial species/groups. SCFAs were analyzed by vacuum distillation followed by gas chromatography. KEY RESULTS: Sixty patients with IBS were included (mean age 38 years, 46 [77%] females): Twenty-one patients were classified as IBS-D (diarrhea), 31 IBS-M (mixed diarrhea and constipation), and eight IBS-C (constipation). Forty-two healthy controls (HCs) (mean age 35 years, 27 [64%] females) were included. Patients had a significantly higher relative frequency of dysbiosis, lower levels of Actinobacteria, and higher levels of Bacilli than HCs. Eight bacterial markers were significantly different across IBS subgroups and HCs, and 13 bacterial markers were weakly correlated with IBS symptoms. Clostridia and Veillonella spp. had a weak negative correlation with constipation scores (GSRS) and a weak positive correlation with loose stools (BSS). Diarrhea scores (GSRS) and looser stool (BSS) were weakly correlated with levels of total SCFAs, acetic and butyric acid. Levels of total SCFAs and acetic acid were weakly correlated with symptom severity (IBS-SSS). CONCLUSIONS & INFERENCES: Patients with IBS had a different fecal bacteria composition compared to HCs, and alterations of SCFAs may contribute to the subtype.

Hydroxysafflor yellow A exerts anti-fibrotic and anti-angiogenic effects through miR-29a-3p/PDGFRB axis in liver fibrosis.

BACKGROUND: Liver fibrosis is a prevalent pathological process in chronic liver diseases characterized by excessive extracellular matrix (ECM) deposition and abnormal angiogenesis. Notably, hepatic stellate cells (HSCs) are the primary source of ECM. Activated HSCs not only secrete numerous pro-fibrotic cytokines but also are endowed with a pro-angiogenic phenotype to promote pathological angiogenesis. Therefore, targeted modulation of HSCs has emerged as a pivotal strategy for addressing liver fibrosis. Hydroxysafflor yellow A (HSYA) is a homology of medicine and food colourant with good pharmacological activity. However, the precise mechanisms of HSYA against liver fibrosis remain unclear. PURPOSE: The objective of this study was to elucidate the impact of HSYA on liver fibrosis and pathological angiogenesis, as well as the underlying mechanisms in vitro and in vivo studies. METHODS: The efficacy and mechanisms of HSYA on TGF-ß1-induced HSCs and VEGFA-induced endothelial cells were investigated by MTT assay, EdU cell proliferation assay, cell scratch assay, Elisa assay, immunofluorescence assay, molecular docking, cell transfection assay, western blot analysis and RT-qPCR analysis. In CCl4-induced liver fibrosis mice model, H&E, Masson, and Sirius red staining were used to observe histopathology. Serum transaminase activity and liver biochemical indexes were tested by biochemical kit. Immunohistochemical, fluorescence in situ hybridization (FISH), western blot analysis and RT-qPCR analysis were implemented to determine the mechanism of HSYA in vivo. RESULTS: Herein, our findings confirmed that HSYA inhibited the proliferation, migration and activation of HSCs, as evidenced by a reduction in cell viability, relative migration rate, EdU staining intensity, and pro-fibrotic mRNAs and proteins expression in vitro. Mechanistically, HSYA played an anti-fibrotic and anti-angiogenic role by partially silencing PDGFRB in activated HSCs, thereby disrupting PDGFRB/MEK/ERK signal transduction and inhibiting the expression of HIF-1α, VEGFA and VEGFR2 proteins. Importantly, PDGFRB was a target gene of miR-29a-3p. Treatment with HSYA reversed the down-regulation of miR-29a-3p and antagonized PDGFRB signaling pathway in TGF-ß1-induced HSCs transfected with miR-29a-3p inhibitor. Consistent with our in vitro study, HSYA exhibited a good hepatoprotective effect in CCl4-induced liver fibrosis mice by reducing serum ALT and AST levels, decreasing the contents of four fibrosis indicators (HA, PIIIP, ColIV and LN) and hydroxyproline, and inhibiting the TGF-ß1/TGFBR signaling pathway. In terms of mechanisms, HSYA alleviated pathological angiogenesis in fibrotic liver by deactivating PDGFRB signaling pathway and impairing the positive expression of CD31. Subsequently, FISH results further corroborated HSYA affected the activation of HSCs and angiogenesis achieved by the concurrent upregulation of miR-29a-3p and downregulation of α-SMA and VEGFA. Additionally, treatment with HSYA also forged a link between HSCs and endothelial cells, as supported by inhibiting the aberrant proliferation of endothelial cells. CONCLUSION: Fundamentally, the current study has illustrated that HSYA ameliorates liver fibrosis by repressing HSCs-mediated pro-fibrotic and pro-angiogenic processes, which is contingent upon the regulatory effect of HSYA on the miR-29a-3p/PDGFRB axis. These findings provide compelling evidence bolstering the potential of HSYA as a therapeutic agent in liver fibrosis.

FOXQ1, deubiquitinated by USP10, alleviates sepsis-induced acute kidney injury by targeting the CREB5/NF-κB signaling axis.

Sepsis-induced acute kidney injury (S-AKI) is a severe and frequent complication that occurs during sepsis. This study aimed to understand the role of FOXQ1 in S-AKI and its potential upstream and downstream regulatory mechanisms. A cecal ligation and puncture induced S-AKI mouse model in vivo and an LPS-induced HK-2 cell model in vitro were used. FOXQ1 was significantly upregulated in CLP mice and downregulated in the LPS-induced HK-2 cells. Upregulation of FOXQ1 improved kidney injury and dysfunction in CLP mice. Overexpression of FOXQ1 remarkably suppressed the apoptosis and inflammatory response via down-regulating oxidative stress indicators and pro-inflammatory factors (IL-1ß, IL-6, and TNF-α), both in vivo and in vitro. From online analysis, the CREB5/NF-κB axis was identified as the downstream target of FOXQ1. FOXQ1 transcriptionally activated CREB5, upregulating its expression. Overexpression of FOXQ1 suppressed the phosphorylation level and nucleus transport of p65. Rescue experiments showed that CREB5 mediates the protective role of FOXQ1 on S-AKI. Furthermore, FOXQ1 was identified as a substrate of USP10, a deubiquitinating enzyme. Ectopic expression of USP10 reduced the ubiquitination of FOXQ1, promoting its protein stability. USP10 upregulation alleviated LPS-induced cell apoptosis and inflammatory response, while suppression of FOXQ1 augmented these trends. Collectively, our results suggest that FOXQ1, deubiquitinated by USP10, plays a protective role in S-AKI induced inflammation and apoptosis by targeting CREB5/NF-κB axis.

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Alzheimer's Disease (AD) is the 5th leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a 3-fold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse (via a model of hindlimb immobilization (HLI)) on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-month-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of APP and tau protein in the hippocampus, 4) and reduced BDNF expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.

Where Do Core Thalamocortical Axons Terminate in Mammalian Neocortex When There Is No Cytoarchitecturally Distinct Layer 4?

Although the mammalian cerebral cortex is most often described as a hexalaminar structure, there are cortical areas (primary motor cortex) and species (elephants, cetaceans, and hippopotami), where a cytoarchitecturally indistinct, or absent, layer 4 is noted. Thalamocortical projections from the core, or first order, thalamic system terminate primarily in layers 4/inner 3. We explored the termination sites of core thalamocortical projections in cortical areas and in species where there is no cytoarchitecturally distinct layer 4 using the immunolocalization of vesicular glutamate transporter 2, a known marker of core thalamocortical axon terminals, in 31 mammal species spanning the eutherian radiation. Several variations from the canonical cortical column outline of layer 4 and core thalamocortical inputs were noted. In shrews/microchiropterans, layer 4 was present, but many core thalamocortical projections terminated in layer 1 in addition to layers 4 and inner 3. In primate primary visual cortex, the sublaminated layer 4 was associated with a specialized core thalamocortical projection pattern. In primate primary motor cortex, no cytoarchitecturally distinct layer 4 was evident and the core thalamocortical projections terminated throughout layer 3. In the African elephant, cetaceans, and river hippopotamus, no cytoarchitecturally distinct layer 4 was observed and core thalamocortical projections terminated primarily in inner layer 3 and less densely in outer layer 3. These findings are contextualized in terms of cortical processing, perception, and the evolutionary trajectory leading to an indistinct or absent cortical layer 4.

Post-surgical Median Arcuate Ligament Syndrome (MALS) Symptom Exacerbation Treated With Osteopathic Manipulative Treatment (OMT): A Case Report.

Median arcuate ligament syndrome (MALS, also known as celiac artery compression syndrome, celiac axis syndrome, celiac trunk compression syndrome, Dunbar syndrome, or Harjola-Marable syndrome) is a rare condition characterized by abdominal pain attributed to the compression of the celiac artery and celiac ganglia by the median arcuate ligament. Pain can occur post-prandially and may be accompanied by weight loss, nausea, or vomiting. Following angiographic diagnosis, current definitive treatment may include open or laparoscopic decompression surgery with celiac ganglion removal (if affected), which has been found to provide relief. In this case report, we outline a young female patient with a MALS diagnosis and subsequent surgery, but whose pain recurred in various stress-related instances even after surgical intervention. After a particular pain episode, osteopathic manipulative treatment (OMT) was applied, with a focus on restoring autonomic balance through the use of various gentle osteopathic treatment techniques. A significant reduction in pain was reported post-treatment, followed by complete pain resolution, indicating a great benefit to the incorporation of OMT into the treatment plan of MALS patients in future osteopathic practice.

Mild cognitive impairment and microbiota: what is known and future perspectives.

Mild cognitive impairment (MCI) is a heterogeneous condition definable as the intermediate clinical state between normal aging and dementia. As a pre-dementia condition, there is a recent growing interest in the identification of non-invasive markers able to predict the progression from MCI to a more advanced stage of the disease. Previous evidence showed the close link between gut microbiota and neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD). Conversely, the actual relationship between gut microbiota and MCI is yet to be clarified. In this work, we provide an overview about the current knowledge regarding the role of gut microbiota in the context of MCI, also assessing the potential for microbiota-targeted therapies. Through the review of the most recent studies focusing on this topic, we found evidence of an increase of Bacteroidetes at phylum level and Bacteroides at genus level in MCI subjects with respect to healthy controls and patients with AD. Despite such initial evidence, the definitive identification of a typical microbiota profile associated with MCI is still far from being achieved. These preliminary results, however, are growingly encouraging research on the role of gut microbiota modulation in improving the cognitive status of pre-dementia subjects. To date, few studies evaluated the role of probiotics in MCI subjects, and they showed favorable results, although still biased by small sample size, heterogeneity of study design and short follow-up.

Hypoxia triggers cardiomyocyte apoptosis via regulating the m6A methylation-mediated LncMIAT/miR-708-5p/p53 axis.

Long-time hypoxia induced cardiomyocyte apoptosis is an important mechanism of myocardial ischemia (MI) injury. Interestingly, long noncoding RNA myocardial infarction-associated transcript (LncMIAT) has been involved in the regulation of MI injury; however, the underlying mechanism by which LncMIAT affects the progression of hypoxia-induced cardiomyocyte apoptosis remains unclear. In the present study, hypoxia was found to promote cardiomyocyte apoptosis through an increased expression of LncMIAT in vitro. Biological investigations and dual-luciferase gene reporter assay further revealed that LncMIAT was able to bind with miR-708-5p to upregulate the p53-mediated cell death of the cardiomyocytes. Silencing of LncMIAT or overexpression of miR-708-5p led to a significant reduction in p53-mediated cardiomyocyte apoptosis. The methylated RNA immunoprecipitation (MeRIP)-qPCR results showed that hypoxia exerted its effects on LncMIAT through AKLBH5-N6-methyladenosine (m6A) methylation and therefore hypoxia was shown to trigger HL-1 cardiomyocyte apoptosis via the m6A methylation-mediated LncMIAT/miR-708-5p/p53 axis. Silencing of AKLBH5 significantly alleviated the m6A methylation-mediated LncMIAT upregulation and p53-mediated cardiomyocyte apoptosis, while promoted miR-708-5p expression. Taken together, the present study highlighted that LncMIAT could act as a key biological target during hypoxia-induced cardiomyocyte apoptosis. In addition, it was shown that hypoxia could promote cardiomyocyte apoptosis through regulation of the m6A methylation-mediated LncMIAT/miR-708-5p/p53 signaling axis.

Gut microbiota and serum metabolomic alterations in modulating the impact of fecal microbiota transplantation on ciprofloxacin-induced seizure susceptibility.

Introduction: The gut microbiota and the microbiota-gut-brain axis have gained considerable attention in recent years, emerging as key players in the mechanisms that mediate the occurrence and progression of many central nervous system-related diseases, including epilepsy. In clinical practice, one of the side effects of quinolone antibiotics is a lower seizure threshold or aggravation. However, the underlying mechanism remains unclear. Methods: We aimed to unravel the intrinsic mechanisms through 16S rRNA sequencing and serum untargeted metabolomic analysis to shed light on the effects of gut microbiota in ciprofloxacin-induced seizure susceptibility and lithium pilocarpine-induced epilepsy rat models. Results: We observed that ciprofloxacin treatment increased seizure susceptibility and caused gut dysbiosis. We also found similar changes in the gut microbiota of rats with lithium pilocarpine-induced epilepsy. Notably, the levels of Akkermansia and Bacteroides significantly increased in both the ciprofloxacin-induced seizure susceptibility and lithium pilocarpine-induced epilepsy rat models. However, Marvinbryantia, Oscillibacter, and Ruminococcaceae_NK4A214_group showed a coincidental reduction. Additionally, the serum untargeted metabolomic analysis revealed decreased levels of indole-3-propionic acid, a product of tryptophan-indole metabolism, after ciprofloxacin treatment, similar to those in the plasma of lithium pilocarpine-induced epilepsy in rats. Importantly, alterations in the gut microbiota, seizure susceptibility, and indole-3-propionic acid levels can be restored by fecal microbiota transplantation. Conclusion: In summary, our findings provide evidence that ciprofloxacin-induced seizure susceptibility is partially mediated by the gut microbiota and tryptophan-indole metabolism. These associations may play a role in epileptogenesis, and impacting the development progression and treatment outcomes of epilepsy.

Beneficial effects of Dendrobium officinale National Herbal Drink on metabolic immune crosstalk via regulate SCFAs-Th17/Treg.

BACKGROUND: The development of gut-liver axis metabolic immune crosstalk is intimately associated with intestinal barrier disorder, intestinal SCFAs-Th17/Treg immunological imbalance, and disorders of the gut microbiota. Prior research has discovered that Dendrobium officinale National Herbal Drink (NHD), a traditional Chinese medicine drink with enhanced immunity, may enhance the immunological response in animals with impaired immune systems brought on by cyclophosphamide by repairing intestinal barrier function and controlling turbulence in the gut microbiota. However, whether NHD can further improve the gut-liver axis metabolic immune crosstalk and its related mechanisms need to be systematically studied. OBJECTIVES: The purpose of this study is to clarify the function and mechanism of NHD in enhancing the gut-liver axis metabolic immunological crosstalk brought on by excessive alcohol intake. METHODS: In this work, we set up a mouse model to analyze the metabolic and immunological crosstalk involving the gut-liver axis across 7 weeks of continuous, excessive drinking. At the same time, high and low doses (20,10 ml/kg) of NHD were given by gavage. The effect of NHD on improving the metabolism of gut-liver axis was evaluated by blood lipid, liver lipid deposition, liver function and intestinal pathophysiology. By measuring serum immunological indices, intestinal barrier, and intestinal immune barrier, the impact of NHD on enhancing immune and intestinal barrier function was assessed. Furthermore, immunohistochemistry, immunofluorescence, 16S rRNA, Western blot, q-PCR and other methods were used to detect gut microbiota, SCFAs-GPR41/43 pathway, intestinal Th17/Treg immune cells and PPAR-α-NPC1L1/SREBP1 pathway to elucidate the mechanism by which NHD enhances the gut-liver axis' metabolic immune crosstalk. RESULTS: Our study demonstrated that NHD has the potential to improve the pathophysiological damage caused by gut-liver axis in model mice. NHD also ameliorated the disorder of lipid metabolism. In addition, it regulated the levels of peripheral blood T cell immunity and serum immune factors. And NHD can restore intestinal mechanical and immune barrier damage. NHD has a favorable impact on the quantity of beneficial bacteria, including uncultured_bacterium_g__norank_f__muribaculacea and uncultured_bacterium_g__Turicibacter. Additionally, it raised the model mice's levels of SCFAs (n-butyric acid, isovaleric acid, etc.). This resulted in the promotion of intestinal GPR41/43-ERK1/2 expression and the reshaping of intestinal CD4+T cell Th17/Treg homeostasis. As a consequence, colon IL-22 and IL-10 levels increased, while colon IL-17A levels decreased. Lastly, NHD raised the amount of intestinal IAP/LPS, regulated the development of PPAR-α-NPC1L1/SREBP1 pathway in gut-liver axis, and improve lipid metabolism disorder. CONCLUSIONS: Our study found that NHD can improve the gut-liver axis metabolic immune crosstalk in model mice caused by excessive drinking. The mechanism might be connected to how NHD controls gut microbiota disorders in model mice, the activation of intestinal SCFAs-GPR41/43 pathway, the remodeling of Th17/Treg immune homeostasis of intestinal CD4+T cells, the improvement of IAP/LPS abnormality, and further mediating the PPAR-α-NPC1L1/SREBP1 pathway of lipid metabolism in gut-liver axis.

Mechanism research on microRNA-669f-5p/deoxycytidylate deaminase axis mediating sevoflurane-induced cognitive dysfunction in aged mice.

OBJECTIVE: To investigate the role of the microRNA (miRNA)-669f-5p/deoxycytidylate deaminase (Dctd) axis in sevoflurane inducing cognitive dysfunction in aged mice. METHODS: Sixty-six C57BL/6J mice were used in the experiment model and were randomly divided into the sevoflurane group and the control group. The mice in the sevoflurane group were anesthetised with 3.4% sevoflurane, whereas those in the control group were air-treated for the same period. The study was then performed using bioinformatics sequencing, as well as in vitro and in vivo validation. RESULTS: The mice in the sevoflurane group showed significant cognitive impairments in terms of a decrease in both spatial learning and memory abilities. Experimental doses of miR-669f-5p agonist exhibited no obvious effect on cognitive function following sevoflurane inhalation, but inhibiting the expression of miR-669f-5p could alleviate the impairments. Based on the results of the bioinformatics sequencing, miR-669f-5p/Dctd and the toll-like receptor (TLR) signalling pathway could be the key miRNA, gene and pathway leading to postoperative cognitive dysfunction following sevoflurane inhalation. The aged mice showed significantly increased expression of miR-669f-5p in the hippocampus following sevoflurane inhalation, and upregulating/inhibiting its expression could increase/decrease TLR expression in the hippocampus. Furthermore, miR-669f-5p could reduce the expression of the Dctd gene by binding to its 3'untranslated region. CONCLUSION: The miR-669f-5p/Dctd axis plays an important role in sevoflurane inducing cognitive dysfunction in aged mice, providing a new direction for further development of therapeutic strategies concerning the prevention and treatment of cognitive dysfunction associated with sevoflurane anaesthesia.

The Gut Microbiota-Brain Axis: A New Frontier in Alzheimer's Disease Pathology.

Dr. Aloysius Alzheimer, a German neuropathologist and psychiatrist, recognized the primary instance of Alzheimer's disease (AD) for a millennium, and this ailment, along with its related dementias, remains a severe overall community issue related to health. Nearly fifty million individuals worldwide suffer from dementia, with Alzheimer's illness contributing to between 60 and 70% of the instances, estimated through the World Health Organization. In addition, 82 million individuals are anticipated to be affected by the global dementia epidemic by 2030 and 152 million by 2050. Furthermore, age, environmental circumstances, and inherited variables all increase the likelihood of acquiring neurodegenerative illnesses. Most recent pharmacological treatments are found in original hypotheses of disease, which include cholinergic (drugs that show affective cholinergic system availability) as well as amyloid-accumulation (a single drug is an antagonist receptor of Nmethyl D-aspartate). In 2020, the FDA provided approval on anti-amyloid drugs. According to mounting scientific data, this gut microbiota affects healthy physiological homeostasis and has a role in the etiology of conditions that range between obesity and neurodegenerative disorders like Alzheimer's. The microbiota-gut-brain axis might facilitate interconnection among gut microbes as well as the central nervous system (CNS). Interaction among the microbiota-gut system as well as the brain occurs through the "two-way" microbiota-gut-brain axis. Along this axis, the stomach as well as the brain develop physiologically and take on their final forms. This contact is constant and is mediated by numerous microbiota-derived products. The gut microbiota, for instance, can act as non-genetic markers to set a threshold for maintaining homeostasis or getting ill. The scientific community has conducted research and found that bowel dysbiosis and gastrointestinal tract dysregulation frequently occur in Alzheimer's disease (AD) patients. In this review, the effects of the microbiota- gut-brain axis on AD pathogenesis will be discussed.

Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma.

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.

Reducing neuroendocrine psychosocial stress response through socio-emotional dyadic but not mindfulness online training.

Introduction: Stress-related diseases pose significant health risks and show wide prevalence. Empirical evidence suggests that contemplative practices, such as socio-emotional dyadic mental exercises, hold promise in mitigating the adverse effects of stress and promoting psychosocial well-being. This study aimed to investigate the differential effects of two online contemplative mental training programs on the psychosocial stress response: the first involved classic mindfulness practices, while the second incorporated a socio-emotional dyadic approach known as Affect Dyad. Methods: The study was conducted as part of the longitudinal CovSocial project's phase 2 in the context of the COVID-19 pandemic. 140 individuals participated in the Trier Social Stress Task (TSST), where the psychosocial stress response was assessed with cortisol saliva samples and subjective stress questionnaires in a cross-sectional design after the active training groups finished their intervention period. Participants were randomly assigned to the socio-emotional training group, mindfulness-based training group, or a control group that did not receive any training. Both training programs consisted of a ten-week intervention period with a daily 12-minute app-based mental training practice and weekly 2-hour online coaching sessions led by mental training teachers. Results: Results showed that the socio-emotional Dyad group but not the mindfulness-based group exhibited significantly lower cortisol levels at 10, 20, 30, and 40 minutes after the stressor as well as lower total cortisol output compared to the control group during the TSST, indicating a reduced hormonal stress response to a social stressor. Subjective markers did not show differences between the three groups. Discussion: These findings indicate that the daily socio-emotional dyadic practice, which emphasizes non-judgmental and empathic listening as well as the acceptance of challenging emotions in the presence of others within one's daily life context, may serve as a protective factor against the adverse effects of psychosocial stress triggered by the fear of negative social judgments. Given the high prevalence of stress-related diseases, such online mental training programs based on dyadic practices may thus represent an efficient and scalable approach for stress reduction.