The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke.

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.

Unlocking The Role of Guanidinium Salts in Interface Engineering for Boosted Performance of Inverted Perovskite Solar Cells.

NiOx-based inverted perovskite solar cells (PSCs) have attracted growing attention due to their low cost and large-scale application potential. However, the efficiency and stability of inverted planar heterojunction PSCs is still unsatisfactory owing to insufficient charge-extraction caused by undesirable interfacial contact between perovskite and NiOx hole transport layers (HTLs). Herein an interfacial passivation strategy with guanidinium salts (guanidinium thiocyanate (GuASCN), guanidine hydrobromide (GuABr), guanidine hydriodate (GuAI)) as passivator is employed to solve this problem. We systematically study the effect of various guanidinium salts on the crystallinity, morphology, and photophysical properties of perovskite films. Guanidine salt as interfacial passivator can decrease interface resistance, reduce carrier non-radiative recombination, and boost carrier extraction. Notably, the GuABr-treated unencapsulated devices can still maintain more than 90 % of their initial PCE after aging for 1600 h at 16-25 °C and 35 %-50 % relative humidity in ambient conditions. This work reveals the significance of counterions in improving the photovoltaic performance and stability of PSCs.

Shared Genes of PPARG and NOS2 in Alzheimer's Disease and Ulcerative Colitis Drive Macrophages and Microglia Polarization: Evidence from Bioinformatics Analysis and Following Validation.

Emerging evidence shows that peripheral systemic inflammation, such as inflammatory bowel disease (IBD), has a close even interaction with central nervous disorders such as Alzheimer's disease (AD). This study is designed to further clarify the relationship between AD and ulcerative colitis (UC, a subclass of IBD). The GEO database was used to download gene expression profiles for AD (GSE5281) and UC (GSE47908). Bioinformatics analysis included GSEA, KEGG pathway, Gene Ontology (GO), WikiPathways, PPI network, and hub gene identification. After screening the shared genes, qRT-PCR, Western blot, and immunofluorescence were used to verify the reliability of the dataset and further confirm the shared genes. GSEA, KEGG, GO, and WikiPathways suggested that PPARG and NOS2 were identified as shared genes and hub genes by cytoHubba in AD and UC and further validated via qRT-PCR and Western blot. Our work identified PPARG and NOS2 are shared genes of AD and UC. They drive macrophages and microglia heterogeneous polarization, which may be potential targets for treating neural dysfunction induced by systemic inflammation and vice versa.

Comprehensive Analysis of PANoptosis-Related Gene Signature of Ulcerative Colitis.

Accumulating evidence shows that the abnormal increase in the mortality of intestinal epithelial cells (IECs) caused by apoptosis, pyroptosis, and necroptosis is closely related to the function of mucous membrane immunity and barrier function in patients with ulcerative colitis (UC). As a procedural death path that integrates the above-mentioned many deaths, the role of PANoptosis in UC has not been clarified. This study aims to explore the characterization of PANoptosis patterns and determine the potential biomarkers and therapeutic targets. We constructed a PANoptosis gene set and revealed significant activation of PANoptosis in UC patients based on multiple transcriptome profiles of intestinal mucosal biopsies from the GEO database. Comprehensive bioinformatics analysis revealed five key genes (ZBP1, AIM2, CASP1/8, IRF1) of PANoptosome with good diagnostic value and were highly correlated with an increase in pro-inflammatory immune cells and factors. In addition, we established a reliable ceRNA regulatory network of PANoptosis and predicted three potential small-molecule drugs sharing calcium channel blockers that were identified, among which flunarizine exhibited the highest correlation with a high binding affinity to the targets. Finally, we used the DSS-induced colitis model to validate our findings. This study identifies key genes of PANoptosis associated with UC development and hypothesizes that IRF1 as a TF promotes PANoptosome multicomponent expression, activates PANoptosis, and then induces IECs excessive death.

The Immuno-Enhancement Effects of Tubiechong (Eupolyphaga sinensis) Lyophilized Powder in Cyclophosphamide-Induced Immunosuppressed Mice.

Tubiechong (Eupolyphaga sinensis) is an important material used in traditional Chinese medicine (TCM). However, the immunoregulation effects of E. sinensis Lyophilized Powder (ESL) are unclear. The in vivo study thus designed to elucidate the immuno-enhancement effects of ESL in immunosuppressed mice induced by cyclophosphamide (CTX). Mice were treated with three doses of ESL (0.5, 1.0 and 2.0 g/kg). Compared with model group, ESL notably increased the immune organ index, mononuclear macrophages function and the level of nature killer cell (NK) (p < 0.05 or p < 0.01), delayed type hypersensitivity (DTH) was also improved (p < 0.05). The level of superoxide dismutase (SOD) and catalase (CAT) were enhanced (p < 0.05), while malonyldialdehyde (MDA) and nitrogen monoxide (NO) were reduced (p < 0.05 or p < 0.01). Meanwhile, cluster determinant (CD)3+ T cell, CD4+ T cell and CD4+/CD8+ ratio were increased (p < 0.01). The cytokines secretion such as interleukin (IL)-2 and tumor necrosis factor alpha (TNF-α) were notably increased (p < 0.05 or p < 0.01), and IL-6 and IL-16 were also enhanced (p < 0.05). Furthermore, ESL significantly inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), down-regulated the expression of Bcl-2 associated X protein (Bax), up-regulated the B cell lymphoma-2 protein (Bcl-2) expression and decreased the Bax/Bcl-2 ratio in spleen tissues (p < 0.05). In brief, all these findings suggest that ESL could effectively improve immune functions via modulating oxidative systems and innate immune cells. Abbreviations: TCM: Traditional Chinese Medicine; ESL: Eupolyphaga sinensis Lyophilized Powder; CCl4: Carbon tetrachloride; ERK: Extracellular regulated protein kinases; CTX: Cyclophosphamide; DTH: Delayed type hypersensitivity; SOD: Superoxide dismutase; CAT: Catalase; MDA: Malonyldialdehyde; NO: Nitrogen monoxide; NK: Nature killer cell; CD: Cluster determinant interleukin; TNF-α: Tumor Necrosis Factor alpha; JNK: c-Jun N-terminal kinase; Bax: Bcl-2 associated X protein; Bcl-2: B cell lymphoma-2 protein; Th1: Type-1 helper; Th2: Type-2 helper; FAMEs: Fatty acid methyl esters; DNFB: 2,4 - Dinitrofluorobenzene; ELISA: Enzyme-linked immuno sorbent assay; MAPK: Mitogen activated protein kinase; Cyt-c: Cytochrome c; SCFAs: Short-chain fatty acids; SDS-PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis.

Electroacupuncture Alleviated Referral Hindpaw Hyperalgesia via Suppressing Spinal Long-Term Potentiation (LTP) in TNBS-Induced Colitis Rats.

Although referred pain or hypersensitivity has been repeatedly reported in irritable bowel syndrome (IBS) patients and experimental colitis rodents, little is known about the neural mechanisms. Spinal long-term potentiation (LTP) of nociceptive synaptic transmission plays a critical role in the development of somatic hyperalgesia in chronic pain conditions. Herein, we sought to determine whether spinal LTP contributes to the referral hyperalgesia in colitis rats and particularly whether electroacupuncture (EA) is effective to alleviate somatic hyperalgesia via suppressing spinal LTP. Rats in the colitis group (induced by colonic infusion of 2,4,6-trinitrobenzenesulfonic acid, TNBS), instead of the control and vehicle groups, displayed evident focal inflammatory destruction of the distal colon accompanied not only with the sensitized visceromotor response (VMR) to noxious colorectal distension (CRD) but also with referral hindpaw hyperalgesia indicated by reduced mechanical and thermal withdrawal latencies. EA at Zusanli (ST36) and Shangjuxu (ST37) attenuated the severity of colonic inflammation, as well as the visceral hypersensitivity and referral hindpaw hyperalgesia in colitis rats. Intriguingly, the threshold of C-fiber-evoked field potentials (CFEFP) was significantly reduced and the spinal LTP was exaggerated in the colitis group, both of which were restored by EA treatment. Taken together, visceral hypersensitivity and referral hindpaw hyperalgesia coexist in TNBS-induced colitis rats, which might be attributed to the enhanced LTP of nociceptive synaptic transmission in the spinal dorsal horn. EA at ST36 and ST37 could relieve visceral hypersensitivity and, in particular, attenuate referral hindpaw hyperalgesia by suppressing the enhanced spinal LTP.

Inhibitory effects and related molecular mechanisms of total flavonoids in Mosla chinensis Maxim against H1N1 influenza virus.

OBJECTIVE: The Shixiangru (Mosla chinensis Maxim) total flavonoids (STF) mainly contain luteolin and apigenin. The study aims to examine the inhibitory effects of STF on anti-H1N1 influenza virus and its related molecular mechanisms in pneumonia mice. METHODS: The viral pneumonia mice were treated with Ribavirin or various doses of STF. We observed histological changes of lung by immunohistochemistry and measured lung index to value anti-influenza virus effects of STF. The concentrations of inflammatory cytokines and anti-oxidant factors were detected by ELISA. RT-PCR and western blot assays were used to determine the expression level of TLR pathway's key genes and proteins in lung tissues. RESULTS: We found that the pathological changes of lung in the viral pneumonia mice obviously alleviated by STF treatments and the STF (288 or 576 mg/kg) could significantly decrease lung indices. Moreover, the up-regulation (IL-6, TNF-α, IFN-γ, and NO) and down-regulation (IL-2, SOD and GSH) of inflammatory cytokines and anti-oxidant factors were associated with higher clearance of virus and reduction of inflammatory lung tissue damage. Meanwhile, the expression levels of TLR3, TLR7, MyD88, TRAF3 and NF-κB p65 of the TLR pathway were reduced by STF treatment. CONCLUSIONS: This study suggested that STF may be a promising candidate for treating H1N1 influenza and subsequent viral pneumonia.

Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor.

The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.

RKNNMDA: Ranking-based KNN for MiRNA-Disease Association prediction.

Cumulative verified experimental studies have demonstrated that microRNAs (miRNAs) could be closely related with the development and progression of human complex diseases. Based on the assumption that functional similar miRNAs may have a strong correlation with phenotypically similar diseases and vice versa, researchers developed various effective computational models which combine heterogeneous biologic data sets including disease similarity network, miRNA similarity network, and known disease-miRNA association network to identify potential relationships between miRNAs and diseases in biomedical research. Considering the limitations in previous computational study, we introduced a novel computational method of Ranking-based KNN for miRNA-Disease Association prediction (RKNNMDA) to predict potential related miRNAs for diseases, and our method obtained an AUC of 0.8221 based on leave-one-out cross validation. In addition, RKNNMDA was applied to 3 kinds of important human cancers for further performance evaluation. The results showed that 96%, 80% and 94% of predicted top 50 potential related miRNAs for Colon Neoplasms, Esophageal Neoplasms, and Prostate Neoplasms have been confirmed by experimental literatures, respectively. Moreover, RKNNMDA could be used to predict potential miRNAs for diseases without any known miRNAs, and it is anticipated that RKNNMDA would be of great use for novel miRNA-disease association identification.

N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury.

N-acetylserotonin (NAS) is an immediate precursor of melatonin, which we have reported is neuroprotective against ischemic injury. Here we test whether NAS is a potential neuroprotective agent in experimental models of ischemic injury. We demonstrate that NAS inhibits cell death induced by oxygen-glucose deprivation or H2O2 in primary cerebrocortical neurons and primary hippocampal neurons in vitro, and organotypic hippocampal slice cultures ex vivo and reduces hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemia in vivo. We find that NAS is neuroprotective by inhibiting the mitochondrial cell death pathway and the autophagic cell death pathway. The neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, and inhibition of the subsequent release of apoptogenic factors cytochrome c, Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9, as well as the suppression of the activation of autophagy under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. However, NAS, unlike melatonin, does not provide neuroprotection through the activation of melatonin receptor 1A. We demonstrate that NAS reaches the brain subsequent to intraperitoneal injection using liquid chromatography/mass spectrometry analysis. Given that it occurs naturally and has low toxicity, NAS, like melatonin, has potential as a novel therapy for ischemic injury.

N-acetyl-L-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model.

BACKGROUND: Whether L-NAT, a cytochrome c release inhibitor and an antagonist of NK-1R, provides protection in ALS is not known. RESULTS: L-NAT delays disease onset and mortality in mSOD1(G93A) ALS mice by inhibiting mitochondrial cell death pathways, inflammation, and NK-1R downregulation. CONCLUSION: L-NAT offers protection in a mouse model of ALS. SIGNIFICANCE: Data suggest the potential of L-NAT as a novel therapeutic strategy for ALS and provide insight into its action mechanisms. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, while inflammation has been implicated in its pathogenesis. Both inhibitors of cytochrome c release and antagonists of the neurokinin 1 receptor (NK-1R) have been reported to provide neuroprotection in ALS and/or other neurodegenerative diseases by us and other researchers. However, whether N-acetyl-L-tryptophan (L-NAT), an inhibitor of cytochrome c release and an antagonist of NK-1R, provides neuroprotection in ALS remains unknown. Here we demonstrate that the administration of L-NAT delayed disease onset, extended survival, and ameliorated deteriorations in motor performance in mSOD1(G93A) ALS transgenic mice. Our data showed that L-NAT reached the spinal cord, skeletal muscle, and brain. In addition, we demonstrate that L-NAT reduced the release of cytochrome c/smac/AIF, increased Bcl-xL levels, and inhibited the activation of caspase-3. L-NAT also ameliorated motor neuron loss and gross atrophy, and suppressed inflammation, as shown by decreased GFAP and Iba1 levels. Furthermore, we found gradually reduced NK-1R levels in the spinal cords of mSOD1(G93A) mice, while L-NAT treatment restored NK-1R levels. We propose the use of L-NAT as a potential therapeutic invention against ALS.

Different manual manipulations and electrical parameters exert different therapeutic effects of acupuncture.

Acupuncture is an important component part of Traditional Chinese Medicine (TCM). The therapeutic effects may be influenced by a variety of factors. Stimulation quantity is one of the factors for achieving good therapeutic effects in acupuncture practice. With the development of science and technology, besides the influence of manual manipulations, the parameters adopted for electroacupuncture have become the benchmark of stimulation quantity. This study, by referring to the related literatures, is designed to explore the influence of manual manipulations and electrical parameters on therapeutic effects of acupuncture. The results from the present study show that different manual manipulations and electrical parameters may exert different therapeutic effects of acupuncture, which are closely related to the characteristics of diseases. Different manual manipulations and electrical parameters should be adopted according to syndrome differentiation of TCM. This is very important in acupuncture treatment.

[Effect of electro-acupuncture on metabolites in the cerebral cortex of ulcerative colitis rats based on Pi/Wei-brain related theory].

OBJECTIVE: To study the effect of electro-acupuncture (EA) at points along Foot Yangming Channel on metabolite of ulcerative colitis (UC) rats' cerebral cortex and to identify key metabolites by referring to Pi/Wei-brain related theory in Chinese medicine (CM). METHODS: The UC rat model was set up by dextran sulfate sodium (DSS) method. Male SD rats were randomly divided into the model group and the EA group, 13 in each group. Another 13 rats were recruited as the blank control group. Rats in the blank control group and the model group received no EA. EA was performed at Zusanli (ST36), Shangjuxu (ST37), and Tianshu (ST25) for 5 days by using disperse-dense wave. Then all rats were sacrificed. Their recto-colon and the ileocecal junction were pathomorphologically observed by light microscope and transmission electron microscope (TEM). Cerebral cortexes were extracted. Water-soluble and lipid-soluble brain tissue metabolites were respectively extracted for metabolic research using 1H nuclear magnetic resonance (1H-NMR). RESULTS: EA could obviously improve the general condition of UC model rats, decrease the value of DAI, reduce the infiltration of inflammatory cells in the intestinal tract, stabilize structures such as mitochondria, endoplasmic reticulum and so on (P <0.05). 1HNMR analysis showed that in the model group, contents of glutamic acid, cholesterol, very low density lipoproein (VLDL) in the pallium obviously decreased, while alanine and low density lipoprotein (LDL) significantly increased. After EA, levels of lactic acid, glutamic acid, total cholesterol (TC), and VLDL all increased, and levels of alanine and LDL decreased. All indices were approximate to those of the blank control group. CONCLUSION: EA at Foot Yangming channel was found to have some effect on metabolites in the brain tissue of UC model rats, which had specific metabonomic material basis and mechanism based on the Pi/Wei-brain related theory.

Effects of moxibustion on visceral hypersensitivity and colonic inflammatory response in mice with chronic ulcerative colitis. / è‰¾ç¸å¯¹æ ¢æ€§æºƒç–¡æ€§ç»“è‚ ç‚Žå°é¼ å† è„é«˜æ•åŠç»“è‚ ç»„ç»‡ç‚Žæ€§ååº”çš„å½±å“.

OBJECTIVES: To observe the effects of moxibustion at "Zusanli" (ST36) on the expression levels of tumor necrosis factor (TNF)-α, TNF receptor 1 (TNF-R1), p38 mitogen-activated protein kinase (P38 MAPK), and transient receptor potential vanilloid 1 (TRPV1) in the colon tissue of mice with chronic ulcerative colitis (UC), so as to explore the underlying mechanisms of moxibustion in improving visceral hypersensitivity in chronic UC. METHODS: Male C57BL/6J mice were randomly divided into normal group, normal with moxibustion (NM) group, model group, and model with moxibustion (MM) group, with 10 mice in each group. The chronic UC model was established by drinking 2.5% dextran sodium sulfate for 3 cycles. Mice in the NM and MM groups received moxibustion at ST36 for 20 min, 5 days per week with a 2-day break, for a total of 4 weeks. The disease activity index (DAI) score of each group was evaluated before and after treatment. The minimum volume threshold of abdominal wall retraction reflex (AWR) was measured to observe the intestinal sensitivity of mice. The colon length was measured. The pathological changes of colon tissue were observed by HE staining. The expression of mucin in colon goblet cells was detected by periodate Scheff staining. The intestinal fibrosis was observed by Masson staining. The number of trypsin-positive cells (i.e., mast cell) and the expression level of TNF-α in colon tissue were detected by immunofluorescence staining. The expression levels of TNF-R1, P38 MAPK and TRPV1 in colon tissue were detected by immunohistochemistry. RESULTS: Compared with the normal group after treatment, the model group showed increased DAI score (P<0.001), decreased AWR minimum volume threshold (P<0.01), shortened colon length (P<0.001), significant inflammatory infiltration in the colon tissue, reduced mucin secretion (P<0.01), increased collagen fiber deposition (P<0.001), and elevated expression levels of TNF-α, TNF-R1, P38 MAPK, and TRPV1 (P<0.001, P<0.01, P<0.05). Compared with the model group, the MM group showed decreased DAI score (P<0.01), increased AWR minimum volume threshold (P<0.001), elongated colon length (P<0.001), reduced inflammatory cell infiltration, improved integrity of mucosal glandular structure, enhanced mucin secretion (P<0.01), decreased collagen fiber deposition (P<0.001), decreased number of mast cells in the colon tissue (P<0.001), and decreased expression levels of TNF-α, TNF-R1, P38 MAPK, and TRPV1 (P<0.001, P<0.01, P<0.05). There were no significant differences in the above index between the NM group and the normal group. CONCLUSIONS: Moxibustion can reduce visceral hypersensitivity, alleviate inflammatory infiltration and fibrotic damage in the colon tissue of mice with chronic UC. These effects may be associated with the down-regulation of TNF-α, TNF-R1, P38 MAPK, and TRPV1 expression in colon.

Peripheral inflammation triggering central anxiety through the hippocampal glutamate metabolized receptor 1.

AIMS: This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. METHODS: Anxiety-like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open-field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll-like receptor 4 (TLR4) inhibitor TAK-242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. RESULTS: DSS-induced colitis increased anxiety-like behaviors, which was reduced by TAK-242. Spatial transcriptome analysis of the hippocampus showed an excitatory-inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. CONCLUSION: Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over-excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety-like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC-associated anxiety.

Tryptophan Metabolism in Alzheimer's Disease with the Involvement of Microglia and Astrocyte Crosstalk and Gut-Brain Axis.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by extracellular Amyloid Aß peptide (Aß) deposition and intracellular Tau protein aggregation. Glia, especially microglia and astrocytes are core participants during the progression of AD and these cells are the mediators of Aß clearance and degradation. The microbiota-gut-brain axis (MGBA) is a complex interactive network between the gut and brain involved in neurodegeneration. MGBA affects the function of glia in the central nervous system (CNS), and microbial metabolites regulate the communication between astrocytes and microglia; however, whether such communication is part of AD pathophysiology remains unknown. One of the potential links in bilateral gut-brain communication is tryptophan (Trp) metabolism. The microbiota-originated Trp and its metabolites enter the CNS to control microglial activation, and the activated microglia subsequently affect astrocyte functions. The present review highlights the role of MGBA in AD pathology, especially the roles of Trp per se and its metabolism as a part of the gut microbiota and brain communications. We (i) discuss the roles of Trp derivatives in microglia-astrocyte crosstalk from a bioinformatics perspective, (ii) describe the role of glia polarization in the microglia-astrocyte crosstalk and AD pathology, and (iii) summarize the potential of Trp metabolism as a therapeutic target. Finally, we review the role of Trp in AD from the perspective of the gut-brain axis and microglia, as well as astrocyte crosstalk, to inspire the discovery of novel AD therapeutics.

Inhibition of miR-199b-5p reduces pathological alterations in osteoarthritis by potentially targeting Fzd6 and Gcnt2.

Osteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miR-199b-5p. In vitro cell experiments demonstrated that miR-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miR-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miR-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miR-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identified Gcnt2 and Fzd6 as potential target genes of MiR-199b-5p. Thus, these results indicated that MiR-199b-5p/Gcnt2 and Fzd6 axis might be a novel therapeutic target for the treatment of OA.

Differentiation of tannin-containing herbal drugs by HPLC fingerprints.

A new HPLC system coupled with multiple detectors - Diode array detector (DAD), fluorescence detector (FLD), electrochemical amperometric detector (ADC) and mass spectrometry detector (MSD) was developed for the characterization and differentiation of tannin-containing herbal drugs included in The European Pharmacopoeia. The HPLC separation system consisted of an Agilent ZORBAX Eclipse XDB C18 column and a gradient water and methanol as the mobile phase which was kept at a flow rate of 0.3 mL x min(-1). Four kinds of detectors were connected by a micro-splitter valve and simultaneously recorded the response of each analytical sample. Thirty-one samples from eight kinds of tannin-containing drugs were measured using this HPLC system and their signals from all detectors were comprehensively processed via principal component analysis (PCA). The statistic result demonstrates that thirty-one batches from different herbal drugs can be reasonably identified and systematically classified by their chemical fingerprints. The proposed multi-detector HPLC method aided by chemometrics not only offers a new pattern for the study of tannin-containing herbs, but also provides a useful foundation for quality control of herbal medicines.

The effect of the Lokomat® robotic-orthosis system on lower extremity rehabilitation in patients with stroke: a systematic review and meta-analysis.

Background: The Lokomat® is a device utilized for gait training in post-stroke patients. Through a systematic review, the objective was to determine whether robot-assisted gait training with the Lokomat® is more effective in enhancing lower extremity rehabilitation in patients with stroke in comparison to conventional physical therapy (CPT). Methods: In this study, a systematic search was conducted in various databases, including CINAHL, MEDLINE, PubMed, Embase, Cochrane Library, Scopus, Web of Science, and Physiotherapy Evidence Database (PEDro), as well as bibliographies of previous meta-analyses, to identify all randomized controlled trials that investigated the use of Lokomat® devices in adult stroke patients. The study aimed to derive pooled estimates of standardized mean differences for six outcomes, namely, Fugl-Meyer Assessment lower-extremity subscale (FMA-LE), Berg Balance Scale (BBS), gait speed, functional ambulation category scale (FAC), timed up and go (TUG), and functional independence measure (FIM), through random effects meta-analyses. Results: The review analyzed 21 studies with a total of 709 participants and found that the use of Lokomat® in stroke patients resulted in favorable outcomes for the recovery of balance as measured by the BBS (mean difference = 2.71, 95% CI 1.39 to 4.03; p < 0.0001). However, the FAC showed that Lokomat® was less effective than the CPT group (mean difference = -0.28, 95% CI -0.45 to 0.11, P = 0.001). There were no significant differences in FMA-LE (mean difference = 1.27, 95% CI -0.88 to 3.42, P = 0.25), gait speed (mean difference = 0.02, 95% CI -0.03 to 0.07, P = 0.44), TUG (mean difference = -0.12, 95% CI -0.71 to 0.46, P = 0.68), or FIM (mean difference = 2.12, 95% CI -2.92 to 7.16, P = 0.41) between the Lokomat® and CPT groups for stroke patients. Conclusion: Our results indicate that, with the exception of more notable improvements in balance, robot-assisted gait training utilizing the Lokomat® was not superior to CPT based on the current literature. Considering its ability to reduce therapists' work intensity and burden, the way in which Lokomat® is applied should be strengthened, or future randomized controlled trial studies should use more sensitive assessment criteria.

MicroRNAs as promising therapeutic agents: A perspective from acupuncture.

MicroRNAs (miRNAs) are gaining recognition as potential therapeutic agents due to their small size, ability to target a wide range of genes, and significant role in disease progression. However, despite their promising potential, nearly half of the miRNA drugs developed for therapeutic purposes have been discontinued or put on hold, and none have advanced to phase III clinical trials. The development of miRNA therapeutics has faced obstacles such as difficulties in validating miRNA targets, conflicting evidence regarding competition and saturation effects, challenges in miRNA delivery, and determining appropriate dosages. These hurdles primarily arise from the intricate functional complexity of miRNAs. Acupuncture, a distinct, complementary therapy, offers a promising avenue to overcome these barriers, particularly by addressing the fundamental issue of preserving functional complexity through acupuncture regulatory networks. The acupuncture regulatory network consists of three main components: the acupoint network, the neuro-endocrine-immune (NEI) network, and the disease network. These networks represent the processes of information transformation, amplification, and conduction that occur during acupuncture. Notably, miRNAs serve as essential mediators and shared biological language within these interconnected networks. Harnessing the therapeutic potential of acupuncture-derived miRNAs can help reduce the time and economic resources required for miRNA drug development and alleviate the current developmental challenges miRNA therapeutics face. This review provides an interdisciplinary perspective by summarizing the interactions between miRNAs, their targets, and the three acupuncture regulatory networks mentioned earlier. The aim is to illuminate the challenges and opportunities in developing miRNA therapeutics. This review paper presents a comprehensive overview of miRNAs, their interactions with acupuncture regulatory networks, and their potential as therapeutic agents. By bridging the miRNA research and acupuncture fields, we aim to offer valuable insights into the obstacles and prospects of developing miRNA therapeutics.