Metabolomics-Based Effects of a Natural Product on Remyelination After Cerebral Ischemia Injury Via GABABR-pCREB-BDNF Pathway.

BACKGROUND: Yi-Qi-Tong-Luo Granules (YQTLs) is a natural compound of Traditional Chinese Medicine authorized by China Food and Drug Administration (CFDA). These granules are employed in the convalescent stage of cerebral infarction and render notable clinical efficacy. This study aims to uncover the underlying mechanisms of YQTLs on remyelination after cerebral ischemia injury. MATERIALS AND METHODS: We established cerebral ischemia model in rats using microsphere-induced multiple cerebral infarction (MCI). We evaluated the pharmacological effects of YQTLs on MCI rats, through Morri's water maze test, open field test, hematoxylin and eosin staining, and glycine silver immersion. We employed liquid chromatography mass spectrometry metabolomics to identify differential metabolites. Enzyme-linked immunosorbent assay was utilized to measure the release of neurotrophins, while immunofluorescence staining was used to assess oligodendrocyte precursor cells differences and myelin regeneration. We used Western blotting to validate the protein expression of remyelination-associated signaling pathways. RESULTS: YQTLs significantly improves cognitive function following cerebral ischemia injury. Pathological tissue staining revealed that YQTLs administration inhibits neuronal denaturation and neurofibrillary tangles. We identified 141 differential metabolites among the sham, MCI, and YQTLs-treated MCI groups. Among these metabolites, neurotransmitters were identified, and notably, gamma-aminobutyric acid (GABA) showed marked improvement in the YQTLs group. The induction of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and PDGFAA, upregulation of olig2 and MBP expression, and promotion of remyelination were evident in YQTLs-treated MCI groups. Gamma-aminobutyric acid B receptors (GABABR), pERK/extracellular regulated MAP kinase, pAKT/protein kinase B, and pCREB/cAMP response element-binding were upregulated following YQTLs treatment. CONCLUSION: YQTLs enhance the binding of GABA to GABABR, thereby activating the pCREB/BDNF signaling pathway, which in turn increases the expression of downstream myelin-associated proteins and promotes remyelination and cognitive function.

Electroacupuncture Alleviates Post-stroke Cognitive Impairment Through Inhibiting miR-135a-5p/mTOR/NLRP3 Axis-mediated Autophagy.

Post-stroke cognitive impairment is a significant challenge with limited treatment options. Electroacupuncture (EA) has shown promise in improving cognitive function after stroke. Our study explores the underlying mechanism of EA in alleviating cognitive impairment through the inhibition of autophagy. We utilized a rat model of stroke induced by middle cerebral artery occlusion (MCAO) to evaluate the efficacy of EA. Treatment with EA was observed to markedly improve cognitive function and reduce inflammation in MCAO rats, as evidenced by decreased neurological deficit scores, shorter latencies in the water maze test, and diminished infarct volumes. EA also attenuated tissue damage in the hippocampus and lowered the levels of pro-inflammatory cytokines and oxidative stress markers. Although autophagy was upregulated in MCAO rats, EA treatment suppressed this process, indicated by a reduction in autophagosome formation and alteration of autophagy-related protein expression. The protective effects of EA were reversed by the autophagy activator rapamycin. EA treatment elevated the levels of microRNA (miR)-135a-5p expression, and suppression of this elevation attenuated the remedial efficacy of EA in addressing cognitive impairment and inflammation. MiR-135a-5p targeted mammalian target of rapamycin (mTOR)/NOD-like receptor protein 3 (NLRP3) signaling to repress autophagy. EA treatment inhibits autophagy and alleviates cognitive impairment in post-stroke rats. It exerts its beneficial effects by upregulating miR-135a-5p and targeting the mTOR/NLRP3 axis.

Is membrane androgen and estrogen receptor signaling imperative in the governing function of the adrenal cortex in the Eurasian beaver (Castor fiber L.)?

There is a need to fully know the physiology of Eurasian beaver due to its essential role in environmental homeostasis. However, a "human factor" impacts this, including stress conditions and environmental pollution. Adrenal glands protect these all. The regulation of endocrine processes by nonclassical androgen and estrogen signaling, the first and fastest control, is still a matter of research. The specific analyses performed here in mature female and male beaver adrenals contained: anatomical and histological examinations, expression and localization of membrane androgen receptor (zinc transporter, Zinc- and Iron-like protein 9; ZIP9) and membrane estrogen receptor coupled with G protein (GPER), and measurement of zinc (Zn2+) and copper (Ca2+) ion levels and corticosterone levels. We revealed normal anatomical localization, size, and tissue histology in female and male beavers, respectively. Equally, ZIP9 and GPER were localized in the membrane of all adrenal cortex cells. The protein expression of these receptors was higher (p < 0.001) in male than female adrenal cortex cells. Similarly, Zn2+ and Ca2+ ion levels were higher (p < 0.05, p < 0.01) in male than female adrenal cortex. The increased corticosterone levels (p < 0.001) were detected in the adrenal cortex of females when compared to males. The present study is the first to report the presence of nonclassical androgen and estrogen signaling and its possible regulatory function in the adrenal cortex of Eurasian beavers. We assume that this first-activated and fast-transmitted regulation can be important in the context of the effect of environmental physical and chemical stressors especially on adrenal cortex cells. The beaver adrenals may constitute an additional supplementary model for searching for universal mechanisms of adrenal cortex physiology and diseases.

Electroacupuncture promotes synaptic plasticity in rats with chronic inflammatory pain-related depression by upregulating BDNF/TrkB/CREB signaling pathway.

BACKGROUND: Chronic inflammatory pain (CIP) frequently coincides with depression among patients. The onset and development of pain and depression are associated with altered neural synaptic plasticity. Electroacupuncture (EA) can effectively relieve CIP and depression. However, the underlying mechanisms have not been fully illustrated. OBJECTIVE: To explore whether EA can relieve CIP and depression by regulating hippocampal synaptic plasticity, and the present study offers foundational evidence for the efficacy of EA in treating CIP-related depression (CIPD). METHODS: Rats were divided into four groups: 0.9% normal saline group, complete Freund's adjuvant (CFA) group, CFA + duloxetine group, and CFA + EA group. Pain hypersensitivity was detected by mechanical withdrawal threshold and thermal paw withdrawal latency, and the depression level was gauged using the open field test, the sucrose preference test, and the forced swimming test. The morphology of the hippocampal neurons was observed using Nissl staining. The protein expression levels of synuclein (Syn), postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factors (BDNFs), tyrosine-protein kinase B (TrKB), p-TrkB, cAMP response element binding protein (CREB), and p-CREB were measured by western blotting and immunofluorescence staining. BDNF and TrkB mRNA expression were detected using quantitative real-time polymerase chain reaction (PCR) (qRT-PCR). The content of 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) was detected using enzyme-linked immunosorbent assay, and the glutamic acid (Glu) content was determined using the ultraviolet colorimetry method. The hippocampal neuron ultrastructure was observed using transmission electron microscopy. RESULTS: EA could alleviate CIP and related depressive behaviors as well as protect the hippocampal neuronal structure from damage and regulate 5-HT/GABA/Glu levels in the hippocampus. Additionally, EA could significantly increase the expression of synapse-associated proteins such as PSD-95 and Syn by activating the BDNF/TrKB/CREB signaling pathway. CONCLUSION: EA improves pain and depressive behaviors in CIPD rats, and the mechanism may be related to synaptic plasticity mediated by the BDNF/TrKB/CREB signaling pathway.

The complementary roles of STAT3 and STAT1 in cancer biology: insights into tumor pathogenesis and therapeutic strategies.

STATs are a family of transcription factors that regulate many critical cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of STATs is frequently observed in tumors and can directly drive cancer pathogenesis. STAT1 and STAT3 are generally viewed as mediating opposite roles in cancer development, with STAT1 suppressing tumorigenesis and STAT3 promoting oncogenesis. In this review, we investigate the specific roles of STAT1 and STAT3 in normal physiology and cancer biology, explore their interactions with each other, and offer insights into therapeutic strategies through modulating their transcriptional activity.

Electroacupuncture alleviates intrauterine adhesion through regulating autophagy in rats.

Autophagy is a well-conserved metabolic system that maintains homeostasis by relying on lysosomal breakdown. The endometrium of patients with intrauterine adhesion (IUA) and an animal model exhibits impaired autophagy. Autophagy is negatively correlated with inflammation. Activation of autophagy can inhibit the inflammatory response, while defects in autophagy will activate the inflammatory response. Here, we studied whether electroacupuncture (EA) inhibits inflammation and promotes endometrial injury repair by activating endometrial autophagy. The IUA animal model was established by mechanical injury plus lipopolysaccharide infection. EA stimulation was applied to the acupoints Guanyuan (CV4), bilateral Sanyinjiao (SP6), and Zusanli (ST36). The results indicated that EA could improve endometrial morphology, attenuate endometrial fibers, and enhance endometrial receptivity in the rat. EA could increase the autophagosomes of endometrial epithelial cells, increase the levels of LC3 and Beclin1, and decrease the level of p62. Additionally, EA may also suppress the nuclear factor kappa-B (NF-κB) signaling pathway and reduce the release of inflammatory factors. Additionally, the effect of EA was comparable to that of the autophagy agonist rapamycin, and the autophagy inhibitor 3-methyladenine reversed the therapeutic effect of EA. Therefore, we assume that EA may facilitate endometrial healing by activating autophagy and reducing NF-κB signal pathway-mediated inflammation.

Quercetin Attenuates Atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics.

OBJECTIVE: To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS: Fourteen apolipoprotein E-deficient (ApoE-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS: Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION: Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.

Monoacylglycerol Lipase Protects the Presynaptic Cannabinoid 1 Receptor from Desensitization by Endocannabinoids after Persistent Inflammation.

Cannabinoid-targeted pain therapies are increasing with the expansion of cannabis legalization, however, their efficacy may be limited by pain-induced adaptations in the cannabinoid system. Cannabinoid receptor subtype 1 (CB1R) inhibition of spontaneous, GABAergic miniature IPSCs (mIPSCs) and evoked IPSCs (eIPSCs) in the ventrolateral periaqueductal gray (vlPAG) were compared in slices from naive and inflamed male and female Sprague Dawley rats. Complete Freund's Adjuvant (CFA) injections into the hindpaw induced persistent inflammation. In naive rats, exogenous cannabinoid agonists robustly reduce both eIPSCs and mIPSCs. After 5-7 d of inflammation, the effects of exogenous cannabinoids are significantly reduced because of CB1R desensitization via GRK2/3, as function is recovered in the presence of the GRK2/3 inhibitor, Compound 101 (Cmp101). Inhibition of GABA release by presynaptic µ-opioid receptors in the vlPAG does not desensitize with persistent inflammation. Unexpectedly, while CB1R desensitization significantly reduces the inhibition produced by exogenous agonists, depolarization-induced suppression of inhibition protocols that promote 2-arachidonoylglycerol (2-AG) synthesis exhibit prolonged CB1R activation after inflammation. 2-AG tone is detected in slices from CFA-treated rats when GRK2/3 is blocked, suggesting an increase in 2-AG synthesis after persistent inflammation. Inhibiting 2-AG degradation with the monoacylglycerol lipase (MAGL) inhibitor JZL184 during inflammation results in the desensitization of CB1Rs by endocannabinoids that is reversed with Cmp101. Collectively, these data indicate that persistent inflammation primes CB1Rs for desensitization, and MAGL degradation of 2-AG protects CB1Rs from desensitization in inflamed rats. These adaptations with inflammation have important implications for the development of cannabinoid-based pain therapeutics targeting MAGL and CB1Rs.SIGNIFICANCE STATEMENT Presynaptic G-protein-coupled receptors are resistant to desensitization. Here we find that persistent inflammation increases endocannabinoid levels, priming presynaptic cannabinoid 1 receptors for desensitization on subsequent addition of exogenous agonists. Despite the reduced efficacy of exogenous agonists, endocannabinoids have prolonged efficacy after persistent inflammation. Endocannabinoids readily induce cannabinoid 1 receptor desensitization if their degradation is blocked, indicating that endocannabinoid concentrations are maintained at subdesensitizing levels and that degradation is critical for maintaining endocannabinoid regulation of presynaptic GABA release in the ventrolateral periaqueductal gray during inflammatory states. These adaptations with inflammation have important implications for the development of cannabinoid-based pain therapies.

Role of purinergic signalling in obesity-associated end-organ damage: focus on the effects of natural plant extracts.

Obesity has become one of the major public health problems in both the developing and developed countries. Recent studies have suggested that the purinergic signalling is involved in obesity-associated end-organ damage through purine P1 and P2 receptors. In the search for new components for the treatments of obesity, we and other researchers have found much evidence that natural plant extracts may be promising novel therapeutic approaches by modulating purinergic signalling. In this review, we summarize a critical role of purinergic signalling in modulating obesity-associated end-organ damage, such as overhigh appetite, myocardial ischemia, inflammation, atherosclerosis, non-alcoholic fatty liver disease (NAFLD), hepatic steatosis and renal inflammation. Moreover, we focus on the potential roles of several natural plant extracts, including quercetin, resveratrol/trans-resveratrol, caffeine, evodiamine and puerarin, in alleviating obesity-associated end-organ damage via purinergic signalling. We hope that the current knowledge of the potential roles of natural plant extracts in regulating purinergic signalling would provide new ideas for the treatment of obesity and obesity-associated end-organ damage.

Contrasting self-recognition rejection systems for self-incompatibility in Brassica and Papaver.

Self-incompatibility (SI) plays a pivotal role in whether self-pollen is accepted or rejected. Most SI systems employ two tightly linked loci encoding highly polymorphic pollen (male) and pistil (female) S-determinants that control whether self-pollination is successful or not. In recent years our knowledge of the signalling networks and cellular mechanisms involved has improved considerably, providing an important contribution to our understanding of the diverse mechanisms used by plant cells to recognise each other and elicit responses. Here, we compare and contrast two important SI systems employed in the Brassicaceae and Papaveraceae. Both use 'self-recognition' systems, but their genetic control and S-determinants are quite different. We describe the current knowledge about the receptors and ligands, and the downstream signals and responses utilized to prevent self-seed set. What emerges is a common theme involving the initiation of destructive pathways that block the key processes that are required for compatible pollen-pistil interactions.

Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition.

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Electroacupuncture-induced activation of GABAergic system alleviates airway inflammation in asthma model by suppressing TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Electroacupuncture (EA) has been shown to attenuate airway inflammation in asthmatic mice; however, the underlying mechanism is not fully understood. Studies have shown that EA can significantly increase the inhibitory neurotransmitter γ-aminobutyric acid (GABA) content in mice, and can also increase the expression level of GABA type A receptor (GABAAR). Furthermore, activating GABAAR may relieve inflammation in asthma by suppressing toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway. Therefore, this study aimed to investigate the role of GABAergic system and TLR4/MyD88/NF-κB signaling pathway in asthmatic mice treated with EA. METHODS: A mouse model of asthma was established, and a series of methods including Western blot and histological staining assessment were employed to detect the level of GABA, and expressions of GABAAR and TLR4/MyD88/NF-κB in lung tissue. In addition, GABAAR antagonist was used to further validate the role and mechanism of GABAergic system in mediating the therapeutic effect of EA in asthma. RESULTS: The mouse model of asthma was established successfully, and EA was verified to alleviate airway inflammation in asthmatic mice. The release of GABA and the expression of GABAAR were significantly increased in asthmatic mice treated with EA compared with untreated asthmatic mice ( P  < 0.01), and the TLR4/MyD88/NF-κB signaling pathway was down-regulated. Moreover, inhibition of GABAAR attenuated the beneficial effects of EA in asthma, including the regulation of airway resistance and inflammation, as well as the inhibitory effects on TLR4/MyD88/NF-κB signaling pathway. CONCLUSION: Our findings suggest that GABAergic system may be involved in mediating the therapeutic effect of EA in asthma, possibly by suppressing the TLR4/MyD88/NF-κB signaling pathway.

[Research progress on the modulation mechanism of electroacupuncture for learning and memory impairment after ischemic stroke].

Electroacupuncture may play a role in treatment of learning and memory impairment after ischemic stroke by regulating phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA)/cAMP response element binding protein (CREB) signaling pathway, nerve growth factor (NGF)/tyrosine kinase-A (TrkA) signaling pathway, Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, Notch signaling pathway, erythropoietin-producing hepatocyte (Eph)/ephrin signaling pathway. The interactions among these pathways should be further explored in treatment of learning and memory impairment after ischemic stroke.

Baicalin attenuates dexamethasone-induced apoptosis of bone marrow mesenchymal stem cells by activating the hedgehog signaling pathway.

BACKGROUND: Perturbations in bone marrow mesenchymal stem cell (BMSC) differentiation play an important role in steroid-induced osteonecrosis of the femoral head (SONFH). At present, studies on SONFH concentrate upon the balance within BMSC osteogenic and adipogenic differentiation. However, BMSC apoptosis as well as proliferation are important prerequisites in their differentiation. The hedgehog (HH) signaling pathway regulates bone cell apoptosis. Baicalin (BA), a well-known compound in traditional Chinese medicine, can affect the proliferation and apoptosis of numerous cell types via HH signaling. However, the potential role and mechanisms of BA on BMSCs are unclear. Thus, we aimed to explore the role of BA in dexamethasone (Dex)-induced BMSC apoptosis in this study. METHODS: Primary BMSCs were treated with 10 -6 mol/L Dex alone or with 5.0 µmol/L, 10.0 µmol/L, or 50.0 µmol/L BA for 24 hours followed by co-treatment with 5.0 µmol/L, 10.0 µmol/L, or 50.0 µmol/L BA and 10 -6 mol/L Dex. Cell viability was assayed through the Cell Counting Kit-8 (CCK-8). Cell apoptosis was evaluated using Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining followed by flow cytometry. The imaging and counting, respectively, of Hochest 33342/PI-stained cells were used to assess the morphological characteristics and proportion of apoptotic cells. To quantify the apoptosis-related proteins (e.g., apoptosis regulator BAX [Bax], B-cell lymphoma 2 [Bcl-2], caspase-3, and cleaved caspase-3) and HH signaling pathway proteins, western blotting was used. A HH-signaling pathway inhibitor was used to demonstrate that BA exerts its anti-apoptotic effects via the HH signaling pathway. RESULTS: The results of CCK-8, Hoechst 33342/PI-staining, and flow cytometry showed that BA did not significantly promote cell proliferation (CCK-8: 0 µmol/L, 100%; 2.5 µmol/L, 98.58%; 5.0 µmol/L, 95.18%; 10.0 µmol/L, 98.11%; 50.0 µmol/L, 99.38%, F   =  2.33, P   >  0.05), but it did attenuate the effect of Dex on apoptosis (Hoechst 33342/PI-staining: Dex+ 50.0 µmol/L BA, 12.27% vs. Dex, 39.27%, t  = 20.62; flow cytometry: Dex + 50.0 µmol/L BA, 12.68% vs. Dex, 37.43%, t  = 11.56; Both P  < 0.05). The results of western blotting analysis showed that BA reversed Dex-induced apoptosis by activating the HH signaling pathway, which down-regulated the expression of Bax, cleaved-caspase 3, and suppressor of fused (SUFU) while up-regulating Bcl-2, sonic hedgehog (SHH), and zinc finger protein GLI-1 (GLI-1) expression (Bax/Bcl-2: Dex+ 50.0 µmol/L BA, 1.09 vs. Dex, 2.76, t  = 35.12; cleaved caspase-3/caspase-3: Dex + 50.0 µmol/L BA, 0.38 vs . Dex, 0.73, t  = 10.62; SHH: Dex + 50.0 µmol/L BA, 0.50 vs . Dex, 0.12, t  = 34.01; SUFU: Dex+ 50.0 µmol/L BA, 0.75 vs . Dex, 1.19, t  = 10.78; GLI-1: Dex+ 50.0 µmol/L BA, 0.40 vs . Dex, 0.11, t  = 30.68. All P  < 0.05). CONCLUSIONS: BA antagonizes Dex-induced apoptosis of human BMSCs by activating the HH signaling pathway. It is a potential candidate for preventing SONFH.

Smilax china L. Polyphenols Improves Insulin Resistance and Obesity in High-fat Diet-induced Mice Through IRS/AKT-AMPK and NF-κB Signaling Pathways.

Smilax china L. is an important herb used in traditional Chinese medicine. In this study, the mechanism of Smilax china L. polyphenols (SCP) on insulin resistance and anti-obesity in mice induced by a high-fat diet (HFD) was investigated. Fifty female mice were randomly divided into five groups: control, HFD and low, medium, and high doses of SCP for 70 d. SCP significantly decreased intraperitoneal adipose tissue index, body weight gain, liver lipids, and serum inflammatory factor levels. Blood glucose and insulin concentrations, as well as insulin resistance index in SCP, were significantly lower than those in HFD. In addition, SCP markedly up-regulated the gene expression of glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), serine-threonine kinase (AKT), Acyl-CoA oxidase (ACO), and protein kinase A (PKA), and down-regulated the expression of mammalian target of rapamycin complex 1 (mTORC1), sterol-responsive element-binding protein-1c (SREBP1c), fatty acid synthase (FAS), 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR), and forkhead box protein O1 (FOXO1). SCP significantly increased the protein expression of AKT, GLUT4, AMP-activated protein kinase (AMPK), phosphorylated-AMPK (p-AMPK), phosphorylated-AKT (p-AKT), and uncoupling protein 1 (UCP-1), and decreased the expression of SREBP1c, FAS, HMGCR, phosphorylation of IKBα (p-IKBα), and nuclear factor kappa B subunit p65 (P65) in the liver. Overall, SCP effectively reduced HFD-induced insulin resistance and obesity in mice, partly through NF-κB and IRS/AKT-AMPK signaling pathways to regulate inflammatory factors. Therefore, SCP may improve lifestyle diseases.

Mechanism of ASK1 involvement in liver diseases and related potential therapeutic targets: A critical pathway molecule worth investigating.

Since the discovery of apoptosis signal-regulated kinase 1 (ASK1), the signal transduction mechanism and pathophysiological process involved in its regulation have been continuously revealed. Many previous studies have identified that ASK1 is involved and plays a critical role in the development of diseases affecting the nervous, cardiac, renal, and other systems. As a mitogen-activated protein kinase (MAPK) kinase kinase, ASK1 mediates apoptosis, necrosis, inflammation, and other pathological processes by activating its downstream c-Jun N-terminal kinase (JNK)/p38 MAPK. Owing to the important role of ASK1, an increasing number of studies in recent years have focused on its status in liver-related diseases. In this paper, we review the mechanisms and targets of ASK1 in liver-related diseases to emphasize its important role in the development of liver disease.

Biejiajian pill inhibits progression of hepatocellular carcinoma by downregulating PDGFRß signaling in cancer-associated fibroblasts.

ETHNOPHARMACOLOGICAL RELEVANCE: Biejiajian pill (BJJP) is a canonical formula that is clinically used to treat chronic liver disease, especially to decrease the incidence of hepatocellular carcinoma (HCC). However, the mechanisms underlying the prevention of HCC progression by BJJP remain unclear. AIM OF THE STUDY: This study aimed to determine whether BJJP inhibits HCC progression by downregulating platelet-derived growth factor receptor beta (PDGFRß) signaling in cancer-associated fibroblasts (CAFs) in a mouse model of diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced HCC. MATERIALS AND METHODS: C57BL/6 male mice were intraperitoneally injected with DEN 2 weeks after birth, followed by repeated injections of CCl4 weekly from 6 weeks of age onwards, to recapitulate features of HCC. At week 14, BJJP was orally administered to mice. The effects of BJJP on HCC progression were evaluated using histology, immunohistochemistry, and serum biochemical marker levels. Transcriptome analysis, molecular docking, quantitative real-time PCR, and Western blot were used to study the genes targeted by BJJP and the associated signaling pathway. The effects of BJJP on PDGFRß signaling in CAFs and the underlying mechanism were demonstrated. RESULTS: BJJP treatment significantly suppressed carcinogenesis and cancer progression, and it ameliorated liver inflammation in mice with HCC. A total of 176 genes, including PDGFRß, were significantly downregulated after BJJP treatment and five components of BJJP with high binding affinity to PDGFRß were identified. BJJP inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK3ß) by suppressing PDGFRß expression in CAFs, and it also downregulated the expression of the downstream proteins hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A). Furthermore, BJJP-containing serum consistently reduced PDGFRß, HGF, and VEGF-A expression levels in HSC-derived CAFs in vitro. Importantly, PDGF-BB induced PDGFRß activation in CAFs and both BJJP and sunitinib (a kinase inhibitor) inhibited PDGF-BB/PDGFRß signaling. CONCLUSION: BJJP inhibits the progression of HCC through suppressing VEGF-A and HGF expression in CAFs by downregulating PDGFRß signaling.

New light on treatment of cervical cancer: Chinese medicine monomers can be effective for cervical cancer by inhibiting the PI3K/Akt signaling pathway.

Cervical cancer (CC), as the most common malignant tumor of the female reproductive system, is infamous for its high morbidity and mortality rates. Its development and metastasis are intricate because numerous signaling pathways are involved. Since the cancer and the PI3K/Akt signaling pathway are closely intertwined, direct inhibition of either the PI3K/Akt pathway or its target genes and molecules may be remarkably constructive for treatment. Albeit remarkable advances in the treatment of CC, existing common anti-cancer medications are not without problems. These problems include myelotoxicity, cardiotoxicity, genotoxicity, and vasospasm, which are the most common and well-recognized toxicities associated with these medications. Therefore, it is necessary and urgent to develop novel, potent, secure, and more reasonably priced anticancer medications that are void of the above problems. Against this backdrop, Chinese medicine monomers have received more attention in recent years owing to their safety, low toxicity, few side effects, and anti-tumor properties. By regulating the PI3K/Akt signaling pathway, Chinese medicine monomers are effective not only in inhibiting CC growth, proliferation, apoptosis, invasion, migration, and reversing drug resistance but also in a variety of targets. Most previous earlier studies focused on the use of a single traditional Chinese medicine monomer to treat CC by regulating the PI3K/Akt signaling pathway rather than a combination of several such monomers. More importantly, to our knowledge, there has hardly been any study providing an exhaustive and comprehensive review of all the Chinese medicine monomers at CC. In response to this scarcity, we attempt in this paper to provide a comprehensive review of all the literature to date on traditional Chinese medicine monomers at cervical cancer, highlight the mechanisms and future prospects for their use in the prevention and treatment of cervical cancer.

Partial changes in apoptotic pathways in hippocampus and hypothalamus of Cc2d1a heterozygous.

Alterations in the apoptosis pathway have been linked to changes in serotonin levels seen in autistic patients. Cc2d1a is a repressor of the HTR1A gene involved in the serotonin pathway. The hippocampus and hypothalamus of Cc2d1a ± mice were analyzed for the expression of apoptosis markers (caspase 3, 8 and 9). Gender differences were observed in the expression levels of the three caspases consistent with some altered activity in the open-field assay. The number of apoptotic cells was significantly increased. We concluded that apoptotic pathways are only partially affected in the pathogenesis of the Cc2d1a heterozygous mouse model. A) Apoptosis is suppressed because the cell does not receive a death signal, or the receptor cannot activate the caspase 8 pathway despite the death signal. B) Since Caspase 8 and Caspase 3 expression is downregulated in our mouse model, the mechanism of apoptosis is not activated.

Nigakinone alleviates DSS-induced experimental colitis via regulating bile acid profile and FXR/NLRP3 signaling pathways.

The correlation of bile acid (BA) metabolism disorder with the pathogenesis of ulcerative colitis (UC) is realized nowadays. Farnesoid X receptor (FXR), a controller for BA homeostasis and inflammation, is a promising target for UC therapy. Nigakinone has potential therapeutic effects on colitis. Herein, we investigated the anti-UC effects and mechanism of nigakinone in colitic animals induced by dextran sulfate sodium (DSS). The related targets involved in the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) signaling pathway were measured. BA-targeted metabolomics was employed to reveal the regulatory effects of nigakinone on BA profile in colitis, while expressions of FXR and its mediated targets referring to BA enterohepatic circulation were determined. The critical role of FXR in the treatment of nigakinone for colitis was studied via molecule-docking, dual-luciferase reporter® (DLR™) assays, FXR silencing cells, and FXR knockout mice. Results showed nigakinone attenuated DSS-induced colitis symptoms, including excessive inflammatory response by NLRP3 activation, and injury of the intestinal mucosal barrier. Nigakinone regulated BA disorders by controlling cholesterol hydroxylase and transporters mediated by FXR, then decreased BA accumulation in colon. Molecular-docking and DLR™ assays indicated FXR might be a target of nigakinone. In vitro, nigakinone restrained BA-induced inflammation and cell damage via FXR activation and inhibition of inflammatory cytokines. However, ameliorating effects of nigakinone on colitis were suppressed by FXR knockout or silencing in vivo or in vitro. Taken together, nigakinone ameliorated experimental colitis via regulating BA profile and FXR/NLRP3 signaling pathway.