Elucidating the hepatoprotective mechanisms of cholic acid against CCl4-Induced acute liver injury: A transcriptomic and metabolomic study.

ETHNOPHARMACOLOGICAL RELEVANCE: Cholic acid (CA) is one of the main active ingredients in Calculus Bovis, a traditional Chinese medicine, which helps to regulate the heart and liver meridians, clearing the heart, opening the mouth, cooling the liver and calming the wind. However, the molecular mechanism of its liver protective effect is still unclear. AIM OF THE STUDY: Growing attention has been directed towards traditional Chinese medicine (TCM), particularly Calculus Bovis, as a potential solution for liver protection. Despite this interest, a comprehensive understanding of its hepatoprotective mechanisms remains lacking. This research seeks to explore the potential protective properties of cholic acid (CA) against CCl4-induced acute liver injury (ALI) in mice, while also examining the mechanisms involved. MATERIALS AND METHODS: In the experiment, a mouse model was employed to ALI using CCl4, and the potential therapeutic effects of orally administered CA at varying doses (15, 30, and 60 mg/kg) were assessed. The study employed a multi-faceted approach, integrating liver transcriptomics with serum metabolomics, and conducting thorough analyses of serum biochemical markers and liver histopathological sections. RESULTS: Oral CA administration markedly reduced the organ indices of the liver, spleen, and thymus in comparison with the model group. It also elevated the expression of superoxide dismutase (SOD) in serum while diminishing the concentrations of ALT, AST, MDA, IL-6, and TNF-α. Moreover, CA ameliorated the pathological damage induced by CCl4. Integrated metabolomic and transcriptomic analyses indicated that the hepatoprotective action of CA on ALI is mediated through the modulation of lipid metabolic pathways-specifically, metabolisms of glycerophospholipid, arachidonic acid, as well as linoleic acid-and by altering the expression of genes such as Ptgr1, PLpp1, Tbxas1, and Cyp2c37. CONCLUSIONS: The current investigation offers insights into the hepatoprotective mechanisms by which CA mitigates ALI caused by CCl4 exposure, thus supporting the further evaluation and development of CA-based therapeutics for ALI.

Therapeutic impact of stachyose on hyperlipidaemia caused by a high-fat diet in mice as revealed by gut microbiota and metabolomics.

Hyperlipidaemia, which is characterized by an excess of lipids or fats in the bloodstream, is a high-risk factor and critical indicator of many metabolic diseases. This study used 16 S rRNA gene sequencing and metabolomics to determine that stachyose (ST) has a therapeutic effect and is a mechanism of hyperlipidaemia. These results show that ST significantly attenuated high-fat diet-induced weight gain and fat deposition while also adjusting the gut microbial composition. Untargeted serum metabolomics identified 12 biomarkers, which suggests that ST may function by regulating metabolic pathways. These results highlight the potential of ST in treating hyperlipidaemia and provides directions for future research including an in-depth investigation of the bioactive components, dosage, and treatment strategies of ST.

Metabolomic and lipidomic studies on the intervention of taurochenodeoxycholic acid in mice with hyperlipidemia.

Bile acids are the main component of animal bile and are directly involved in the metabolic process of lipids in vivo. Taurochenodeoxycholic acid (TCDCA) is the primary biologically active substance in bile acids and has biological functions such as antioxidant, antipyretic, anti-inflammatory, and analgesic activities and improves immunity. In the present study, we assessed the impact of TCDCA on hyperlipidemia development in mouse models. Mice were fed a high-fat diet (HFD) to induce hyperlipidemia and orally administered different doses of TCDCA orally for 30 days. Then, indicators such as triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in mice were detected. Using HE and ORO staining techniques, the morphology of the mice's liver tissue was detected. Based on metabolomic and lipidomic analyses, we determined the mechanism of TCDCA in treating hyperlipidemia. The results showed that TCDCA had a significant ameliorating effect on dietary hyperlipidemia. In addition, it exerted therapeutic effects through glycerophospholipid metabolism.

The traditional herb Polygonum hydropiper from China: a comprehensive review on phytochemistry, pharmacological activities and applications.

CONTEXT: Polygonum hydropiper L. (Polygonaceae) (PH) is a traditional Chinese traditional medicine with a pungent flavor and mild drug properties. PH is mainly distributed in the channel tropism in the stomach and large intestine. PH has multiple uses and can be used to treat a variety of diseases for a long time. OBJECTIVE: This review summarizes the phytochemical and pharmacological activities, and applications of PH from 1980 to 2022. We also provide suggestions for promoting further research and developing additional applications of PH. METHODS: The data and information on PH from 1980 to 2022 reviewed in this article were obtained from scientific databases, including Science Direct, PubMed, Science Citation Index, SciFinder Scholar (SciFinder), Springer, American Chemical Society (ACS) Publications, and China National Knowledge Infrastructure (CNKI), etc. Some information was obtained from classic literature on traditional Chinese medicines. The search terms were Polygonum hydropiper, phytochemistry compositions of Polygonum hydropiper, pharmacological activities of Polygonum hydropiper, and applications of Polygonum hydropiper. RESULTS: The comprehensive analysis of the literature resulted in 324 compounds being isolated, identified, and reported from PH. Regarding traditional uses, the majority of phytochemical and pharmacological studies have indicated the diverse bioactivities of PH extracts, flavonoids, and volatile oil elements, including antibacterial, antifungal, insecticidal, antioxidant, and anti-inflammatory. CONCLUSIONS: PH has a long history of diversified medicinal uses, some of which have been verified in modern pharmacological studies. Further detailed studies are required to establish scientific and reasonable quality evaluation standards and action mechanisms of active constituents from PH.

A Study Against Colon Cancer Mechanism of Xanthium Sibiricum Herba Based on Computer Simulation and Bioinformatics.

INTRODUCTION: Cancer is one of the leading causes of death worldwide, accounting for nearly one in six deaths in 2020. As a folk medicine, Xanthium sibiricum Herba (XSH) has been used many times in clinical practice for the treatment of various diseases. With the increasing number of cancer patients, there is a clinical need to find effective anti-cancer drugs. AIM: This study aims to explores the bioactivity and the anti-cancer mechanism of XSH. METHODS: In this study, bioinformatics, network pharmacology, molecular docking, molecular dynamics simulation techniques, and apoptosis assay were used to explore the bioactivity and the anti-cancer mechanism of XSH. RESULTS: Finally, seven active ingredients in XSH after the screening were obtained, the two most active compounds were ß-sitosterol and aloe-emodin, and good anti-cancer activity of XSH was predicted. DISCUSSION: Four core targets were obtained from the PPI network map, namely Caspase-3 (CASP3), Transcription factor AP-1 (JUN), Myc proto-oncogene protein (MYC), and cellular tumor antigen p53 (TP53). GO and KEGG analyses showed that the mechanism of XSH anti-cancer is mainly related to the apoptosis process, and the main signaling pathways are enriched in the p53 signaling pathway, Apoptosis, and MAPK signaling. The molecular docking and molecular dynamics simulation results showed that CASP3, JUN, MYC, and TP53 had a high affinity with ß-sitosterol and aloe-emodin. Bioinformatics analyses demonstrated the importance of core targets. Apoptosis assay showed that XSH could significantly promote the apoptosis of cancer cells, and inhibit their proliferation and migration, especially colon cancer cells. CONCLUSION: This study uncovered the main active components, bioactivities, and potential targets of XSH, and further revealed the multi-component, multi-target, and multi-pathway mechanism of XSH for cancer treatment and promoting apoptosis.

Saikosaponin A and Its Epimers Alleviate LPS-Induced Acute Lung Injury in Mice.

The purpose of this work was to illustrate the effect of processing with vinegar on saikosaponins of Bupleurum chinense DC. (BC) and the protective effects of saikosaponin A (SSA), saikosaponin b1 (SSb1), saikosaponin b2 (SSb2), and saikosaponin D (SSD) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice. We comprehensively evaluated the anti-inflammatory effects and potential mechanisms of SSA, SSb1, SSb2, and SSD through an LPS-induced ALI model using intratracheal injection. The results showed that SSA, SSb1, SSb2, and SSD significantly decreased pulmonary edema; reduced the levels of IL-6, TNF-α, and IL-1ß in serum and lung tissues; alleviated pulmonary pathological damage; and decreased the levels of the IL-6, TNF-α, and IL-1ß genes and the expression of NF-κB/TLR4-related proteins. Interestingly, they were similar in structure, but SSb2 had a better anti-inflammatory effect at the same dose, according to a principal component analysis. These findings indicated that it may not have been comprehensive to only use SSA and SSD as indicators to evaluate the quality of BC, especially as the contents of SSb1 and SSb2 in vinegar-processed BC were significantly increased.

[Optimization of polysaccharide extraction from Hippocampus by deep neural network and Box-Behnken design-response surface methodology].

In this paper, the extraction rate of crude polysaccharides and the yield of polysaccharides from Hippocampus served as test indicators. The comprehensive evaluation indicators were assigned by the R language combined with the entropy weight method. The Box-Behnken design-response surface methodology(BBD-RSM) and the deep neural network(DNN) were employed to screen the optimal parameters for the polysaccharide extraction from Hippocampus. These two modeling methods were compared and verified experimentally for the process optimization. This study provides a reference for the industrialization of effective component extraction from Chinese medicinals and achieves the effective combination of modern technology and traditional Chinese medicine.

Saikosaponin D Rescues Deficits in Sexual Behavior and Ameliorates Neurological Dysfunction in Mice Exposed to Chronic Mild Stress.

Often associated with sexual dysfunction (SD), chronic stress is the main contributing risk factor for the pathogenesis of depression. Radix bupleuri had been widely used in traditional Chinese medicine formulation for the regulation of emotion and sexual activity. As the main active component of Radix bupleuri, saikosaponin D (SSD) has a demonstrated antidepressant effect in preclinical studies. Herein, we sought to investigate the effect of SSD to restore sexual functions in chronically stressed mice and elucidate the potential brain mechanisms that might underly these effects. SSD was gavage administered for three weeks during the induction of chronic mild stress (CMS), and its effects on emotional and sexual behaviors in CMS mice were observed. The medial posterodorsal amygdala (MePD) was speculated to be involved in the manifestation of sexual dysfunctions in CMS mice. Our results revealed that SSD not only alleviated CMS-induced depressive-like behaviors but also rescued CMS-induced low sexual motivation and poor sexual performance. CMS destroyed astrocytes and activated microglia in the MePD. SSD treatment reversed the changes in glial pathology and inhibited neuroinflammatory and oxidative stress in the MePD of CMS mice. The neuronal morphological and functional deficits in the MePD were also alleviated by SSD administration. Our results provide insights into the central mechanisms involving the brain associated with sexual dysfunction. These findings deepen our understanding of SSD in light of the psychopharmacology of stress and sexual disorders, providing a theoretical basis for its potential clinical application.

The Ghrelin/Growth Hormone Secretagogue Receptor System Is Involved in the Rapid and Sustained Antidepressant-Like Effect of Paeoniflorin.

Major depressive disorder (MDD) is a debilitating mental illness affecting people worldwide. Although significant progress has been made in the development of therapeutic agents to treat this condition, fewer than half of all patients respond to currently available antidepressants, highlighting the urgent need for the development of new classes of antidepressant drugs. Here, we found that paeoniflorin (PF) produced rapid and sustained antidepressant-like effects in multiple mouse models of depression, including the forced swimming test and exposure to chronic mild stress (CMS). Moreover, PF decreased the bodyweight of mice without affecting food intake and glucose homeostasis, and also reduced the plasma levels of total ghrelin and the expression of ghrelin O-acyltransferase in the stomach; however, the plasma levels of ghrelin and the ghrelin/total ghrelin ratio were unaffected. Furthermore, PF significantly increased the expression of growth hormone secretagogue receptor 1 alpha (GHSR1α, encoded by the Ghsr gene) in the intestine, whereas the levels of GHSR1α in the brain were only marginally downregulated following subchronic PF treatment. Finally, the genetic deletion of Ghsr attenuated the antidepressant-like effects of PF in mice exposed to CMS. These results suggested that increased GHSR1α expression in the intestine mediates the antidepressant-like effects of PF. Understanding peripheral ghrelin/GHSR signaling may provide new insights for the screening of antidepressant drugs that produce fast-acting and sustained effects.

Daturataturin A, a withanolide in Datura metel L., induces HaCaT autophagy through the PI3K-Akt-mTOR signaling pathway.

Daturataturin A (DTA), a withanolide compound in Datura metel L., exhibits excellent anti-inflammatory and anti-proliferative activities. Here, we report the study of DTA-induced proliferation and inflammation in human immortalized keratinocytes (HaCaTs) and the associated molecular mechanisms. HaCaTs are a model of the epidermal proliferative state of cells. The pharmacodynamics and mechanism of DTA were studied by western blot, immunofluorescence, apoptosis and proliferation detection, and real-time quantitative polymerase chain reaction. We confirmed that DTA induced HaCaT autophagy, which, in turn, induced HaCaT senescence and, ultimately, led to cell cycle arrest. DTA also negatively regulated inflammation through the activation of autophagy. This may be one of the mechanisms underlying the action of Datura metel L. preparation used for the treatment of psoriasis.

Effect of Hordei Fructus Germinatus on differential gene expression in the prolactin signaling pathway in the mammary gland of lactating rats.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, Hordei Fructus Germinatus (HFG) is the germinated and dried fruit of Hordeum vulgare L, which is commonly used in clinical Chinese medicine. Traditional Chinese Medicine (TCM) theory holds that HFG can be both medicinal and edible, which means that it is derived from food medicine. Raw HFG and roasted HFG are used to treat hypogalactia, hyperprolactinemia and indigestion. In recent years, the lactogenic and galactophygous effects of HFG have attracted increasing attention. Nevertheless, there is much confusion over the use of raw and processed HFG, and the mechanism of its lactogenic effect seems remains poorly understood. AIM OF THE STUDY: This study aimed to explore the lactogenic effect of raw HFG and roasted HFG on rats with overloaded lactation and to reveal the underlying molecular mechanism. MATERIALS AND METHODS: Raw and processed HFG water decoctions were given to overloaded lactation model rats at a dose of 1.7800 g kg-1·d-1, and the control group was given the same volume of water. The lactogenic effect of raw and processed HFG was evaluated by measuring daily lactation, body weight and pup body weight, serum PRL, E2, and GH contents after parturition, and the pathological characteristics of mammary tissue sections. cDNA microarrays can be used to screen diverse gene expression patterns and signaling pathways related to prolactin. The expression of relevant differentially expressed genes was verified by real-time PCR and western blotting. RESULTS: In vivo experiments demonstrated that the raw HFG water decoction stimulated mammogenesis, accelerated the transformation of the lobular acinar system, resulted in denser mammary epithelial cells and thicker glandular ducts that were full of milk and facilitated the secretion of milk. Moreover, HFG increased PRL, E2, and GH levels, pup body weight, daily lactation and the body weight of lactating rats. Following gene chip identification, KEGG pathway enrichment analysis revealed genes that were highly related to prolactin in the prolactin signaling pathway and JAK-STAT signaling pathway, and the main differentially expressed genes were Jak2 (down), Stat5α (up), cyclin D1 (up), SOCS1 (up), CISH (down) and PRLR (up). Compared with the control group, RT-PCR results indicated that Jak2 and CISH were downregulated and that Stat5α, cyclin D1, SOCS1 and PRLR were upregulated. Western blot assays showed that PRLR, STAT5α and cyclin D1 levels in the mammary glands of the raw HFG water decoction group were significantly increased, which was consistent with the results of cDNA microarray screening. CONCLUSION: The present study reveals that raw HFG effectively enhances lactation in rats, possibly by influencing the prolactin/JAK-STAT signaling pathway.

Liver Soluble Epoxide Hydrolase Regulates Behavioral and Cellular Effects of Chronic Stress.

Major depression is a serious global health concern; however, the pathophysiology underlying this condition remains unclear. While numerous studies have focused on brain-specific mechanisms, few have evaluated the role of peripheral organs in depression. Here, we show that the liver activates an intrinsic metabolic pathway that can modulate depressive-like behavior. We find that chronic stress specifically increases the protein levels of monomeric and oligomeric soluble epoxide hydrolase (sEH), a key enzyme in epoxyeicosatrienoic acid (EET) signaling, in the liver. Hepatic deletion of Ephx2 (which encodes sEH) results in antidepressant-like effects, while the hepatic overexpression of sEH induces depressive phenotypes. The activity of sEH in hepatocytes modulates the plasma levels of 14,15-EET, which then interacts with astrocytes in the medial prefrontal cortex to mediate the effects of hepatic Ephx2 deletion. These results suggest that targeting mechanisms underlying the hepatic response to stress would increase our therapeutic options for the treatment of depression.

Axonal iron transport in the brain modulates anxiety-related behaviors.

Iron is essential for a broad range of biochemical processes in the brain, but the mechanisms of iron metabolism in the brain remain elusive. Here we show that iron functionally translocates among brain regions along specific axonal projections. We identified two pathways for iron transport in the brain: a pathway from ventral hippocampus (vHip) to medial prefrontal cortex (mPFC) to substantia nigra; and a pathway from thalamus (Tha) to amygdala (AMG) to mPFC. While vHip-mPFC transport modulates anxiety-related behaviors, impairment of Tha-AMG-mPFC transport did not. Moreover, vHip-mPFC iron transport is necessary for the behavioral effects of diazepam, a well-known anxiolytic drug. By contrast, genetic or pharmacological promotion of vHip-mPFC transport produced anxiolytic-like effects and restored anxiety-like behaviors induced by repeated restraint stress. Taken together, these findings provide key insights into iron metabolism in the brain and identify the mechanisms underlying iron transport in the brain as a potential target for development of novel anxiety treatments.

Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors.

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of Ephx2 (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release in vitro and in vivo Moreover, astrocytic ATP release was required for the antidepressant-like effect of Ephx2 deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress.SIGNIFICANCE STATEMENT Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.

Down-Regulation of Neuregulin1/ErbB4 Signaling in the Hippocampus Is Critical for Learning and Memory.

Hippocampal function is important for learning and memory, and dysfunction of the hippocampus has been linked to the pathophysiology of neuropsychiatric diseases such as schizophrenia. Neuregulin1 (NRG1) and ErbB4, two susceptibility genes for schizophrenia, reportedly modulate long-term potentiation (LTP) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, little is known regarding the contribution of hippocampal NRG1/ErbB4 signaling to learning and memory function. Here, quantitative real-time PCR and Western blotting were used to assess the mRNA and protein levels of NRG1 and ErbB4. Pharmacological and genetic approaches were used to manipulate NRG1/ErbB4 signaling, following which learning and memory behaviors were evaluated using the Morris water maze, Y-maze test, and the novel object recognition test. Spatial learning was found to reduce hippocampal NRG1 and ErbB4 expression. The blockade of NRG1/ErbB4 signaling in hippocampal CA1, either by neutralizing endogenous NRG1 or inhibiting/ablating ErbB4 receptor activity, enhanced hippocampus-dependent spatial learning, spatial working memory, and novel object recognition memory. Accordingly, administration of exogenous NRG1 impaired those functions. More importantly, the specific ablation of ErbB4 in parvalbumin interneurons also improved learning and memory performance. The manipulation of NRG1/ErbB4 signaling in the present study revealed that NRG1/ErbB4 activity in the hippocampus is critical for learning and memory. These findings might provide novel insights on the pathophysiological mechanisms of schizophrenia and a new target for the treatment of Alzheimer's disease, which is characterized by a progressive decline in cognitive function.

Astrocyte-derived ATP modulates depressive-like behaviors.

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.