The objective of this study was to investigate the therapeutic effects of paeoniflorin (PA) on cognitive impairment and to elucidate its potential mechanisms in MRL/lpr mice, a model of systemic lupus erythematosus-associated cognitive dysfunction.

Cognitive performance and behavioral responses were assessed using a comprehensive battery of tests, including the Morris water maze, the Novel object recognition test, and the Y maze. Neuropathological changes in the hippocampal regions were visualized through Nissl, HE and Immunohistochemistry staining. Protein expression levels of receptor for advanced glycation end-products (RAGE) and LC3B were quantified by immunofluorescence, while the ultrastructure of autophagic organelles was examined using transmission electron microscopy (TEM). Inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were quantified in both serum and hippocampal homogenates by enzyme-linked immunosorbent assay (ELISA). The hippocampal expression of advanced glycation end-products (AGEs), RAGE, p62, Beclin-1, and key proteins involved in the mitogen-activated protein kinase (MAPK) pathways, including p38MAPK, ERK, and mTOR were analyzed by Western blotting.

Paeoniflorin ameliorates cognitive dysfunction, neuronal damage, pro-inflammatory cytokine production in MRL/lpr mice. Paeoniflorin suppresses RAGE and autophagy levels and P38 MAPK/ERK/mTOR signaling pathway activation in the hippocampus of MRL/lpr mice.

Paeoniflorin may exert its neuroprotective effects by modulating the AGEs/RAGE/P38MAPK/ERK/mTOR autophagy signaling pathway.

Neuropsychiatric disorders significantly impact global health and socioeconomic well-being, highlighting the urgent need for effective treatments. Chronic inflammation, often driven by the innate immune system, is a key feature of many neuropsychiatric conditions. NOD-like receptors (NLRs), which are intracellular sensors, detect danger signals and trigger inflammation. Among these, NLR protein (NLRP) inflammasomes play a crucial role by releasing pro-inflammatory cytokines and inducing a particular cell death process known as pyroptosis. Pyroptosis is defined as a proinflammatory form of programmed cell death executed by cysteine-aspartic proteases, also known as caspases. Currently, the role of pyroptotic flux has emerged as a critical factor in innate immunity and the pathogenesis of multiple diseases. Emerging evidence suggests that the induction of pyroptosis, primarily due to NLRP inflammasome activation, is involved in the pathophysiology of various neuropsychiatric disorders, including depression, stress-related issues, schizophrenia, autism spectrum disorders, and neurodegenerative diseases. Within this framework, the current review explores the complex relationship between pyroptosis and neuropsychiatric diseases, aiming to identify potential therapeutic targets for these challenging conditions.

Depression is a common mental disorder characterized by prolonged loss of interest and low mood, accompanied by symptoms such as sleep disturbances and cognitive impairments. In severe cases, there may be a tendency toward suicide. Depression can be caused by a series of highly complex pathological mechanisms; However, its key pathogenic mechanism remains unclear. As a novel programmed cell death (PCD) pathway and inflammatory cell death mode, pyroptosis involves a series of tightly regulated gene expression events. It may play a significant role in the pathogenesis and management of depression by modulating neuroinflammatory processes. In addition, a large number of studies have shown that various pharmacologically active natural products can regulate pyroptosis through multiple targets and pathways, demonstrating significant potential in the treatment of depression. These natural products offer advantages such as low costs and minimal side effects, making them a viable supplement or alternative to traditional antidepressants. In this review, we summarized recent research on natural products that regulate pyroptosis and neuroinflammation to improve depression. The aim of this review was to contribute to a scientific basis for the discovery and development of more natural antidepressants in the future.

To review the antidepressant effects of natural products targeting pyroptosis-mediated neuroinflammation, data were collected from the Web of Science, ScienceDirect databases, and PubMed to classify and summarize the relationship between pyroptosis and neuroinflammation in depression, as well as the pharmacological mechanisms of natural products.

Multiple researches have revealed that pyroptosis-mediated neuroinflammation serves as a pivotal contributory factor in the pathological process of depression. Natural products, such as terpenoids, terpenes, phenylethanol glycosides, and alkaloids, have antidepressant effects by regulating pyroptosis to alleviate neuroinflammation.

We comprehensively reviewed the regulatory effects of natural products in depression-related pyroptosis pathways, providing a uniquely insightful perspective for the research, development, and application of natural antidepressants. However, future research should further explore the modulatory mechanisms of natural products in regulating pyroptosis, which is of great importance for the genration of effective antidepressants.

Sepsis patients with diabetes are at a high clinical risk. It is well reported that XueBiJing injection has good clinical benefit in sepsis individuals. However, there is no relevant report about the efficacy and safety of XBJ in sepsis patients with comorbid diabetes.

Data of two large randomized controlled clinical trials (XBJ-SAP (ChiCTR-TRC-13003534) and EXIT-SEP (NCT0323874)) were combined, and post hoc analyses were performed. Sepsis patients with diabetes were further divided into the XBJ-treated group and placebo group based on inclusion and exclusion criteria. The primary (28-day mortality) and secondary outcomes (mortality in the ICU and in the post-randomization hospital, acute physiology, and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score) were compared between the XBJ treatment and placebo groups in sepsis patients with the diabetes status at baseline. Moreover, the occurrence of adverse events (AEs) was also assessed.

At the study baseline, a total of 378 sepsis patients (227 men [60.0%] and 151 women [40.0%]; mean [SD] age, 60.3 [11.1] years) were considered to have diabetes, of which 177 received XBJ and 201 received placebo administration. Among these sepsis patients with diabetes, the mortality at 28 days was significantly lower in the XBJ group than in the placebo group (29 of 173 patients [16.8%] vs. 56 of 198 patients [28.3%], P = 0.01), and the absolute risk difference was 11.5% (95% CI, 3.1%-19.9%). Furthermore, there was no difference in the overall incidence of adverse events (AEs) when XBJ was used (24.4% [42 of 172 patients] vs. 27.7% [54 of 195 patients].

The present study underscores the pivotal role of XBJ in modulating the immune response among sepsis patients suffering from diabetes mellitus, exploring the positive effects of XBJ on sepsis patients with diabetes mellitus. The efficacy and safety of XBJ compared with those of the placebo were consistent with the overall trial findings, demonstrating that XBJ is efficacious in sepsis patients with diabetes and suggesting that there is no need for special safety precautions.

ChiCTR-TRC-13003534 and NCT0323874.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

Major depression has been an area of extensive research during the last decades, for it represents a leading cause of disability and suicide. The stark rise of depression rates influenced by life stressors, economic threats, pandemic era, and resistance to classical treatments, has made the disorder rather challenging. Adult hippocampal neurogenesis and plasticity are particularly sensitive to the dynamic interplay between autophagy and inflammation. In fact, the intricate balance between the two processes contributes to neuronal homeostasis and survival.

Having demonstrated promising potentials in AMPK activation, a major metabolic sensor and autophagy regulator, empagliflozin (Empa) was investigated for possible antidepressant properties in the reserpine rat model of depression.

While the reserpine protocol elicited behavioral, biochemical, and histopathological changes relevant to depression, Empa outstandingly hindered these pathological perturbations. Importantly, hippocampal autophagic response markedly declined with reserpine which disrupted the AMPK/mTOR/Beclin1/LC3B machinery and, conversely, neuro-inflammation prevailed under the influence of the NLRP3 inflammasome together with oxidative/nitrative stress. Consequently, AMPK-mediated neurotrophins secretion obviously deteriorated through PKCζ/NF-κB/BDNF/CREB signal restriction. Empa restored hippocampal monoamines and autophagy/inflammation balance, driven by AMPK activation. By promoting the atypical PKCζ phosphorylation (Thr403) which subsequently phosphorylates NF-κB at Ser311, AMPK successfully reinforced BDNF/CREB signal and hippocampal neuroplasticity. The latter finding was supported by hippocampal CA3 toluidine blue staining to reveal intact neurons.

The current study highlights an interesting role for Empa as a regulator of autophagic and inflammatory responses in the pathology of depression. The study also pinpoints an unusual contribution for NF-κB in neurotrophins secretion via AMPK/PKCζ/NF-κB/BDNF/CREB signal transduction. Accordingly, Empa can have special benefits in diabetic patients with depressive symptoms.

The influence of p-NF-κB (Ser311) on NLRP3 inflammasome assembly and activation has not been investigated, which can represent an interesting point for further research.

Inflammation assumes a vital role in the pathogenesis of depression and in antidepressant treatment. Paeoniflorin (PF), a monoterpene glycoside analog possessing anti-inflammatory attributes, exhibits therapeutic efficacy on depression-like behavior in mice. The objective of this study was to evaluate the antidepressant effects of PF on depression elicited by the chronic unpredictable mild stress (CUMS) model and the precise neural sequence associated with the inflammatory process. In this study, we established an in vivo mouse model induced by CUMS and an in vitro BV2 cell model induced by LPS+ATP. The mechanism of PF for depression was assessed by the SIRT1 selective inhibitor EX-527. The findings demonstrated that PF significantly alleviated the damage of BV2 cells treated with LPS and ATP, inhibited the generation of ROS, up-regulated the expression of SIRT1 mRNA, and down-regulated the expression of nuclear NF-κB, p65, NLRP3, Caspase-1 and GSDMD-N in vitro. In vivo, PF mitigated the depressive-like behavior induced by CUMS, reduced the number of neurons, and decreased the secretion of pro-inflammatory factors IL-1β, IL-6, and TNF-α in the hippocampus. Immunohistochemical results indicated that PF attenuated CUMS-induced hyperactivation of microglia. Moreover, the expression level of SIRT1 in the hippocampus was augmented, while the protein levels of NF-κB, p65, NLRP3, Caspase-1, IL-1β and GSDMD-N were diminished after PF treatment. Additionally, the selective inhibition of SIRT1 attenuated the therapeutic effect of PF on depression. These results imply that PF possesses antidepressant properties that rely on SIRT1 signaling to regulate NLRP3 inflammasome inactivation.

Chronic exposure to methamphetamine (METH) has been suggested to cause METH use disorder and severe cognitive impairment. Paeoniflorin (PF) is a monoterpenoid glycoside with various beneficial effects, including anti-inflammatory, antioxidant and antidepressant. The current study was designed to investigate the effect of PF (30 mg/kg, i.p.) on the rewarding effect of METH (2.5 mg/kg, i.p.) and the associated cognitive impairment, using the animal model of conditioned place preference, new location reorganization test, new object reorganization test and Y-maze test. METH induced conditioned place preference, accompanied by increased expression of synapse-associated proteins in the ventral target areas (VTA) and nucleus accumbens (NAc). In addition, METH induced significant cognitive impairment and decreased the expression of synapse-associated proteins in the hippocampus (Hip). Administration of PF decreased the rewarding effect of METH and the expression of synapse-associated proteins in the VTA or NAc. PF was also effective to improve METH-induced cognitive impairment by upregulating the expression of synapse-associated proteins in the Hip. Therefore, PF could be a potential agent for the treatment of METH use disorder and the associated cognitive impairment.

To decipher the antidepression effect of Chaigui Granules (CGKL) from the relationship between depression and microbial molecules based on multi-omics.

Male SD rats were subjected to chronic unpredictable mild stress (CUMS) for seven weeks. The antidepressants CGKL extract and CGKL were administered for the following four weeks. The behavior test and the content of monoamine neurotransmitters were used to evaluate the efficacy of CGKL. The 16S rRNA sequencing, LC-MS technology and molecular biological techniques were used to explore the pharmacological mechanism of CGKL.

CGKL treatment obviously alleviated the depressive behavioral indicators and regulated the content of monoamine neurotransmitters, and presented dose-dependent manner. CGKL could also improve the arginine metabolism disorder of gut microbiota in the jejunum. Meanwhile, the contents of arginine and its metabolites in the serum and hippocampus were regulated to normal levels. Further investigation indicated that the expression of related rate-limiting enzyme genes and proteins in the hippocampus was validated by qRT-PCR and Western blotting. The results showed that the gut microbiota, metabolites, and genes or proteins of rate-limiting enzymes involved in the arginine pathway were significantly regulated by CGKL.

The present study demonstrates that CGKL might exert antidepressant effects through regulating arginine metabolism, and its mechanism may be related to modulating the gut microbiota and related metabolic enzyme.

Depression is a widespread disease, with high mortality and recurrence rates. Recent studies have shown that elevated cytokine levels are implicated in the molecular mechanisms of depression. Oxidative stress contributes to the stimulation of cytokine production. Growing evidence suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect on the hippocampus by suppressing oxidative stress and inflammation. However, the effect and mechanism of Gs-Re in the treatment of depression remain understudied. This study aimed to evaluate the neuroprotective and antidepressant-like effects of Gs-Re and the possible underlying mechanisms. In this article, the antidepressant-like effect of the Gs-Re was studied both in vitro (H2O2-induced oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive model mice). Our results indicated that, at the cellular level, Gs-Re effectively enhanced cell survival following H2O2 stimulation, inhibited the mass production of oxidative stress markers (MDA and ROS), and prevented the occurrence of apoptosis. Moreover, Gs-Re significantly reduced the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α and restored the abnormal mitochondrial membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced neuroinflammation and depressive-like behaviors in vivo and inhibited microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB signaling pathway induced by H2O2 or reserpine in HT-22 cells or in the mouse hippocampus were significantly reversed by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like behavior and eliminated the inhibition of oxidative stress and neuroinflammation in vivo. This study suggested that Gs-Re produces neuroprotective and depressive effects by inhibiting oxidative stress and inflammation and activating the BDNF/TrkB/ERK/CREB pathway.

Paeoniae Radix Rubra (PRR) known as Chishao, in China, is the dried root of Paeonia lactiflora Pall. or Paeonia veitchii Lynch, with a history of over 2000 years in traditional Chinese medicine, is employed to clear heat, cool the blood, dispel blood stasis, and alleviate pain. Phytochemical investigations identified 264 compounds that contained monoterpenes and their glycosides, sesquiterpenes, triterpenes, steroids, flavonoids, lignans, tannins, volatile oils, and other compounds. It has been reported to have different pharmacological activities, including cardiovascular-protective, antidepressive, neuroprotective, antitumor, hepatoprotective, and anti-inflammatory effects. This study offers a comprehensive review covering ethnopharmacology, phytochemistry, pharmacological activities, therapeutic mechanism for blood stasis syndrome, and quality control of PRR. The comprehensive analysis aims to achieve a thorough understanding of its effects and serves as a foundation for future research and development.

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

Huangqi Guizhi Wuwu Decoction (HQGZWWD) has shown promising potential in treating various cardiovascular diseases. This study aimed to elucidate the molecular basis and therapeutic role of HQGZWWD in the treatment of doxorubicin (DOX)-induced myocardial injury. The HPLC fingerprint of HQGZWWD was used to analyze the active components. A DOX-induced myocardial damage rat model was developed, and the therapeutic effects of HQGZWWD were evaluated using echocardiography, myocardial enzyme levels, and hematoxylin and eosin staining. Network pharmacology was used to screen treatment targets, and western blotting and immunohistochemistry were performed to assess cellular pyroptosis levels. Oxidative stress levels were measured using assay kits, and mitochondrial damage was examined using transmission electron microscopy. An in vitro model of DOX-induced cell damage was established, and treatment was administered using serum containing HQGZWWD and N-acetylcysteine (NAC). Oxidative stress levels were detected using assay kits and DCFH-DA, whereas cellular pyroptosis levels were assessed through WB, immunofluorescence, and ELISA assays. HQGZWWD ameliorated DOX-induced myocardial injury. Network pharmacology identified IL-1β and IL-18 as crucial targets. HQGZWWD downregulated the protein levels of the inflammatory factors IL-1β and IL-18, inhibited the expression of GSDMD-NT, and simultaneously suppressed the synthesis of Caspase-1, ASC, NLRP3, and Caspase-11. Additionally, HQGZWWD inhibited oxidative stress, and the use of NAC as an oxidative stress inhibitor resulted in significant inhibition of the GSDMD-NT protein in H9C2 cells. These findings highlight the myocardial protective effects of HQGZWWD by inhibiting oxidative stress and suppressing both canonical and non-canonical pyroptotic pathways.

Depression is one of the most common forms of psychopathology, which is associated with gut microbiota dysfunction. Dihydroartemisinin (DHA) has been shown to regulate gut microbiota and ameliorate neuropathies, but whether it can be used to treat depression remains unclear. Our study found that DHA treatment raised the preference for sugar water in chronic unpredictable mild stress (CUMS)-induced mice and reduced the immobility time in open field, forced swimming and tail suspension experiments, and promoted doublecortin expression. Additionally, DHA up-regulated the diversity and richness of intestinal microbiota in depression-like mice, and restored the abnormal abundance of microbiota induced by CUMS, such as Turicibacter, Lachnospiraceae, Erysipelotrichaceae, Erysipelatoclostridium, Eubacterium, Psychrobacter, Atopostipes, Ileibacterium, Coriobacteriacea, Alistipes, Roseburia, Rikenella, Eggerthellaceae, Ruminococcus, Tyzzerella, and Clostridia. Furthermore, KEGG pathway analysis revealed that gut microbiota involved in the process of depression may be related to glucose metabolism, energy absorption and transport, and AMPK signaling pathway. These results indicated that DHA may play a protective role in CUMS-induced depression by mediating gut-microbiome.

Depression is a common and serious psychological condition, which seriously affects individual well-being and functional ability. Traditional treatment methods include drug therapy and psychological counseling; however, these methods have different degrees of side effects and limitations. In recent years, nonconvulsive electrotherapy (NET) has attracted increasing attention as a noninvasive treatment method. However, the clinical efficacy and potential mechanism of NET on depression are still unclear. We hypothesized that NET has a positive clinical effect in the treatment of depression, and may have a regulatory effect on serum inflammatory factors during treatment.

To assess the effects of NET on depression and analyze changes in serum inflammatory factors.

This retrospective study enrolled 140 patients undergoing treatment for depression between May 2017 and June 2022, the observation group that received a combination of mindfulness-based stress reduction (MBSR) and NET treatment (n = 70) and the control group that only received MBSR therapy (n = 70). The clinical effectiveness of the treatment was evaluated by assessing various factors, including the Hamilton Depression Scale (HAMD)-17, self-rating idea of suicide scale (SSIOS), Pittsburgh Sleep Quality Index (PSQI), and levels of serum inflammatory factors before and after 8 wk of treatment. The quality of life scores between the two groups were compared. Comparisons were made using t and χ2 tests.

After 8 wk of treatment, the observation group exhibited a 91.43% overall effectiveness rate which was higher than that of the control group which was 74.29% (64 vs 52, χ2 = 7.241; P < 0.05). The HAMD, SSIOS, and PSQI scores showed a significant decrease in both groups. Moreover, the observation group had lower scores than the control group (10.37 ± 2.04 vs 14.02 ± 2.16, t = 10.280; 1.67 ±0.28 vs 0.87 ± 0.12, t = 21.970; 5.29 ± 1.33 vs 7.94 ± 1.35, t = 11.700; P both < 0.001). Additionally, there was a notable decrease in the IL-2, IL-1β, and IL-6 in both groups after treatment. Furthermore, the observation group exhibited superior serum inflammatory factors compared to the control group (70.12 ± 10.32 vs 102.24 ± 20.21, t = 11.840; 19.35 ± 2.46 vs 22.27 ± 2.13, t = 7.508; 32.25 ± 4.6 vs 39.42 ± 4.23, t = 9.565; P both < 0.001). Moreover, the observation group exhibited significantly improved quality of life scores compared to the control group (Social function: 19.25 ± 2.76 vs 16.23 ± 2.34; Emotions: 18.54 ± 2.83 vs 12.28 ± 2.16; Environment: 18.49 ± 2.48 vs 16.56 ± 3.44; Physical health: 19.53 ± 2.39 vs 16.62 ± 3.46; P both < 0.001) after treatment.

MBSR combined with NET effectively alleviates depression, lowers inflammation (IL-2, IL-1β, and IL-6), reduces suicidal thoughts, enhances sleep, and improves the quality of life of individuals with depression.

Human genetic studies indicate that suicidal ideation and behavior are both heritable. Most studies have examined associations between aberrant gene expression and suicide behavior, but behavior risk is linked to the severity of suicidal ideation. Through a gene network approach, this study investigates how gene co-expression patterns are associated with suicidal ideation and severity using RNA-seq data in peripheral blood from 46 live participants with elevated suicidal ideation and 46 with no ideation. Associations with the presence of suicidal ideation were found within 18 co-expressed modules (p < 0.05), as well as in 3 co-expressed modules associated with suicidal ideation severity (p < 0.05, not explained by severity of depression). Suicidal ideation presence and severity-related gene modules with enrichment of genes involved in defense against microbial infection, inflammation, and adaptive immune response were identified and investigated using RNA-seq data from postmortem brain that revealed gene expression differences with moderate effect sizes in suicide decedents vs. non-suicides in white matter, but not gray matter. Findings support a role of brain and peripheral blood inflammation in suicide risk, showing that suicidal ideation presence and severity are associated with an inflammatory signature detectable in blood and brain, indicating a biological continuity between ideation and suicidal behavior that may underlie a common heritability.

Genus Paeonia, which is the main source of Traditional Chinese Medicine (TCM) Paeoniae Radix Rubra (Chishao in Chinese), Paeoniae Radix Alba (Baishao in Chinese) and Moutan Cortex (Mudanpi in Chinese), is rich in active pharmaceutical ingredient such as monoterpenoid glycosides (MPGs). MPGs from Paeonia have extensive pharmacological effects, but the pharmacological effects and molecular mechanisms of MPGs has not been comprehensively reviewed.

MPGs compounds are one of the main chemical components of the genus Paeonia, with a wide variety of compounds and strong pharmacological activities, and the structure of the mother nucleus-pinane skeleton is similar to that of a cage. The purpose of this review is to summarize the pharmacological activity and mechanism of action of MPGs from 2012 to 2023, providing reference direction for the development and utilization of Paeonia resources and preclinical research.

Keywords and phrases are widely used in database searches, such as PubMed, Web of Science, Google Scholar and X-Mol to search for citations related to the new compounds, extensive pharmacological research and molecular mechanisms of MPGs compounds of genus Paeonia.

Modern research confirms that MPGs are the main compounds in Paeonia that exert pharmacological effects. MPGs with extensive pharmacological characteristics are mainly concentrated in two categories: paeoniflorin derivatives and albiflflorin derivatives among MPGs, which contains 32 compounds. Among them, 5 components including paeoniflorin, albiflorin, oxypaeoniflorin, 6'-O-galloylpaeoniflorin and paeoniflorigenone have been extensively studied, while the other 28 components have only been confirmed to have a certain degree of anti-inflammatory and anticomplementary effects. Studies of pharmacological effects are widely involved in nervous system, endocrine system, digestive system, immune system, etc., and some studies have identified clear mechanisms. MPGs exert pharmacological activity through multilateral mechanisms, including anti-inflammatory, antioxidant, inhibition of cell apoptosis, regulation of brain gut axis, regulation of gut microbiota and downregulation of mitochondrial apoptosis, etc. CONCLUSION: This systematic review delved into the pharmacological effects and related molecular mechanisms of MPGs. However, there are still some compounds in MPGs whose pharmacological effects and pharmacological mechanisms have not been clarified. In addition, extensive clinical randomized trials are needed to verify the efficacy and dosage of MPGs.

Xiaoyao Wan (XYW) is a prescription medicine of traditional Chinese medicine (TCM) with the effects of "soothing the liver and relieving depression," and "strengthening spleen and nourishing blood". XYW has been widely concerned in the treatment of depression and has become one of the commonly used classic formulas in clinical practice. However, the pharmacodynamic substance basis and the quality control studies of XYW are hitherto quite limited. Here, we aim to fully utilize an advanced ultra - performance liquid chromatography-quadrupole - Orbitrap mass spectrometry (UPLC-Q-Orbitrap-MS), headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) and headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) technique to deep characterization of the pharmacological substance basis and quantitatively evaluate the quality of XYW. Firstly, 299 compounds were identified or tentatively characterized, including 198 non-volatile organic compounds (n-VOCs) and 101 volatile organic compounds (VOCs). Secondly, principal component analysis (PCA) and hierarchical cluster analysis (HCA) was used to analyze quality differences in XYW at different manufacturers. Thirdly, a parallel reaction monitoring (PRM) method was established and validated to quantify the fourteen major effective substances in different manufacturers of XYW, which were chosen as the benchmarked substances to evaluate the quality of XYW. In conclusion, this study shows that the strategy provides a useful method for quality control of TCM and offers a practical workflow for exploring the quality consistency of TCM.

Liver Stagnation and Spleen Deficiency (LSSD) is a Chinese Medicine (CM) pattern commonly observed in gastrointestinal (GI) diseases, yet its biological nature remains unknown. This limits the global use of CM medications for treating GI diseases. Recent studies emphasize the role of gut microbiota and their metabolites in the pathogenesis and treatment of LSSD-associated GI diseases. There is increasing evidence supporting that an altered gut microbiome in LSSD patients or animals contributes to GI and extra-intestinal symptoms and affects the effectiveness of CM therapies. The gut microbiota is considered to be an essential component of the biological basis of LSSD. This study aims to provide an overview of existing research findings and gaps for the pathophysiological study of LSSD from the gut microbiota perspective in order to understand the relationship between the CM pattern and disease progression and to optimize CM-based diagnosis, prevention, and therapy.

Neuroinflammation plays an important role in spinal cord injury (SCI), and an increasing number of studies have focused on the role of astrocytes in neuroinflammation. Pyroptosis is an inflammation-related form of programmed cell death, and neuroinflammation induced by astrocytes in the form of pyroptosis has been widely reported in many central nervous system diseases. Recent studies have found that erythropoietin has significant anti-inflammatory and neuroprotective effects in SCI; however, it has not been reported whether erythropoietin can reduce neuroinflammation by inhibiting neural cell pyroptosis in SCI.

A GEO dataset (GSE153720) was used to analyse the expression of pyroptosis-related genes in sham astrocytes and astrocytes 7 days, 1 month and 3 months after SCI. TargetScan and miRDB databases were used to predict the miRNA that could bind to the 3'UTR of rat Gsdmd. Primary rat spinal astrocytes were used for in vitro experiments, and the modified version of Allen's method was used to establish the rat SCI model. Western blotting, quantitative real-time polymerase chain reaction, flow cytometry, immunofluorescence, lactate dehydrogenase release assay and propidium iodide staining were used to detect the pyroptosis phenotype. A dual luciferase reporter gene assay was used to verify that miR-325-3p can bind to the 3'UTR of Gsdmd.

We found that pyroptosis-related genes mediated by the canonical NLRP3 inflammasome were highly expressed in astrocytes in an SCI animal model by bioinformatic analysis. We also observed that erythropoietin could reduce astrocyte pyroptosis in vivo and in vitro. In addition, we predicted miRNAs that regulate Gsdmd, the pyroptosis executor, and verified that erythropoietin inhibits astrocyte pyroptosis in SCI through the miR-325-3p/Gsdmd axis.

We demonstrated that erythropoietin can inhibit astrocyte pyroptosis through the miR-325-3p/Gsdmd axis. This study is expected to provide a new mechanism for erythropoietin in the treatment of SCI and a more reliable theoretical basis for clinical research.

Depression holds the title of the largest contributor to worldwide disability, with the numbers expected to continue growing. Currently, there are neither reliable biomarkers for the diagnosis of the disease nor are the current medications sufficient for a lasting response in nearly half of patients. In this comprehensive review, we analyze the previously established pathophysiological models of the disease and how the interplay between NLRP3 inflammasome activation and depression might offer a unifying perspective. Adopting this inflammatory theory, we explain how NLRP3 inflammasome activation emerges as a pivotal contributor to depressive inflammation, substantiated by compelling evidence from both human studies and animal models. This inflammation is found in the central nervous system (CNS) neurons, astrocytes, and microglial cells. Remarkably, dysregulation of the NLRP3 inflammasome extends beyond the CNS boundaries and permeates into the enteric and peripheral immune systems, thereby altering the microbiota-gut-brain axis. The integrity of the brain blood barrier (BBB) and intestinal epithelial barrier (IEB) is also compromised by this inflammation. By emphasizing the central role of NLRP3 inflammasome activation in depression and its far-reaching implications, we go over each area with potential modulating mechanisms within the inflammasome pathway in hopes of finding new targets for more effective management of this debilitating condition.

The risks of Zinc oxide nanoparticles (ZnO NPs) applications in biological medicine, food processing industry, agricultural production and the biotoxicity brought by environmental invasion of ZnO NPs both gradually troubled the public due to the lack of research on detoxification strategies. TFEB-regulated autophagy-pyroptosis pathways were found as the crux of the hepatotoxicity induced by ZnO NPs in our latest study. Here, our study served as a connecting link between preceding toxic target and the following protection mechanism of Paeoniflorin (PF). According to a combined analysis of network pharmacology/molecular docking-intestinal microbiota-metabolomics first developed in our study, PF alleviated the hepatotoxicity of ZnO NPs from multiple aspects. The hepatic inflammatory injury and hepatocyte pyroptosis in mice liver exposed to ZnO NPs was significantly inhibited by PF. And the intestinal microbiota disorder and liver metabolic disturbance were rescued. The targets predicted by bioinformatics and the signal trend in subacute toxicological model exhibited the protectiveness of PF related to the SIRT1-mTOR-TFEB pathway. These evidences clarified multiple protective mechanisms of PF which provided a novel detoxification approach against ZnO NPs, and further provided a strategy for the medicinal value development of PF.

Pyroptosis is an inflammatory and lysis type of programmed cell death. In the canonical pyroptosis signaling pathway, the NLRP3 inflammasome activates inflammatory caspase-1, which then shears cut the executor protein GSDMD. The N domains of GSDMD move to heterogeneous membranes, form pores, and release inflammatory cytokines IL-1β and IL-18, causing cell membrane swelling and rupture. Pyroptosis is mainly regulated by the key proteins in the signaling pathway, including inflammasome, caspase-1, GSDMD, IL-1β, and IL-18, as well as their agonists and inhibitors. Appropriate pyroptosis can improve host defense mechanisms, while excessive pyroptosis would derive pathological effects on central nervous system, leding to neuroinflammatory response, blood-brain barrier damage, and cognitive disfunction.

Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.

Depression is a severe mental illness that endangers human health. Depressed individuals are prone to sleep less and to the loss of appetite for food; their thinking and cognition processes, as well as mood, may even be affected. Danzhi Xiaoyao San (DXS), documented in the Internal Medicine Summary, has been used for hundreds of years in China and is widely applied traditionally to treat liver qi stagnation, liver and spleen blood deficiency, menstrual disorders, and spontaneous and night sweating. DXS can also clear heat and drain the liver. Presently, it is used frequently in the treatment of depression based on its ability to clear the liver and alleviate depression.

To summarize clinical and preclinical studies on the antidepressant-like effects of DXS, understand the material basis and mechanisms of these effects, and offer new suggestions and methods for the clinical treatment of depression.

"Danzhi Xiaoyao", "Danzhixiaoyao", "Xiaoyao", "depression" and active ingredients were entered as keywords in PubMed, Google Scholar, CNKI and WANFANG DATA databases in the search for material on DXS and its active ingredients. The PRISMA guidelines were followed in this review process.

Per clinical reports, DXS has a therapeutic effect on patients with depression but few side effects. DXS and its active ingredients allegedly produce their neuroprotective antidepressant-like effects by modulating monoamine neurotransmitter levels, inhibiting the hypothalamic-pituitary-adrenal (HPA) axis hyperfunction, reducing neuroinflammation and increasing neurotrophic factors.

Overall, DXS influences multiple potential mechanisms to exert its antidepressant-like effects thanks to its multicomponent character. Because depression is not caused by a single mechanism, probing the antidepressant-like effects of DXS could further help understand the pathogenesis of depression and discover new antidepressant drugs.

Enterovirus 71 (EV71) infection is one of the main causes of severe hand, foot and mouth disease (HFMD), which is usually accompanied by a marked inflammatory response. The excessive inflammatory response has been implicated to serve an important role in EV71-caused HFMD. Pyroptosis is a type of inflammatory programmed cell death. Therefore, a novel treatment strategy against EV71 infection could aim to alleviate the inflammatory response through inhibition of EV71-induced pyroptosis. The present study revealed that metformin had this therapeutic potential. A cell model of EV71 infection was established, cell viability was measured by CCK8 assay, cell damage was measured by LDH release kit, and the dead and dying cells were excluded by propidium iodide staining. The intracellular levels of DEP domain-containing mTOR interacting protein (DEPTOR) and pyroptosis-associated molecules were measured by western blot analysis, the NLRP3 expression was assessed by immunofluorescence labeling, and virus titers in cell culture supernatants were determined by a cell culture infectious dose 50 assay. The results demonstrated that EV71 infection could induce pyroptosis in a time- and dose-dependent manner, and metformin could inhibit EV71-induced pyroptosis. The mechanism of metformin inhibiting EV71-induced pyroptosis was explored next. Subsequent experiments indicated that metformin could increase the levels of DEPTOR, which were decreased by EV71. Finally, overexpression of DEPTOR in cells could reduce EV71-induced pyroptosis. Overall, the present study demonstrated that metformin could exert a novel pharmacodynamic anti-pyroptosis effect in the treatment of EV71 infection by upregulating DEPTOR expression.

Pyroptosis is a type of programmed cell death that induces myocardial ischemia-reperfusion injury (I/RI), which leads to cardiac dysfunction and even lethal reperfusion injury. MiR-122 is a liver-specific miRNA associated with coronary heart disease, but its role in pyroptosis activation in myocardial I/RI remains unclear. Thus, this study aimed to determine whether miR-122 inhibition exerts myocardial I/RI protection in in vivo and in vitro models. An I/RI model was established in vivo using C57BL/J6 male mice. MiR-122 expression was upregulated in the heart tissues from the I/RI group. Quantitative results of echocardiography parameters showed that miR-122 inhibition improved cardiac function and downregulated interleukin (IL)-1β, IL-18, caspase 1, and caspase 11. However, pretransfection with recombinant adeno-associated virus type 9 encoding a DUSP4-specific siRNA (AAV9-siDUSP4) blocked the protective effects of miR-122 inhibition. A hypoxia/reoxygenation (H/R) model was established to mimic the I/R condition in vitro using H9C2 cells. Results showed that miR-122 inhibition increased superoxide dismutase activity (SOD) and cell viability and decreased malondialdehyde (MDA) level, IL-1β, IL-18, caspase 1, caspase 11, and cell death. These protective effects were abolished by transfection with DUSP4-specific siRNA. In summary, miR-122 expression is upregulated in I/RI, and miR-122 inhibition alleviates I/RI by suppressing pyroptosis through targeting DUSP4. Thus, miR-122 may be a novel therapeutic target for treating myocardial I/RI.

Human genetic studies indicate that suicidal ideation and behavior are both heritable. Most studies have examined associations between aberrant gene expression and suicide behavior, but behavior risk is linked to severity of suicidal ideation. Through a gene network approach, this study investigates how gene co-expression patterns are associated with suicidal ideation and severity using RNA-seq data in peripheral blood from 46 live participants with elevated suicidal ideation and 46 with no ideation. Associations with presence and severity of suicidal ideation were found within 18 and 3 co-expressed modules respectively (p < 0.05), not explained by severity of depression. Suicidal ideation presence and severity-related gene modules with enrichment of genes involved in defense against microbial infection, inflammation, and adaptive immune response were identified, and tested using RNA-seq data from postmortem brain that revealed gene expression differences in suicide decedents vs. non-suicides in white matter, but not gray matter. Findings support a role of brain and peripheral blood inflammation in suicide risk, showing that suicidal ideation presence and severity is associated with an inflammatory signature detectable in blood and brain, indicating a biological continuity between ideation and suicidal behavior that may underlie a common heritability.

Major depressive disorder (MDD) is a debilitating psychiatric disorder which is common and endangers human physical and mental health. Studies have shown that hesperidin could improve the symptoms of depression with unclear mechanisms.

In this study, hesperidin was administered to chronic unpredictable mild stress (CUMS) depressed mice before behavioral test, network pharmacology analysis, RNA expression microarray analysis, pathway validation and molecular docking experiments.

we found that hesperidin intervention could significantly improve the depressive symptoms and downregulate the expression level of pyroptosis pathway including caspase 1 (Casp1), interleukin 18 (IL18), interleukin-1β (IL-1β) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). In addition, we found that hesperidin could possibly bind to NLRP3.

Our study demonstrated that hesperidin had huge potential as anti-depressive neuroprotectant, and may play a role in treating MDD by regulating NLRP3-mediated pyroptosis.

The causes of depression are complex. Many factors are involved in its pathogenesis, including the individual's biological and social environment. Although numerous studies have reported that the gut microbiota plays a significant role in depression, drugs that regulate the gut microbiota to treat depression have not yet been comprehensively reviewed. At the same time, more and more attention has been paid to the characteristics of traditional Chinese medicine (TCM) in improving depression by regulating gut microbiota. In ancient times, fecal microbiota transplantation was recorded in TCM for the treatment of severe diseases. There are also records in Chinese ancient books about the use of TCM to adjust gut microbiota to treat diseases, which has opened up a unique research field in TCM. Therefore, this article focuses on the pharmacological effects, targets, and mechanisms of TCM in improving depression by mediating the influence of gut microbiota.

To summarize the role the gut microbiota plays in depression, highlight potential regulatory targets, and elucidate the anti-depression mechanisms of TCMs through regulation of the gut microbiota.

A systematic review of 256 clinical trials and pharmaceutical studies published until June 2022 was conducted in eight electronic databases (Web of Science, PubMed, SciFinder, Research Gate, ScienceDirect, Google Scholar, Scopus, and China Knowledge Infrastructure), according to the implemented PRISMA criteria, using the search terms "traditional Chinese medicine," "depression," and "gut microbiota."

Numerous studies reported the effects of different gut bacteria on depression and that antidepressants work through the gut microbiota. TCM preparations based on compound Chinese medicine, the Chinese Materia Medica, and major bioactive components exerted antidepressant-like effects by improving levels of neurotransmitters, short-chain fatty acids, brain-derived neurotrophic factor, kynurenine, and cytokines via regulation of the gut microbiota.

This review summarized the anti-depression effects of TCM on the gut microbiota, providing evidence that TCMs are safe and effective in the treatment of depression and may provide a new therapeutic approach.

The present article provides a detailed concept of the role of NLRP3 inflammasome in the pathophysiology of depression-like chronic diseases where inflammation and release of various cytokines plays a pivotal role in exaggerating the condition. The various pathways involved in NLRP3 activation are the main target of NLRP3 inhibitors for the therapeutic management of depression as per the recent clinical and research studies conducted so far. Further various drug inhibitors for NLRP3 available in preclinical and clinical trials have been discussed in detail. Hence, blockage of the action of NLRP3 inflammasome is crucial to anticipate the inflammatory cytokine release from the mediators that contributes to cause depression.

Increasing evidence suggests that the failure of clinical antidepressants may be related with neuroinflammation. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is an intracellular multiprotein complex, and has been considered as a key contributor to the development of neuroinflammation. Inhibition of NLRP3 inflammasome is an effective method for depression treatment. In this review, we summarized current researches highlighting the role of NLRP3 inflammasome in the pathology of depression. Firstly, we discussed NLRP3 inflammasome activation in patients with depression and animal models. Secondly, we outlined the possible mechanisms driving the activation of NLRP3 inflammasome. Thirdly, we discussed the pathogenetic role of NLRP3 inflammasome in depression. Finally, we overviewed the current and potential antidepressants targeting the NLRP3 inflammasome. Overall, the inhibition of NLRP3 inflammasome activation may be a potential therapeutic strategy for inflammation-related depression.

Gastric cancer (GC) ranks fifth in prevalence among carcinomas worldwide. Both pyroptosis and long noncoding RNAs (lncRNAs) play crucial roles in the occurrence and development of gastric cancer. Therefore, we aimed to construct a pyroptosis-associated lncRNA model to predict the outcomes of patients with gastric cancer.

Pyroptosis-associated lncRNAs were identified through co-expression analysis. Univariate and multivariate Cox regression analyses were performed using the least absolute shrinkage and selection operator (LASSO). Prognostic values were tested through principal component analysis, a predictive nomogram, functional analysis and Kaplan‒Meier analysis. Finally, immunotherapy and drug susceptibility predictions and hub lncRNA validation were performed.

Using the risk model, GC individuals were classified into two groups: low-risk and high-risk groups. The prognostic signature could distinguish the different risk groups based on principal component analysis. The area under the curve and the conformance index suggested that this risk model was capable of correctly predicting GC patient outcomes. The predicted incidences of the one-, three-, and five-year overall survivals exhibited perfect conformance. Distinct changes in immunological markers were noted between the two risk groups. Finally, greater levels of appropriate chemotherapies were required in the high-risk group. AC005332.1, AC009812.4 and AP000695.1 levels were significantly increased in gastric tumor tissue compared with normal tissue.

We created a predictive model based on 10 pyroptosis-associated lncRNAs that could accurately predict the outcomes of GC patients and provide a promising treatment option in the future.

Depression is one of the most debilitating and severe psychiatric disorders and a serious public health concern. Currently, many treatments are indicated for depression, including traditional Chinese medicinal formulae such as Xiao-Yao-San (XYS), which has effective antidepressant effects in clinical and animal studies.

To summarize current evidence of XYS in terms of the preclinical and clinical studies and to identify the multi-level, multi-approach, and multi-target potential antidepressant mechanisms of XYS and active components of XYS by a comprehensive search of the related electronic databases.

The following electronic databases were searched from the beginning to April 2022: PubMed, MEDLINE, Web of Science, Google Scholar, and China National Knowledge Infrastructure.

This review summarizes the antidepressant mechanisms of XYS and its active ingredients, which are reportedly correlated with monoamine neurotransmitter regulation, synaptic plasticity, and hypothalamic-pituitary-adrenal axis, etc. CONCLUSION: XYS plays a critical role in the treatment of depression by the regulation of several factors, including the monoaminergic systems, hypothalamic-pituitary-adrenal axis, synaptic plasticity, inflammation, brain-derived neurotrophic factor levels, brain-gut axis, and other pathways. However, more clinical and animal studies should be conducted to further investigate the antidepressant function of XYS and provide more evidence and recommendations for its clinical application. Our review provides an overview of XYS and guidance for future research direction.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, whose pathophysiology has been linked to the neuroinflammatory process. The increased activity of the Nod-like receptor pyrin containing protein 3 (NLRP3) inflammasome, an intracellular multiprotein complex, is intrinsically implicated in neuroinflammation by promoting the maturation and release of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. Interestingly, individuals suffering from MDD have higher expression of NLRP3 inflammasome components and proinflammatory cytokines when compared to healthy individuals. In part, intense activation of the inflammasome may be related to autophagic impairment. Noteworthy, some conventional antidepressants induce autophagy, resulting in less activation of the NLRP3 inflammasome. In addition, the fast-acting antidepressant ketamine, some bioactive compounds and physical exercise have also been shown to have anti-inflammatory properties via inflammasome inhibition. Therefore, it is suggested that modulation of inflammasome-driven pathways may have an antidepressant effect. Here, we review the role of the NLRP3 inflammasome in the pathogenesis of MDD, highlighting that pathways related to its priming and activation are potential therapeutic targets for the treatment of MDD.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disease. Tong-Xie-Yao-Fang (TXYF), the traditional Chinese herbal medicine prescription, is a classic and effective prescription for the treatment of IBS-D, but its mechanism of action is not fully clarified.

To evaluate the efficacy of TXYF in the treatment of IBS-D and to explore its potential mechanism of action.

Changes in the serum levels of 50 free amino acids were targeted for detection by high-performance liquid chromatography (HPLC), and the expression of glucose-regulated protein 78 (GRP78), general control nonderepressible 2 (GCN2), and endoplasmic reticulum-resident kinase (PERK) was detected by immunohistochemistry examinations in healthy volunteers and IBS-D patients. The IBS-D rat was constructed by the three-factor superposition method of neonatal maternal separation, 2,4,6-trinitrobenzene sulfonic acid enema, and chronic unpredictable stress stimulation. The treatment effect of TXYF on IBS-D rats was observed by recording the body weight, grasp force, fecal water content (FWC), and abdominal withdrawal reflex (AWR) of rats before and after treatment. The effects of GCN2/PERK-eukaryotic initiation factor-2 (eIF2α) -activating transcription Factor 4 (ATF4) pathway proteins and gene expression were analyzed by western blotting, reverse transcription-polymerase chain reaction (RT-qPCR), and immunohistochemistry evaluations.

Compared with healthy volunteers, IBS-D patients exhibited lower levels of cysteine, γ-aminoacetic acid (GABA), homoproline, and lysine, and immunohistochemistry showed strong activation of GRP78, a marker of endoplasmic reticulum stress. Differential expression of GCN2 and PERK proteins was detected in IBS-D patients and rat colons. In the IBS-D rats, TXYF improved the body weight and grasp force, reduced the FWC, and improved the AWR score. TXYF increased the levels of p-GCN2 and GCN2 and reduced the levels of GRP78, p-PERK, PERK, p-eIF2α, and eIF2α, thereby affecting the expression of the apoptosis-related transcription factors ATF4, CHOP, Caspase-3, and Bcl-2.

Our study showed that TXYF improved IBS-D by inhibiting apoptosis. The anti-apoptosis effects were potentially mediated by regulating the GCN2/PERK-eIF2a-ATF4 signaling pathway.

The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation.

Depression is a serious psychological disorder with a rapidly increasing incidence in recent years. Clinically, selective serotonin reuptake inhibitors are the main therapy. These drugs, have serious adverse reactions, however. Traditional Chinese medicine has the characteristics of multiple components, targets, and pathways, which has huge potential advantages for the treatment of depression. The antidepressant potential of the herbal combination of Bupleurum chinense DC (Chaihu) and Paeonia lactiflora Pall (Baishao) has been extensively studied previously. In this review, we summarized the antidepressant active components and mechanism of Chaihu-Baishao herb pair. We found that it works mainly through relieving oxidative stress, regulating HPA axis, and protecting neurons. Nevertheless, current research of this combined preparation still faces many challenges. On one hand, most of the current studies only stay at the level of animal models, lacking of sufficient clinical double-blind controlled trials for further verification. In addition, studies on the synergistic effect between different targets and signaling pathways are scarce. On the other hand, this preparation has numerous defects such as poor stability, low solubility, and difficulty in crossing the blood-brain barrier.