Piperazine ferulate inhibits diabetic nephropathy by suppressing AGE/RAGE-mediated inflammatory signaling in rats and podocytes.

Objective: Diabetic nephropathy (DN) is a serious complication that may occur during the later stages of diabetes, and can be further exacerbated by podocyte damage. Piperazine ferulate (PF) has well-defined nephroprotective effects and is used clinically in the treatment of chronic nephritis and other kidney diseases. However, the renoprotective effects and mechanisms of PF on DN are not clear. This study aims to investigate the protective effect of PF on DN and its mechanism of action, to inform the clinical application of PF in DN treatment. Methods: Network pharmacology was performed to predict the mechanism of action of PF in DN. Male Sprague Dawley rats were intraperitoneally injected with STZ (60 mg/kg) to establish a DN model, and then assessed for renal injury after 12 weeks of administration. In vitro, rat podocytes were treated with 25 mmol/L glucose and cultured for 24 h, followed by an assessment of cell injury. Results: Our results showed that PF significantly improved renal function, reduced renal pathological changes, decreased inflammatory response, and alleviated podocyte damage in DN rats. PF also attenuated glucose-induced podocyte injury in vitro. Regarding molecular mechanisms, our study demonstrated that PF downregulated the expression of genes and proteins related to AGE-RAGE-mediated inflammatory signaling. Conclusion: In summary, PF exerts its renoprotective effects by decreasing inflammation and protecting against podocyte injury through the inhibition of the AGE/RAGE/NF-κB/NLRP3 pathway. Overall, these data support the clinical potential of PF as a renoprotective agent in DN.

Phytochemistry, pharmacological properties and pharmacokinetics of Citri Reticulatae Pericarpium: A systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: Citri Reticulatae Pericarpium (CRP), known as Chen Pi in China, is the most commonly used medicine for regulating qi. As a traditional medicine, CRP has been extensively used in the clinical treatment of nausea, vomiting, cough and phlegm for thousands of years. It is mainly distributed in Guangdong, Sichuan, Fujian and Zhejiang in China. Due to its high frequency of use, many scholars have conducted a lot of research on it and the related chemical constituents it contains. In this review, the research progress on phytochemistry, pharmacology, pharmacokinetics and toxicology of CRP are summarized. AIM OF THE REVIEW: The review aims to sort out the methods of extraction and purification, pharmacological activities and mechanisms of action, pharmacokinetics and toxicology of the chemical constituents in CRP, in order to elaborate the future research directions and challenges for the study of CRP and related chemical constituents. MATERIALS AND METHODS: Valid and comprehensive relevant information was collected from China National Knowledge Infrastructure, Web of Science, PubMed and so on. RESULTS: CRP contains a variety of compounds, of which terpenes, flavonoids and alkaloids are the main components, and they are also the primary bioactive components that play a pharmacological role. Flavonoids and terpenes are extracted and purified by aqueous and alcoholic extraction methods, assisted by ultrasonic and microwave extraction, in order to achieve higher yields with less resources. Pharmacological studies have shown that CRP possesses a variety of highly active chemical components and a wide range of pharmacological activities, including anti-tumor, anti-inflammatory, immunomodulatory, hepatoprotective, therapeutic for cardiovascular-related disorders, antioxidant, antibacterial, and neuroprotective effects. CONCLUSIONS: There is a diversity in the chemical compositions of CRP, which have multiple biological activities and promising applications. However, the pharmacological activities of CRP are mainly dependent on the action of its chemical components, but the relationship between the structure of chemical components and the biological effects has not been thoroughly investigated, and therefore, the structure-activity relationship is an issue that needs to be elucidated urgently. In addition, the pharmacokinetic studies of the relevant components can be further deepened and the correlation studies between pharmacological effects and syndromes of TCM can be expanded to ensure the effectiveness and rationality of CRP for human use.

Association of the dietary inflammatory index with complicated diabetic kidney disease in people with diabetes mellitus: evidence from NHANES 2009-2018.

AIMS: Diabetic kidney disease (DKD) significantly impairs quality of life in individuals with diabetes mellitus (DM). The influence of the Dietary Inflammatory Index (DII) on DKD, which is associated with adverse health outcomes, is not well-understood. METHODS: We analyzed 2712 subjects from the National Health and Nutrition Examination Survey (NHANES) spanning 2011-2018, aiming to elucidate the relationship between DII and DKD. RESULTS: DKD was diagnosed in 1016 participants (37.46%). Elevated DII levels were significantly associated with an increased DKD risk, as evidenced by multivariate logistic regression (Odds Ratio [OR] = 1.40, 95% Confidence Interval [CI] 1.12-1.75, P < 0.05). Further analysis after adjusting for covariates highlighted a notable non-linear correlation between DII and DKD risk, at DII values below 0.45, the risk of DKD increases with higher DII levels, whereas it stabilizes beyond this point. Subgroup analysis additionally revealed that diabetic men have a significantly higher DKD risk compared to women (P < 0.05). CONCLUSION: Our study indicates a pronounced link between higher DII scores and increased risk of DKD among DM patients. These findings underscore the paramount importance of dietary management in DM treatment, stressing the need for interventions focused on reducing dietary inflammation to decelerate DKD progression.

Unlocking renal Restoration: Mesaconine from Aconitum plants restore mitochondrial function to halt cell apoptosis in acute kidney injury.

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. Traditional Chinese medicine has employed Fuzi for kidney diseases; however, concerns about neurotoxicity and cardiotoxicity have constrained its clinical use. This study explored mesaconine, derived from processed Fuzi, as a promising low-toxicity alternative for AKI treatment. In this study, we assessed the protective effects of mesaconine in gentamicin (GM)-induced NRK-52E cells and AKI rat models in vitro and in vivo, respectively. Mesaconine promotes the proliferation of damaged NRK-52E cells and down-regulates intracellular transforming growth factor ß1 (TGF-ß1) and kidney injury molecule 1 (KIM-1) to promote renal cell repair. Concurrently, mesaconine restored mitochondrial morphology and permeability transition pores, reversed the decrease in mitochondrial membrane potential, mitigated mitochondrial dysfunction, decreased ATP production, inhibited inflammatory factor release, and reduced early apoptosis rates. In vivo, GM-induced AKI rat models exhibited elevated AKI biomarkers, in which mesaconine was effectively reduced, indicating improved renal function. Mesaconine enhanced superoxide dismutase activity, reduced malondialdehyde content, alleviated inflammatory infiltrate, mitigated tubular and glomerular lesions, and downregulated NF-κB (nuclear factor-κb) p65 expression, leading to decreased tumor necrosis factor-α (TNF-α) and IL-1ß (interleukin-1ß) levels in GM-induced AKI animals. Furthermore, mesaconine inhibited the expression of renal pro-apoptotic proteins (Bax, cytochrome c, cleaved-caspase 9, and cleaved-caspase 3) and induced the release of the anti-apoptotic protein bcl-2, further suppressing apoptosis. This study highlighted the therapeutic potential of mesaconine in GM-induced AKI. Its multifaceted mechanisms, including the restoration of mitochondrial dysfunction, anti-inflammatory and antioxidant effects, and apoptosis mitigation, make mesaconine a promising candidate for further exploration in AKI management.

The anti-depression effect and potential mechanism of the petroleum ether fraction of CDB: Integrated network pharmacology and metabolomics.

The combination of Chaidangbo (CDB) is an antidepressant traditional Chinese medicine (TCM) prescription simplified by Xiaoyaosan (a classic antidepressant TCM prescription) through dismantling research, which has the effect of dispersing stagnated liver qi and nourishing blood in TCM theory. Although the antidepressant effect of CBD has been confirmed in animal studies, the material basis and possible molecular mechanism for antidepressant activity in CBD have not been clearly elucidated. Herein, we investigated the effects and potential mechanisms of CDB antidepressant fraction (petroleum ether fraction of CDB, PEFC) on chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice using network pharmacology and metabolomics. First, a UPLC-QE/MS was employed to identify the components of PEFC. To extract active ingredients, SwissADME screening was used to the real PEFC components that were found. Potential PEFC antidepressant targets were predicted based on a network pharmacology approach, and a pathway enrichment analysis was performed for the predicted targets. Afterward, a CUMS mouse depression model was established and LC-MS-based untargeted hippocampal metabolomics was performed to identify differential metabolites, and related metabolic pathways. Finally, the protein expressions in mouse hippocampi were determined by Western blot to validate the network pharmacology and metabolomics deduction. A total of 16 active compounds were screened in SwissADME that acted on 73 core targets of depression, including STAT3, MAPKs, and NR3C1; KEGG enrichment analysis showed that PEFC modulated signaling pathways such as PI3K-Akt signaling pathway, endocrine resistance, and MAPK to exert antidepressant effects. PEFC significantly reversed abnormalities of hippocampus metabolites in CUMS mice, mainly affecting the synthesis and metabolism of glycine, serine, and threonine, impacting catecholamine transfer and cholinergic synapses and regulating the activity of the mTOR signaling pathway. Furthermore, Western blot analysis confirmed that PEFC significantly influenced the main protein levels of the PI3K/Akt/mTOR signaling pathways in the hippocampus of mice subjected to CUMS. This study integrated metabolomics, network pharmacology and biological verification to explore the potential mechanism of PEFC in treating depression, which is related to the regulation of amino acid metabolism dysfunction and the activation of PI3K/Akt/mTOR signaling pathways in the hippocampus. The comprehensive strategy also provided a reasonable way for unveiling the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in TCM with antidepressant effect.

The protective effect and mechanism of piperazine ferulate in rats with 5/6 nephrectomy-caused chronic kidney disease.

Chronic kidney disease (CKD) is a type of chronic disease in which multiple factors are responsible for the structural and functional disorders of the kidney. Piperazine ferulate (PF) has anti-platelet and anti-fibrotic effects, and its mechanism of action remains to be elucidated. This study aimed to investigate the protective effect of PF against CKD in rats and to determine its mechanism of action. Network pharmacology was used to predict potential PF action targets in the treatment of CKD and to further validate them. A rat model of CKD was established; blood was collected, etc., for the assessment of the renal function; renal pathologic damage was examined using hematoxylin and eosin (HE) staining and Masson staining; changes in the levels of TGF-ß1 and α-SMA were determined with ELISA; EPOR, FN, and COL I expression were detected utilizing immunohistochemistry; and HIF-1α, HIF-2α, and EPO protein molecules were analyzed deploying western blotting. PF reduces Scr, BUN, and 24 h UP levels; decreases FN and COL I expression; and attenuates renal injury. Additionally, PF inhibited TGF-ß1 and stimulated the production of HIF-1α and HIF-2α, which downregulated α-SMA and upregulated EPO. PF attenuated the progression of the CKD pathology, and the mechanism of its action is possibly associated with the promotion of HIF-1α/HIF-2α/EPO production and TGF-ß1 reduction.

Potential therapeutic effects of Chinese herbal medicine in postpartum depression: Mechanisms and future directions.

ETHNOPHARMACOLOGICAL RELEVANCE: Postpartum depression (PPD) is a common psychiatric disorder in women after childbirth. Per data from epidemiologic studies, PPD affects about 5%-26.32% of postpartum mothers worldwide. Biological factors underlying this condition are multiple and complex and have received extensive inquiries for the roles they play in PPD. Chinese herbal medicine (CHM), which is widely used as a complementary and alternative therapy for neurological disorders, possesses multi-component, multi-target, multi-access, and low side effect therapeutic characteristics. CHM has already shown efficacy in the treatment of PPD, and a lot more research exploring the mechanisms of its potential therapeutic effects is being conducted. AIM OF THE REVIEW: This review provides an in-depth and comprehensive overview of the underlying mechanisms of PPD, as well as samples the progress made in researching the potential role of CHM in treating the disorder. MATERIALS AND METHODS: Literature was searched comprehensively in scholarly electronic databases, including PubMed, Web of Science, Scopus, CNKI and WanFang DATA, using the search terms "postpartum depression", "genetic", "hormone", "immune", "neuroinflammation", "inflammation", "neurotransmitter", "neurogenesis", "brain-gut axis", "traditional Chinese medicine", "Chinese herbal medicine", "herb", and an assorted combination of these terms. RESULTS: PPD is closely associated with genetics, as well as with the hormones, immune inflammatory, and neurotransmitter systems, neurogenesis, and gut microbes, and these biological factors often interact and work together to cause PPD. For example, inflammatory factors could suppress the production of the neurotransmitter serotonin by inducing the regulation of tryptophan-kynurenine in the direction of neurotoxicity. Many CHM constituents improve anxiety- and depression-like behaviors by interfering with the above-mentioned mechanisms and have shown decent efficacy clinically against PPD. For example, Shen-Qi-Jie-Yu-Fang invigorates the neuroendocrine system by boosting the hormone levels of hypothalamic pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axes, regulating the imbalance of Treg/T-helper cells (Th) 17 and Th1/Th2, and modulating neurotransmitter system to play antidepressant roles. The Shenguiren Mixture interferes with the extracellular signal-regulated kinase (ERK) pathway to enhance the number, morphology and apoptosis of neurons in the hippocampus of PPD rats. Other herbal extracts and active ingredients of CHM, such as Paeoniflorin, hypericin, timosaponin B-III and more, also manage depression by remedying the neuroendocrine system and reducing neuroinflammation. CONCLUSIONS: The pathogenesis of PPD is complex and diverse, with the main pathogenesis not clear. Still, CHM constituents, like Shen-Qi-Jie-Yu-Fang, the Shenguiren Mixture, Paeoniflorin, hypericin and other Chinese Medicinal Formulae, active monomers and Crude extracts, treats PPD through multifaceted interventions. Therefore, developing more CHM components for the treatment of PPD is an essential step forward.

Rosmarinic acid alleviate CORT-induced depressive-like behavior by promoting neurogenesis and regulating BDNF/TrkB/PI3K signaling axis.

Rosmarinic acid (RA), a natural phenolic acid compound with a variety of bioactive properties. However, the antidepressant activity and mechanism of RA remain unclear. The aim of this study is to investigate the effects and potential mechanisms of RA on chronic CORT injection induced depression-like behavior in mice. Male C57BL/6 J mice were intraperitoneally injected with CORT (10 mg/kg) and were orally given RA daily (10 or 20 mg/kg) for 21 consecutive days. In vitro, the HT22 cells were exposed to CORT (200 µM) with RA (12.5, 25 or 50 µM) and LY294002 (a PI3K inhibitor) or ANA-12 (a TrkB inhibitor) treatment. The depression-like behavior and various neurobiological changes in the mice and cell injury and levels of target proteins in vitro were subsequently assessed. Here, RA treatment decreased the expression of p-GR/GR, HSP90, FKBP51, SGK-1 in mice hippocampi. Besides, RA increased the average optical density of Nissl bodies and number of dendritic spines in CA3 region, and enhanced Brdu and DCX expression and synaptic transduction in DG region, as well as up-regulated both the BDNF/TrkB/CREB and PI3K/Akt/mTOR signaling. Moreover, RA reduced structural damage and apoptosis in HT22 cells, increased the differentiation and maturation of them. More importantly, LY294002, but not ANA-12, reversed the effect of RA on GR nuclear translocation. Taken together, RA exerted antidepressant activities by modulating the hippocampal glucocorticoid signaling and hippocampal neurogenesis, which related to the BDNF/TrkB/PI3K signaling axis regulating GR nuclear translocation, provide evidence for the application of RA as a candidate for depression.

The antidepressant-like effects of Danzhi Xiaoyao San and its active ingredients.

BACKGROUND: 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. PURPOSE: 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. METHODS: "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. RESULTS: 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. CONCLUSION: 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.

[Mechanism of essential oil from Schizonepeta tenuifolia in treatment of depression based on network pharmacology and experimental verification].

This paper aimed to explore the antidepressant effect of the essential oil from Schizonepeta tenuifolia Briq.(EOST) on the treatment of depression and its mechanism by using a combination of network pharmacology and the mouse model of lipopolysaccharide(LPS)-induced depression. The chemical components in EOST were identified using gas chromatography-mass spectrometer(GC-MS), and 12 active components were selected as the study objects. The targets related to EOST were obtained by Traditional Chinese Medicines Systems Pharmacology(TCMSP) and SwissTargetPrediction database. The targets related to depression were screened out through GeneCards, Therapeutic Target Database(TTD), and Online Mendelian Inheritance in Man(OMIM) database. The Venny 2.1 was applied to screen out the common targets of EOST and depression. The targets were imported into Cytoscape 3.7.2 to generate "drug-active component-diease-target" network diagram. The protein-protein interaction(PPI) network was constructed using STRING 11.5 database and Cytoscape 3.7.2, and the core targets were screened out. DAVID 6.8 database was used for Gene Ontology(GO) func-tional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and subsequently the enrichment results were visualized through the bioinformatics platform. The mouse model of depression was induced by intraperitoneally injecting with LPS in mice. Before modeling, mice were administrated orally with EOST. The antidepressant effect of EOST was evalua-ted by tail suspension test(TST), forced swimming test(FST), and novelty suppressed feeding test(NSFT) after modeling. The content of interleukin(IL)-1ß was determined by enzyme-linked immunosorbent assay(ELISA), and the protein expression levels of IL-1ß and pro IL-1ß in the hippocampus were determined by Western blot. There were 12 main components and 179 targets in EOAT, of which, 116 targets were related to depression, mainly involved in neuroactive ligand-receptor interaction, calcium signaling pathway, and cyclic adenosine monophosphate(cAMP) signaling pathway. Biological processes such as synaptic signal transduction, G-protein coupled receptor signaling pathway, and chemical synaptic transmission were involved. Molecular functions such as neurotransmitter receptor activity, RNA polymerase Ⅱ transcription factor activity, and heme binding were involved. In mice experiments, the results showed that EOST at 100 mg·kg~(-1) and 50 mg·kg~(-1) significantly shortened the immobility time in TST and FST as well as the feeding latency in NSFT compared with the model group, decreased the levels of serum IL-1ß and NO, and reduced the protein expression levels of IL-1ß and pro IL-1ß in the hippocampus. In conclusion, EOST shows a good antidepressant effect in a multi-component, multi-target, and multi-pathway manner. The mechanism may be attributed to the fact that EOST can down-regulate the protein expression levels of IL-1ß and pro IL-1ß, decrease the release of inflammatory factors, and reduce neuroinflammation response.

Piperazine ferulate attenuates gentamicin-induced acute kidney injury via the NF-κB/NLRP3 pathway.

BACKGROUND: Piperazine ferulate (PF) is widely used in chronic nephritis and nephrotic syndrome in clinic. PF can improve diseases related inflammation by inhibiting the activation of nuclear factor kappa-B (NF-κB) signal. Acute kidney injury (AKI) is usually associated with the occurrence and development of renal inflammation. However, the nephroprotective effect and anti-inflammatory mechanisms of PF on AKI are not clear. PURPOSE: This study aimed to investigate the nephroprotective effects of PF on gentamicin (GM) induced AKI in rats and its potential mechanisms. METHODS: Male Sprague Dawley (SD) rats were intraperitoneally injected with GM (100 mg/kg/day) with or without PF (50 and 100 mg/kg/day) for 7 consecutive days. In vitro, the NRK-52e cells were exposed to GM (7 mg/ml) with or without PF (62.5 µg/ml) treatment. The renal injury and cell damage were assessed subsequently. RESULTS: Our findings showed that PF treatment can significantly improve renal function, reduce renal pathological changes, and attenuate inflammatory response in rats treated with gentamicin. Besides, PF could significantly reduce the cell damage and cellular inflammatory response. In terms of mechanisms, our study revealed that PF can evidently inhibit the activation of NF-κB and nod-like receptor family pyrin domain protein 3 (NLRP3) inflammasome. Meanwhile, it could down regulate the expressions of protein and gene of p-IKKα, p-IKKß, p-p65, p65, p50, p105, NLRP3 and IL-1ß. CONCLUSION: Our findings showed that PF may improve inflammation by inhibiting the NF-κB/NLRP3 pathway, so as to attenuate AKI.