Bone-Targeted Supramolecular Nanoagonist Assembled by Accurate Ratiometric Herbal-Derived Therapeutics for Osteoporosis Reversal.

Developing novel strategies for defeating osteoporosis has become a world-wide challenge with the aging of the population. In this work, novel supramolecular nanoagonists (NAs), constructed from alkaloids and phenolic acids, emerge as a carrier-free nanotherapy for efficacious osteoporosis treatment. These precision nanoagonists are formed through the self-assembly of berberine (BER) and chlorogenic acid (CGA), utilizing noncovalent electrostatic, π-π, and hydrophobic interactions. This assembly results in a 100% drug loading capacity and stable nanostructure. Furthermore, the resulting weights and proportions of CGA and BER within the NAs are meticulously controlled with strong consistency when the CGA/BER assembly feed ratio is altered from 1:1 to 1:4. As anticipated, our NAs themselves could passively target osteoporotic bone tissues following prolonged blood circulation, modulate Wnt signaling, regulate osteogenic differentiation, and ameliorate bone loss in ovariectomy-induced osteoporotic mice. We hope this work will open a new strategy to design efficient herbal-derived Wnt NAs for dealing with intractable osteoporosis.

Ameliorative effects of berberine and selenium against paracetamol-induced hepatic toxicity in rats.

Background: Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities. Aim: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats. Methods: This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies. Results: Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-α, and TGF-ß1 levels, and marked elevation in the IgM levels. Conclusion: Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.

[Research Progress on the Role of Berberine in Hematologic Malignancies and Its Related Mechanisms --Review].

Berberine, a traditional Chinese medicine, is an isoquinoline alkaloid extracted from the rhizome of Coptis chinensis. It has anti-inflammatory and antidiarrheal effects and is commonly used in the treatment of infections and gastrointestinal diseases. In recent years, studies have found that berberine can play a wide range of anti-cancer effects in the treatment of leukemia, lymphoma, multiple myeloma, etc. In hematologic malignancies, berberine can induce autophagy, promote apoptosis, regulate cell cycle, inhibit inflammatory response, cause oxidative damage to cancer cells and interact with miRNA to inhibit the proliferation, migration and colony formation of cancer cells. This paper will review the role and related mechanisms of berberine in hematological malignancies.

Combination drug therapy by herbal nanomedicine prevent multidrug resistance protein 1: promote apoptosis in Lung Carcinoma.

Given the numerous adverse effects of lung cancer treatment, more research on non-toxic medications is urgently needed. Curcumin (CUR) and berberine (BBR) combat drug resistance by controlling the expression of multidrug resistant pump (MDR1). Fascinatingly, combining these medications increases the effectiveness of preventing lung cancer. Their low solubility and poor stability, however, restrict their therapeutic efficacy. Because of the improved bioavailability and increased encapsulation effectiveness of water-insoluble medicines, surfactant-based nanovesicles have recently received a great deal of attention. The current study sought to elucidate the Combination drug therapy by herbal nanomedicine prevent multidrug resistance protein 1: promote apoptosis in Lung Carcinoma. The impact of several tween (20, 60, and 80) types with varied hydrophobic tails on BBR/CUR-TNV was evaluated. Additionally, the MDR1 activity and apoptosis rate of the BBR/CUR-TNV combination therapy were assessed. The encapsulation effectiveness of TNV was affected by the type of tween. With the TNV made from tween 60, cholesterol, and PEG (47.5: 47.5:5), more encapsulation effectiveness was attained. By combining CUR with BBR, especially when given in TNV, apoptosis increased. Additionally, when CUR and BBR were administered in combination, they significantly reduced the risk of MDR1 development. The current work suggests that the delivery of berberine and curcumin as a combination medication therapy via tween-based nanovesicles may be a potential lung cancer treatment.

Berberine promotes the degradation of phenylacetic acid to prevent thrombosis by modulating gut microbiota.

BACKGROUND: Berberine is the main bioactive constituent of Coptis chinensis, a quaternary ammonium alkaloid. While berberine's cardiovascular benefits are well-documented, its impact on thrombosis remains not fully understood. PURPOSE: This study investigates the potential of intestinal microbiota as a novel target for preventing thrombosis, with a focus on berberine, a natural compound known for its effectiveness in managing cardiovascular conditions. METHODS: Intraperitoneal injection of carrageenan induces the secretion of chemical mediators such as histamine and serotonin from mast cells to promote thrombosis. This model can directly and visually observe the progression of thrombosis in a time-dependent manner. Thrombosis was induced by intravenous injection of 1 % carrageenan solution (20 mg/kg) to all mice except the vehicle control group. Quantitative analysis of gut microbiota metabolites through LC/MS. Then, the gut microbiota of mice was analyzed using 16S rRNA sequencing to assess the changes. Finally, the effects of gut microbiota on thrombosis were explored by fecal microbiota transplantation. RESULTS: Our research shows that berberine inhibits thrombosis by altering intestinal microbiota composition and related metabolites. Notably, berberine curtails the biosynthesis of phenylacetylglycine, a thrombosis-promoting coproduct of the host-intestinal microbiota, by promoting phenylacetic acid degradation. This research underscores the significance of phenylacetylglycine as a thrombosis-promoting risk factor, as evidenced by the ability of intraperitoneal phenylacetylglycine injection to reverse berberine's efficacy. Fecal microbiota transplantation experiment confirms the crucial role of intestinal microbiota in thrombus formation. CONCLUSION: Initiating our investigation from the perspective of the gut microbiota, we have, for the first time, unveiled that berberine inhibits thrombus formation by promoting the degradation of phenylacetic acid, consequently suppressing the biosynthesis of PAG. This discovery further substantiates the intricate interplay between the gut microbiota and thrombosis. Our study advances the understanding that intestinal microbiota plays a crucial role in thrombosis development and highlights berberine-mediated intestinal microbiota modulation as a promising therapeutic approach for thrombosis prevention.

In Vitro and In Silico of Cholinesterases Inhibition and In Vitro and In Vivo Anti-Melanoma Activity Investigations of Extracts Obtained from Selected Berberis Species.

Berberis species have a long history of use in traditional Chinese medicine, Ayurvedic medicine, and Western herbal medicine. The aim of this study was the quantification of the main isoquinoline alkaloids in extracts obtained from various Berberis species by HPLC, in vitro and in silico determination of anti-cholinesterase activity, and in vitro and in vivo investigations of the cytotoxic activity of the investigated plant extracts and alkaloid standards. In particular, Berberis species whose activity had not been previously investigated were selected for the study. In the most investigated Berberis extracts, a high content of berberine and palmatine was determined. Alkaloid standards and most of the investigated plant extracts exhibit significant anti-cholinesterase activity. Molecular docking results confirmed that both alkaloids are more favourable for forming complexes with acetylcholinesterase compared to butyrylcholinesterase. The kinetic results obtained by HPLC-DAD indicated that berberine noncompetitively inhibited acetylcholinesterase, while butyrylcholinesterase was inhibited in a mixed mode. In turn, palmatine exhibited a mixed inhibition of acetylcholinesterase. The cytotoxic activity of berberine and palmatine standards and plant extracts were investigated against the human melanoma cell line (A375). The highest cytotoxicity was determined for extract obtained from Berberis pruinosa cortex. The cytotoxic properties of the extract were also determined in the in vivo investigations using the Danio rerio larvae xenograft model. The obtained results confirmed a significant effect of the Berberis pruinosa cortex extract on the number of cancer cells in a living organism. Our results showed that extracts obtained from Berberis species, especially the Berberis pruinosa cortex extract, can be recommended for further in vivo experiments in order to confirm the possibility of their application in the treatment of neurodegenerative diseases and human melanoma.

LC-MS-Based Metabolomics Reveals the Mechanism of Protection of Berberine against Indomethacin-Induced Gastric Injury in Rats.

Berberine is a natural isoquinoline alkaloid with low toxicity, which exists in a wide variety of medicinal plants. Berberine has been demonstrated to exhibit potent prevention of indomethacin-induced gastric injury (GI) but the related mechanism remains unclear. In the present study, liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was applied for the first time to investigate the alteration of serum metabolites in the protection of berberine against indomethacin-induced gastric injury in rats. Subsequently, bioinformatics was utilized to analyze the potential metabolic pathway of the anti-GI effect of berberine. The pharmacodynamic data indicated that berberine could ameliorate gastric pathological damage, inhibit the level of proinflammatory factors in serum, and increase the level of antioxidant factors in serum. The LC-MS-based metabolomics analysis conducted in this study demonstrated the presence of 57 differential metabolites in the serum of rats with induced GI caused by indomethacin, which was associated with 29 metabolic pathways. Moreover, the study revealed that berberine showed a significant impact on the differential metabolites, with 45 differential metabolites being reported between the model group and the group treated with berberine. The differential metabolites were associated with 24 metabolic pathways, and berberine administration regulated 14 of the 57 differential metabolites, affecting 14 of the 29 metabolic pathways. The primary metabolic pathways affected were glutathione metabolism and arachidonic acid metabolism. Based on the results, it can be concluded that berberine has a gastroprotective effect on the GI. This study is particularly significant since it is the first to elucidate the mechanism of berberine's action on GI. The results suggest that berberine's action may be related to energy metabolism, oxidative stress, and inflammation regulation. These findings may pave the way for the development of new therapeutic interventions for the prevention and management of NSAID-induced GI disorders.

Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization.

Alveolar bone regeneration has been strongly linked to macrophage polarization. M1 macrophages aggravate alveolar bone loss, whereas M2 macrophages reverse this process. Berberine (BBR), a natural alkaloid isolated and refined from Chinese medicinal plants, has shown therapeutic effects in treating metabolic disorders. In this study, we first discovered that culture supernatant (CS) collected from BBR-treated human bone marrow mesenchymal stem cells (HBMSCs) ameliorated periodontal alveolar bone loss. CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro. To clarify the underlying mechanism, the bioactive materials were applied to different animal models. We discovered macrophage colony-stimulating factor (M-CSF), which regulates macrophage polarization and promotes bone formation, a key macromolecule in the CS. Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats. Colony-stimulating factor 1 receptor (CSF1R) inhibitor or anti-human M-CSF (M-CSF neutralizing antibody, Nab) abolished the therapeutic effects of the CS of BBR-treated HBMSCs. Moreover, AKT phosphorylation in macrophages was activated by the CS, and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab. These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis. Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets. Overall, our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

Inhibition of inflammation by berberine: Molecular mechanism and network pharmacology analysis.

BACKGROUND: Traditional Chinese Medicine (TCM), renowned for its holistic approach with a 2000-year history of utilizing natural remedies, offers unique advantages in disease prevention and treatment. Berberine, found in various Chinese herbs, has been employed for many years, primarily for addressing conditions such as diarrhea and dysentery. Berberine has recently become a research focus owing to its pharmacological activities and benefits to human bodies. However, little is known about the anti-inflammatory mechanism of berberine. PURPOSE: To summarize recent findings regarding the pharmacological effects and mechanisms of berberine anti-inflammation and highlight and predict the potential therapeutic effects and systematic mechanism of berberine. METHODS: Recent studies (2013-2023) on the pharmacological effects and mechanisms of berberine anti-inflammation were retrieved from Web of Science, PubMed, Google Scholar, and Scopus up to July 2023 using relevant keywords. Network pharmacology and bioinformatics analysis were employed to predict the therapeutic effects and mechanisms of berberine against potential diseases. RESULTS: The related pharmacological mechanisms of berberine anti-inflammation include the inhibition of inflammatory cytokine production (e.g., IL-1ß, IL-6, TNF-α), thereby attenuating the inflammatory response; Inhibiting the activation of NF-κB signaling pathway and IκBα degradation; Inhibiting the activation of MAPK signaling pathway; Enhancing the activation of the STAT1 signaling pathway; Berberine interacts directly with cell membranes through a variety of pathways, thereby influencing cellular physiological activities. Berberine enhances human immunity and modulates immune system function, which is integral to addressing certain autoimmune and tumour-related health concerns. CONCLUSION: This study expounds on the correlation between berberine and inflammatory diseases, encapsulating the mechanisms through which berberine treats select typical inflammatory ailments. Furthermore, it delves into a deeper understanding of berberine's effectiveness by integrating network pharmacology and molecular docking techniques in the context of treating inflammatory diseases. It provides guidance and reference for berberine's subsequent revelation of the modern scientific connotation of Chinese medicine.

Berberine alleviates inflammation in polycystic ovary syndrome by inhibiting hyaluronan synthase 2 expression.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous metabolic and endocrine disorder that causes anovulatory infertility and abnormal folliculogenesis in women of reproductive age. Several studies have revealed inflammation in PCOS follicles, and recent evidence suggests that Berberine (BBR) effectively reduces inflammatory responses in PCOS, however, the underlying mechanisms remain unclear. PURPOSE: To determine the underlying mechanisms by which BBR alleviates inflammation in PCOS. STUDY DESIGN: Primary human GCs from healthy women and women with PCOS, and KGN cells were used for in vitro studies. ICR mice were used for in vivo studies. METHODS: Gene expression was measured using RT-qPCR. HAS2, inflammatory cytokines, and serum hormones were assayed by ELISA. Protein expression profiles were assayed by Western blot. Chronic low-grade inflammatory mouse models were developed by intraperitoneal injection with LPS, and PCOS mouse models were established by subcutaneous intraperitoneal injection of DHEA. BBR and 4-MU were administered by gavage. Ovarian morphologic changes were evaluated using H&E staining. HAS2 expression in the ovary was assayed using Western blot and immunohistochemistry. RESULTS: Our results confirmed that HAS2 expression and hyaluronan (HA) accumulation are closely associated with inflammatory responses in PCOS. Data obtained from in vitro studies showed that HAS2 and inflammatory genes (e.g., MCP-1, IL-1ß, and IL-6) are significantly upregulated in PCOS samples and LPS-induced KGN cells compared to their control groups. In addition, these effects were reversed by blocking HAS2 expression or HA synthesis using BBR or 4-MU, respectively. Furthermore, HAS2 overexpression induces the expression of inflammatory genes in PCOS. These results were further confirmed in LPS- and DHEA-induced mouse models, where inflammatory genes were reduced by BBR or 4-MU, and ovarian morphology was restored. CONCLUSIONS: Our results define previously unknown links between HAS2 and chronic low-grade inflammation in the follicles of women with PCOS. BBR exerts its anti-inflammatory effects by down-regulating HAS2. This study provides a novel therapeutic target for alleviating ovarian inflammation in women with PCOS.

Berberine Alleviates Ischemic Brain Injury by Enhancing Autophagic Flux via Facilitation of TFEB Nuclear Translocation.

Berberine has been demonstrated to alleviate cerebral ischemia/reperfusion injury, but its neuroprotective mechanism has yet to be understood. Studies have indicated that ischemic neuronal damage was frequently driven by autophagic/lysosomal dysfunction, which could be restored by boosting transcription factor EB (TFEB) nuclear translocation. Therefore, this study investigated the pharmacological effects of berberine on TFEB-regulated autophagic/lysosomal signaling in neurons after cerebral stroke. A rat model of ischemic stroke and a neuronal ischemia model in HT22 cells were prepared using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD), respectively. Berberine was pre-administered at a dose of 100[Formula: see text]mg/kg/d for three days in rats and 90[Formula: see text][Formula: see text]M in HT22 neurons for 12[Formula: see text]h. 24[Formula: see text]h after MCAO and 2[Formula: see text]h after OGD, the penumbral tissues and OGD neurons were obtained to detect nuclear and cytoplasmic TFEB, and the key proteins in the autophagic/lysosomal pathway were examined using western blot and immunofluorescence, respectively. Meanwhile, neuron survival, infarct volume, and neurological deficits were assessed to evaluate the therapeutic efficacy. The results showed that berberine prominently facilitated TFEB nuclear translocation, as indicated by increased nuclear expression in penumbral neurons as well as in OGD HT22 cells. Consequently, both autophagic activity and lysosomal capacity were simultaneously augmented to alleviate the ischemic injury. However, berberine-conferred neuroprotection could be greatly counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Meanwhile, autophagy inhibitor 3-Methyladenine (3-MA) also slightly neutralized the pharmacological effect of berberine on ameliorating autophagic/lysosomal dysfunction. Our study suggests that berberine-induced neuroprotection against ischemic stroke is elicited by enhancing autophagic flux via facilitation of TFEB nuclear translocation in neurons.

Berberine Metabolites Stimulate GLP-1 Secretion by Alleviating Oxidative Stress and Mitochondrial Dysfunction.

Berberine (BBR) is a principal component of Rhizoma coptidis known for its therapeutic potential in treating diseases such as type 2 diabetes mellitus (T2DM) and obesity. Despite the trace levels of BBR in plasma, it's believed that its metabolites play a pivotal role in its biological activities. While BBR is recognized to promote GLP-1 production in intestinal L cells, the cytoprotective effects of its metabolites on these cells are yet to be explored. The present study investigates the effects of BBR metabolites on GLP-1 secretion and the underlying mechanisms. Our results revealed that, out of six BBR metabolites, berberrubine (BBB) and palmatine (PMT) significantly increased the production and glucose-stimulated secretion of GLP-1 in GLUTag cells. Notably, both BBB and PMT could facilitate GLP-1 and insulin secretion and enhance glucose tolerance in standard mice. Moreover, a single dose of PMT could markedly increase plasma GLP-1 and improve glucose tolerance in mice with obesity induced by a high-fat diet. In palmitic acid or TNF[Formula: see text]-treated GLUTag cells, BBB and PMT alleviated cell death, oxidative stress, and mitochondrial dysfunction. Furthermore, they could effectively reverse inflammation-induced inhibition of the Akt signaling pathway. In general, these insights suggest that the beneficial effects of orally administered BBR on GLP-1 secretion are largely attributed to the pharmacological activity of BBB and PMT by their above cytoprotective effects on L cells, which provide important ideas for stimulating GLP-1 secretion and the treatment of T2DM.

Anti-inflammatory, antioxidant, and immunomodulatory effects of Berberis vulgaris and its constituent berberine, experimental and clinical, a review.

Berberis vulgaris (B. vulgaris or barberry) is a medicinal plant that has been used for various purposes in traditional medicine. Berberine is one of the main alkaloids isolated from B. vulgaris and other plants. Both B. vulgaris and berberine have shown anti-inflammatory, antioxidant, and immunomodulatory effects in different experimental models and clinical trials. This review aims to summarize the current evidence on the mechanisms and applications of B. vulgaris and berberine in modulating inflammation, oxidative stress, and immune responses. The literature search was performed using PubMed, Scopus, and Google Scholar databases until August 2023. The results indicated that B. vulgaris and berberine could inhibit the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin 6 (IL-6), and interleukin-17 (IL-17), and enhance the expression of anti-inflammatory cytokines, such as interleukin 10 (IL-10) and transforming growth factor-ß (TGF-ß), in various cell types and tissues. B. vulgaris and berberine can also scavenge free radicals, increase antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and reduce lipid peroxidation and DNA damage. B. vulgaris and berberine have been reported to exert beneficial effects in several inflammatory, oxidative, and immune-related diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, allergic diseases, and infections. However, more studies are needed to elucidate the optimal doses, safety profiles, and potential interactions of B. vulgaris and berberine with other drugs or natural compounds.

Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. METHODS: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. RESULTS: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1ß, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. CONCLUSION: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Green-Synthesized Silver and Selenium Nanoparticles Using Berberine: A Comparative Assessment of In Vitro Anticancer Potential on Human Hepatocellular Carcinoma Cell Line (HepG2).

A well-known natural ingredient found in several medicinal plants, berberine (Ber), has been shown to have anticancer properties against a range of malignancies. The limited solubility and bioavailability of berberine can be addressed using Ber-loaded nanoparticles. In this study, we compared the in vitro cytotoxic effects of both Ber-loaded silver nanoparticles (Ber-AgNPs) and Ber-loaded selenium nanoparticles (Ber-SeNPs) in the human liver cancer cell line (HepG2) and mouse normal liver cells (BNL). The IC50 values in HepG2 for berberine, Ber-AgNPs, Ber-SeNPs, and cisplatin were 26.69, 1.16, 0.04, and 0.33 µg/mL, respectively. Our results show that Ber and its Ag and Se nanoparticles exerted a good antitumor effect against HepG2 cells by inducing apoptosis via upregulating p53, Bax, cytosolic cytochrome C levels, and caspase-3 activity, and the down-regulation of Bcl-2 levels. Similarly, incubation with Ber and both Ber-NPs (Ag and Se) led to a significant dose-dependent elevation in inflammatory markers' (TNF-α, NF-κB, and COX-2) levels compared to the control group. In addition, it led to the arrest of the G1 cell cycle by depleting the expression of cyclin D1 and CDK-2 mRNA. Furthermore, Ber and both Ber-NPs (Ag and Se) caused a significant dose-dependent increase in LDH activity in HepG2 cells. Furthermore, our findings offer evidence that Ber and its nanoparticles intensified oxidative stress in HepG2 cells. Furthermore, the migration rate of cells subjected to berberine and its nanoforms was notably decreased compared to that of control cells. It can be inferred that Ber nanoparticles exhibited superior anticancer efficacy against HepG2 compared to unprocessed Ber, perhaps due to their improved solubility and bioavailability. Furthermore, Ber-SeNPs exhibited greater efficacy than Ber-AgNPs, possibly as a result of the inherent anticancer characteristics of selenium.

Cytotoxic and epigenetic effects of berberine-loaded chitosan/pectin nanoparticles on AGS gastric cancer cells: Role of the miR-185-5p/KLF7 axis, DNMTs, and global DNA methylation.

Poor bioavailability, solubility, and absorption of berberine (Ber) limit its widespread application. Here, we formulated novel chitosan/pectin nanoparticles (NPs) loaded with Ber to address delivery problems and promote the anticancer properties of Ber in AGS gastric cancer cells. The ionic gelification method was used to synthesize NPs-Ber. Physicochemical characterization of NPs-Ber was performed using FE-SEM, DLS, PDI, ζ potential, and FTIR. The cytotoxic effects of NPs-Ber on AGS cells were evaluated using the MTT assay. Apoptosis and cell cycle arrest were examined by flow cytometry. The gene expression levels of miR-185-5p, KLF7, caspase-3, and DNMTs were determined using RT-qPCR. In addition, the 5-methylcytosine level in the genomic DNA was quantified using ELISA. FE-SEM images revealed a denser and more packed matrix for NPs-Ber, and FTIR analysis confirmed the formation of NPs-Ber. The size (550.39 nm), PDI (0.134), and ζ potential (-16.52 mV) confirmed the stability of the prepared NPs-Ber. NPs-Ber showed a continuous release pattern following the Korsmeyer-Peppas model such that 81.36 % of Ber was released from the formulation after 240 min. Compared to NPs and free Ber, NPs-Ber was found to possess higher anticancer activity in AGS cells. This result was indicated by the viability test and further clarified by augmented apoptosis and cell cycle arrest at the G0/G1 phase. The IC50 value of NP-Ber against AGS cells was significantly lower than those of free Ber and NPs. Interestingly, our results showed that NPs-Ber considerably changed the expression levels of miR-185-5p, KLF7, caspase-3, and DNMTs (DNMT1, 3A, and 3B) compared with unloaded NPs and free Ber. Additionally, 5-methylated cytosine (5-mC) levels in cells treated with NPs-Ber were significantly higher than those in cells treated with unloaded NPs or free Ber. In summary, the present study demonstrated that Ber encapsulation in NPs enhances its cytotoxic and epigenetic effects on AGS cells, suggesting the promising potential of NPs-Ber in GC therapy.

METTL3-dependent N6-methyladenosine modification is involved in berberine-mediated neuroprotection in ischemic stroke by enhancing the stability of NEAT1 in astrocytes.

Ischemic stroke (IS) is one of the principal causes of disability and death worldwide. Berberine (BBR), derived from the traditional Chinese herbal medicine Huang Lian, has been reported to inhibit the progression of stroke, but the specific mechanism whereby BBR modulates the progression of ischemic stroke remains unclear. N6-methyladenosine (m6A) modification is the most typical epigenetic modification of mRNA post-transcriptional modifications, among which METTL3 is the most common methylation transferase. During the study, the middle cerebral artery occlusion/reperfusion (MCAO/R) was established in mice, and the mice primary astrocytes and neurons induced by oxygen-glucose deprivation/reoxygenation (OGD/R) was simulated in vitro. Level of LncNEAT1, miR-377-3p was detected via RT-qPCR. The levels of Nampt and METTL3 were measured by Western blot. CCK8 and LDH assay was performed to detect cell viability. Here, we found that berberine alleviates MCAO/R-induced ischemic injury and up-regulates the expression of Nampt in astrocytes, miR-377-3p inhibits the expression of Nampt in astrocytes after OGD/R, thus promoting neuronal injury. NEAT1 binds to miR-377-3p in OGD/R astrocytes and plays a neuronal protective role as a ceRNA. METTL3 can enhance NEAT1 stability in OGD/R astrocytes by modulating m6A modification of NEAT1. Taken together, our results demonstrate that berberine exerts neuroprotective effects via the m6A methyltransferase METTL3, which regulates the NEAT1/miR-377-3p/Nampt axis in mouse astrocytes to ameliorate cerebral ischemia/reperfusion (I/R) injury.

Berberine promotes lacteal junction zippering and ameliorates diet-induced obesity through the RhoA/ROCK signaling pathway.

BACKGROUND: Obesity has emerged as a global epidemic. Recent research has indicated that diet-induced obesity can be prevented by promoting lacteal junction zippering. Berberine, which is derived from natural plants, is found to be promising in weight reduction, but the underlying mechanism remains unspecified. PURPOSE: To determine whether berberine protects against obesity by regulating the lacteal junction and to explore potential molecular mechanisms. METHODS: Following the induction of the diet-induced obese (DIO) model, mice were administered low and high doses of berberine for 4 weeks. Indicators associated with insulin resistance and lipid metabolism were examined. Various methods, such as Oil Red O staining, transmission electron microscopy imaging, confocal imaging and others were used to observe the effects of berberine on lipid absorption and the lacteal junction. In vitro, human dermal lymphatic endothelial cells (HDLECs) were used to investigate the effect of berberine on LEC junctions. Western Blot and immunostaining were applied to determine the expression levels of relevant molecules. RESULTS: Both low and high doses of berberine reduced body weight in DIO mice without appetite suppression and ameliorated glucolipid metabolism disorders. We also found that the weight loss effect of berberine might contribute to the inhibition of small intestinal lipid absorption. The possible mechanism was related to the promotion of lacteal junction zippering via suppressing the ras homolog gene family member A (RhoA)/Rho-associated kinase (ROCK) signaling pathway. In vitro, berberine also promoted the formation of stable mature junctions in HDLECs, involving the same signaling pathway. CONCLUSION: Berberine could promote lacteal junction zippering and ameliorate diet-induced obesity through the RhoA/ROCK signaling pathway.

Jiao-tai-wan and its effective component-berberine improve diabetes and depressive disorder through the cAMP/PKA/CREB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiao-tai-wan (JTW), a classic herbal formula of traditional Chinese medicine recorded in Han Shi Yi Tong, has been used to alleviate sleep disorders since ancient times. In modern pharmacological research, JTW has been adopted for treating diabetes mellitus and even exerts antidepressant effects. However, the potential mechanisms deserve further elucidation. AIM OF THE STUDY: The prevalence of diabetes mellitus combined with depressive disorder (DD) is continuing to increase, yet it is currently under-recognized and its treatment remains inadequate. The present study aims to explore the underlying therapeutics and mechanisms of JTW on DD. MATERIALS AND METHODS: Chronic restraint stress was used on db/db mice to construct a mouse model of DD. The therapeutic effects of JTW were assessed by glucolipid metabolic indexes, behavioral tests, and depression-related neurotransmitter levels. The inflammatory status and cell apoptosis of different mice were investigated and the changes in the cAMP/PKA/CREB pathway were detected. Combining the results of fingerprinting with molecular docking, the active components of JTW were screened. A cellular model was constructed by intervention of glucose combined with corticosterone (CORT). The levels of apoptosis and depression-related neurotransmitters in HT-22 cells were examined, and the changes in the cAMP/PKA/CREB pathway were tested. Finally, the activator and inhibitor of the PKA protein were used for reverse validation experiments. RESULTS: JTW could improve the impaired glucose tolerance, lipid metabolism disorders, and depression-like symptoms in DD mice. Meanwhile, JTW could alleviate the inflammatory status, suppress the microglia activation, and improve hippocampal neuron apoptosis in DD mice. The dual effects of JTW might be associated with the activation of the cAMP/PKA/CREB pathway. Berberine (Ber) was identified for the in vitro experiment, it could reverse the apoptosis of HT-22 cells and up-regulate the depression-related neurotransmitter levels, and the effects of Ber were related to the activation of the cAMP/PKA/CREB pathway as well. CONCLUSION: JTW could exert both hypoglycemic and antidepressant effects through activating the cAMP/PKA/CREB signaling pathway, its active component, Ber, could improve the damage to HT-22 cells induced by glucose combined with CORT via the activation of the cAMP/PKA/CREB pathway. Ber may be one of the effective components of the dual effects of JTW.

Berberine modulates the immunometabolism and differentiation of CD4+ T cells alleviating experimental arthritis by suppression of M1-exo-miR155.

BACKGROUND: The inflammatory cascade mediated by macrophages and T cells is considered to be an important factor in promoting the progression of rheumatoid arthritis (RA). Our previous study found that berberine (BBR) can therapeutically impact adjuvant arthritis (AA) in rats through the regulation of macrophage polarization and the balance of Th17/Treg. However, whether BBR's effects on CD4+T cells response are related to its suppression of M1 macrophage still unclear. PURPOSE: The study aimed to estimate the mechanism of BBR in regulating the immunometabolism and differentiation of CD4+T cells are related to exosome derived from M1-macrophage (M1-exo). STUDY-DESIGN/METHODS: Mice model of collagen-induced arthritis (CIA) was established to investigate the antiarthritic effect of BBR was related with regulation of M1-exo to balance T cell subsets. Bioinformatics analysis using the GEO database and meta-analysis. In vitro, we established the co-culture system involving M1-exo and CD4+ T cells to examine whether BBR inhibits CD4+T cell activation and differentiation by influencing M1-exo-miR155. Exosome was characterized using transmission electron microscopy and western blot analysis, macrophage and CD4+T cell subpopulation were detected by flow cytometry. Further, the metabolic profiles of CD4+T cells were assessed by ECAR, OCR, and the level of glucose, lactate, intracellular ATP. RESULT: BBR reinstates CD4+ T cell homeostasis and reduces miR155 levels in both M1-exo and CD4+ T cells obtained from mice with CIA. In vitro, we found exosomes are indispensable for M1-CM on T lymphocyte activation and differentiation. BBR reversed M1-exo facilitating the activation and differentiation of CD4+T cells. Furthermore, BBR reversed glycolysis reprogramming of CD4+T cells induced by M1-exo, while these regulation effects were significantly weakened by miR155 mimic. CONCLUSION: The delivery of miR-155 by M1-exo contributes to CD4+ T cell immunometabolism dysfunction, a process implicated in the development of RA. The anti-arthritic effect of BBR is associated with the suppression of glycolysis and the disruption of CD4+ T cell subsets balance, achieved by reducing the transfer of M1-exo-miR155 into T cells.