Ajuga decumbens, a traditional Chinese medicine, possesses anti-breast cancer effects. Its main component, 8-O-acetylharpagide, exhibits potential anticancer activity; however, the active metabolites and mechanisms underlying its effects remain unclear.

The metabolism and excretion of 8-O-acetylharpagide in rats were investigated using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry analysis of bile, urine, and feces. Active metabolites were identified and evaluated using network pharmacology, molecular docking, and Western blotting assays.

A total of 21 metabolites were identified, with demethylation, hydrolysis, and glucuronidation being the primary metabolic pathways. M3 and M5 were identified as key metabolites, showing strong binding affinity to cancer-related targets, such as AKT1, MMP9, and STAT3. M5 displayed strong pharmacokinetic properties, including better lipid solubility and reduced polarity. Network pharmacology analysis indicated that these metabolites exert anticancer effects by modulating the PI3K/AKT signaling pathway. In vivo experiments demonstrated that oral administration of 8-O-acetylharpagide significantly inhibited the proliferation of 4T1 tumor tissues by suppressing the expression of the AKT/NF-κB/MMP9 signaling axis. This may be related to inhibition of the expression of the AKT/NF-κB/MMP9 signaling axis in 4T1 tumor tissues after metabolism of 8-O-acetylharpagide to M5 and M3.

As a prodrug, 8-O-acetylharpagide is metabolized to M5, which may subsequently exert an anti-breast cancer effect through downregulation of the AKT/NF-κB/MMP9 signaling axis. This study provides a theoretical basis for the clinical application of Ajuga decumbens in breast cancer therapy.

Background: Oral administration remains the most common route for drug absorption. Emerging evidence highlights the important role of gut microbiome in the pharmacokinetics of oral medications. Glycyrrhizic acid (GL), a widely used hepatoprotective drug, is orally administrated and subsequently biotransformed by the gut microbiota into its active metabolite, glycyrrhetinic acid (GA), which exerts a therapeutic effect. However, it remains unclear whether the disturbance of the gut microbiome directly impacts the metabolism of GL. Methods: Antibiotic cocktail and probiotic Lacticaseibacillus rhamnosus R0011 were applied as two interventions targeting the gut microbiome. Pharmacokinetic parameters were evaluated by LC-MS, and 16S rRNA sequencing was applied to analyze the gut microbiome composition. The transcriptome analysis of Caco-2 cells was used to elucidate the regulation mechanism of polar metabolites resulting from gut microbiome perturbation. Results: R0011 supplementation could significantly increase the Area Under Curve (AUC) value of GA, which was positively correlated with the change in gut microbiome composition. In contrast, the plasma levels of GA were nearly undetectable following antibiotic intervention. Furthermore, the relative expressions of transporter multidrug resistance gene 1 (MDR1) in the ileum were site specifically downregulated under the probiotic intervention. The polar gut microbial metabolites may play a crucial role in differentiated regulating MDR1 expression, likely through the modulation of transcription factors FoxO1 and TP53. Conclusions: Our research provides new insights into the regulatory mechanism by which the gut microbiome affects the bioabsorption of orally administrated drugs, potentially offering strategies to optimize drug bioavailability and improve clinical efficacy.

Delayed tooth extraction socket (TES) healing can cause failure of subsequent oral implantation and increase socioeconomic burden on patients. Excessive amounts of M1 macrophages, apoptotic neutrophils (ANs), and neutrophil extracellular traps (NETs) impair alveolar bone regeneration during TES healing. In the present study, we first discovered that conditioned medium (CM) collected from berberine-treated human bone marrow mesenchymal stem cells (BBR-HB-CM) accelerated TES healing. BBR-HB-CM contained bioactive materials that promoted the polarization of macrophages from M1 to M2, impeded the formation of ANs and NETs, and modulated M2 macrophage efferocytosis in vivo and in vitro. Mechanistically, BBR-HB-CM promoted bone formation by inhibiting macrophage-myofibroblast transition and reprogrammed macrophage polarization through p85/AKT/mTOR pathway-dependent autophagy. The 3-methyladenine abolished the therapeutic effects of BBR-HB-CM. Further studies revealed that BBR-HB-CM accelerated TES healing in rats with type 2 diabetes mellitus. Overall, our results demonstrated that BBR-HB-CM had high potential to promote rapid TES healing.

Recent advances in understanding the modulatory functions of gut and gut microbiota on human diseases facilitated our focused attention on the contribution of the gut to the pathophysiological alterations of many extraintestinal organs, including the liver, heart, brain, lungs, kidneys, bone, skin, reproductive, and endocrine systems. In this review, we applied the "gut-X axis" concept to describe the linkages between the gut and other organs and discussed the latest findings related to the "gut-X axis," including the underlying modulatory mechanisms and potential clinical intervention strategies.

Oxyberberine (OBB) is a naturally occurring isoquinoline alkaloid that is believed to possess various health-promoting properties, including anti-fungus, hepatoprotection, anti-inflammation, and anti-intestinal mucositis effects. Despite several studies reporting the health benefits of OBB in treating ulcerative colitis (UC), its specific mechanism of action has yet to be fully elucidated.

This investigation is designed to explore the potential protective efficacy of OBB and the latent mechanism using an in vitro model of UC-like inflammatory intestinal cells.

Caco-2 cells were pretreated with OBB and subsequently exposed to lipopolysaccharide (LPS). The transepithelial electrical resistance (TEER), paracellular permeability, and the distribution and expression of tight- and adherent junction proteins were determined to assess barrier integrity. The levels of proinflammatory cytokines, reactive oxygen species (ROS), Nrf2, and NF-κB signaling cascade were analyzed via ELISA, qRT-PCR, immunofluorescence, or Western blotting.

OBB was found to mitigate the effects of LPS on Caco-2 cell monolayers, as evidenced by the improvement in TEER and the decrease in FITC-dextran flux. Moreover, OBB ameliorated the LPS-induced decrease in the distribution and expression of several tight junction markers, including ZO-1, occludin, and E-cadherin. In addition, OBB treatment effectively inhibited LPS-induced increases in ROS, apoptosis, and Keap1 and decreases in Nrf2 and HO-1. LPS-induced elevations in nuclear NF-κB p65 and p-IκBα were suppressed by OBB. In addition, ML385, an antagonist of Nrf2, abolished the protective role of OBB.

OBB has a pronounced beneficial effect on LPS-induced damage to enteral barrier function, and the regulation of the Nrf2/NF-κB pathway is an important mechanism responsible for the protection afforded by OBB.

Sanguinarine (SAN) is an alkaloid with multiple biological activities, mainly extracted from Sanguinaria canadensis or Macleaya cordata. The low bioavailability of SAN limits its utilization. At present, the nature and mechanism of SAN intestinal absorption are still unclear. The pharmacokinetics, single-pass intestinal perfusion test (SPIP), and equilibrium solubility test of SAN in rats were studied. The absorption of SAN at 20, 40, and 80 mg/L in different intestinal segments was investigated, and verapamil hydrochloride (P-gp inhibitor), celecoxib (MPR2 inhibitor), and ko143 (BCRP inhibitor) were further used to determine the effect of efflux transporter proteins on SAN absorption. The equilibrium solubility of SAN in three buffer solutions (pH 1.2, 4.5 and 6.8) was investigated. The oral pharmacokinetic results in rats showed that SAN was rapidly absorbed (Tmax=0.5 h), widely distributed (Vz/F = 134 L/kg), rapidly metabolized (CL = 30 L/h/kg), and had bimodal phenomena. SPIP experiments showed that P-gp protein could significantly affect the effective permeability coefficient (Peff) and apparent absorption rate constant (Ka) of SAN. Equilibrium solubility test results show that SAN has the best solubility at pH 4.5. In conclusion, SAN is a substrate of P-gp, and its transport modes include efflux protein transport, passive transport and active transport.

Drug safety is a paramount concern in the field of drug development, with researchers increasingly focusing on the bidirectional regulation of gut microbiota in this context. The gut microbiota plays a crucial role in maintaining drug safety. It can influence drug transport processes in the body through various mechanisms, thereby modulating their efficacy and toxicity. The main mechanisms include: (1) The gut microbiota directly interacts with drugs, altering their chemical structure to reduce toxicity and enhance efficacy, thereby impacting drug transport mechanisms, drugs can also change the structure and abundance of gut bacteria; (2) bidirectional regulation of intestinal barrier permeability by gut microbiota, promoting the absorption of nontoxic drugs and inhibiting the absorption of toxic components; (3) bidirectional regulation of the expression and activity of transport proteins by gut microbiota, selectively promoting the absorption of effective components or inhibiting the absorption of toxic components. This bidirectional regulatory role enables the gut microbiota to play a key role in maintaining drug balance in the body and reducing adverse reactions. Understanding these regulatory mechanisms sheds light on novel approaches to minimize toxic side effects, enhance drug efficacy, and ultimately improve drug safety. This review systematically examines the bidirectional regulation of gut microbiota in drug transportation from the aforementioned aspects, emphasizing their significance in ensuring drug safety. Furthermore, it offers a prospective outlook from the standpoint of enhancing therapeutic efficacy and reducing drug toxicity, underscoring the importance of further exploration in this research domain. It aims to provide more effective strategies for drug development and treatment.

Many active ingredients in traditional Chinese medicines generally have the characteristic of poor oral absorption but definite efficacy. It is necessary to establish a comprehensive technical system to explain the "PK-PD relationship" of them. Dehydrocorydaline (DHC), the quality control component in the Chinese patent drug "Kedaling Tablets", has poor oral absorption but clear efficacy for coronary heart disease. Using DHC as a model drug, the changes in absorption and pharmacological effects of DHC in rats before and after inhibiting nitroreductase (NR) from gut microbiota were studied. The results showed that after inhibiting of NR activity, the plasma concentration of DHC in rats was decreased, the serum level of total cholesterol, triglyceride and low-density lipoprotein cholesterol were significantly increased. The levels of tumor necrosis factor-α, interleukin-1β, hypersensitive C-reactive protein, intercellular cell adhesion molecule-1 and Monocyte chemoattractant protein-1 were significantly increased, and pathological sections also showed that the efficacy of DHC decreased after inhibiting the activity of NR. We further investigated the drug metabolism of DHC under NR and found that DHC was metabolized into a hydrogenated metabolite, which may have stronger membrane permeability. In summary, NR may mediate the absorption degree and efficacy of DHC in vivo by metabolizing DHC into absorbable metabolite.

Microbiome and radiotherapy represent bidirectionally interacting entities. The human microbiome has emerged as a pivotal modulator of the efficacy and toxicity of radiotherapy; however, a reciprocal effect of radiotherapy on microbiome composition alterations has also been observed. This review explores the relationship between the microbiome and extracranial solid tumors, particularly focusing on the bidirectional impact of radiotherapy on organ-specific microbiome. This article aims to provide a systematic review on the radiotherapy-induced microbial alteration in-field as well as in distant microbiomes. In this review, particular focus is directed to the oral and gut microbiome, its role in the development and progression of cancer, and how it is altered throughout radiotherapy. This review concludes with recommendations for future research, such as exploring microbiome modification to optimize radiotherapy-induced toxicities or enhance its anti-cancer effects.

Berberine (BBR), an isoquinoline alkaloid found in medicinal plants such as Coptidis rhizoma, Berberis sp., and Hydrastis canadensis, is a distinctive compound known for its dual ability to exhibit broad-spectrum antifungal activity while offering beneficial effects to the host. These attributes make it a highly valuable candidate for antifungal therapy and as an antibiotic adjuvant. This review provides a comprehensive evaluation of BBR's antifungal properties, focusing on its in vitro and in vivo activity, underlying mechanisms, and its influence on fungal pathogenicity, including virulence, biofilm formation, and resistance. Additionally, the antifungal potential of BBR extracts, derivatives, and nanoformulations is examined in detail. BBR demonstrates fungicidal effects through multiple mechanisms. It targets critical fungal components such as mitochondria, cell membranes, and cell walls, while also inhibiting enzymatic activity and transcription processes. Furthermore, it suppresses the expression of virulence factors, effectively diminishing fungal pathogenicity. Beyond its direct antifungal activity, BBR exerts beneficial effects on the host by modulating gut microbiota, thereby bolstering host defenses against fungal infections and reducing potential adverse effects. BBR's interaction with conventional antifungal drugs presents a unique complexity, particularly in the context of resistance mechanisms. When used in combination therapies, conventional antifungal drugs enhance the intracellular accumulation of BBR, thereby amplifying its antifungal potency as the primary active agent. These synergistic effects position BBR as a promising candidate for combination strategies, especially in addressing drug-resistant fungal infections and persistent biofilms. As antifungal resistance and biofilm-associated infections continue to rise, the multifaceted properties of BBR and its advanced formulations highlight their significant therapeutic potential. However, the scarcity of robust in vivo and clinical studies limits a full understanding of its efficacy and safety profile. To bridge this gap, future investigations should prioritize well-designed in vivo and clinical trials to thoroughly evaluate the therapeutic effectiveness and safety of BBR in diverse clinical settings. This approach could pave the way for its broader application in combating fungal infections.

Oxyberberine (OBB), a natural metabolite of berberine, has been shown to exhibit inhibitory effects on gluconeogenesis in our previous work. This work was designed to investigate the potential effects and underlying mechanisms of OBB on hepatic gluconeogenesis. Our work found that OBB significantly inhibited the expressions of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), and decreased the glucose production in palmitic acid-induced HepG2 cells. Then, AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways were confirmed by transcriptomics and network pharmacology analyses. It was shown that AMPK activation may phosphorylate and promote nuclear exclusion of FoxO1 and CRTC2, two key regulators of hepatic gluconeogenesis transcriptional pathways, resulting in the inhibition of gluconeogenesis under OBB administration. Afterwards, AMPK/Akt/FoxO1, AMPK/CRTC2 signaling pathways were evidenced by western blot, immunoprecipitation and confocal immunofluorescence, and the targeted inhibitor (Compound C) and siRNA of AMPK were applied for further mechanism verification. Moreover, it was found that OBB treatment activated AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways to decrease hepatic gluconeogenesis in db/db mice. Similarly, the in vivo inhibitory effects of OBB on gluconeogenesis were also diminished by AMPK inhibition. Our work demonstrated that OBB can inhibit hepatic gluconeogenesis in vitro and in vivo, and its underlying mechanisms were associated with AMPK-mediated suppression of FoxO1 and CRTC2 signaling axes.

Berberine (BBR), a benzylisoquinoline alkaloid obtained from natural medicines such as coptidis rhizoma, has a wide range of pharmacological activities such as protecting the nervous system, protecting the cardiovascular system, anti-inflammatory, antidiabetic, antihyperlipidemic, antitumor, antibacterial, and antidiarrheal. However, factors such as poor solubility, low permeability, P-glycoprotein (P-gp) efflux, and hepatic-intestinal metabolism result in BBR having a low bioavailability (< 1%), which restricts its application in clinical settings. Therefore, improving its bioavailability is a prerequisite for its clinical applications. This review summarizes the various pharmacological effects of BBR and analyzes the main reasons for its poor bioavailability. It introduces methods to improve the bioavailability of BBR through the use of absorption enhancers and P-gp inhibitors, structural modification of BBR, and preparation of BBR salts and cocrystals as well as the development of new formulations and focuses on the bioavailability study of the new formulations of BBR. The research of BBR was also prospected in order to provide reference for the further research of BBR.

Premature ovarian insufficiency (POI) is an immune-related condition. Dihydroberberine (dhBBR) plays a regulatory role in maintaining the T-helper 17 (Th17)/regulatory T (Treg) cell balance. This study aimed to explore the action mechanisms of dhBBR on POI.

In vivo, female BALB/c mice were used as POI models, treated with dhBBR, or injected with recombinant interleukin (rIL)-17 and anti-CD25 monoclonal antibody. Hematoxylin and eosin staining was used to validate the model and assess the therapeutic effects of dhBBR. mRNA expression levels of cytochrome P450 (Cyp)-17a1, Cyp19a1, Cyp11a1, steroidogenic acute regulatory protein, and luteinizing hormone receptor in mouse ovaries were quantified via quantitative polymerase chain reaction (qPCR). Enzyme-linked immunosorbent assay was used to determine the cytokine and sex hormone levels. Immunohistochemical staining for cleaved-caspase 3 and Ki-67 were performed to assess ovarian cell apoptosis and proliferation. Flow cytometry was used to analyze the Th17/Treg cell balance in the ovary and spleen. In vitro cytotoxicity of dhBBR was measured using the cell counting kit-8 assay. GTP-Ras homolog enriched in brain (Rheb) activity was determined via immunofluorescence assay. Co-immunoprecipitation was performed to assess Rheb activity, Th17 or Treg induction, and binding between Rheb and mammalian target of rapamycin (mTOR) after dhBBR treatment. Flow cytometry and qPCR assays were used to verify the effect of dhBBR on CD4 + cell differentiation. Finally, Rheb/mTOR pathway activation was confirmed via western blotting of proteins, including mTOR, p-mTOR, p70S6K, p-p70S6K, 4E-BP1, and p-4E-BP1.

dhBBR improved the ovarian function in a dose-dependent manner. It also decreased ovarian cell apoptosis and increased cell proliferation. It decreased Th1 and Th17 cell proportions but increased Treg cell proportions in the ovaries and spleens of POI model mice. Cell experiments revealed that dhBBR promoted CD4 + cell differentiation into Treg cells. Co-immunoprecipitation revealed Rheb as the dhBBR target that bound to mTOR. However, MHY1485 restored dhBBR-induced changes in forkhead box P3, IL-10, transforming growth factor-β1, IL-17, IL-22, retinoic acid-related orphan receptor-γt and p-mTOR levels in Th17- and Treg-induced CD4 + cells.

Overall, dhBBR targeted the Rheb/mTOR pathway to promote CD4 + cell differentiation into Treg cells and alleviate POI.

The global spread of multi-drug-resistant (MDR) bacteria is rapidly increasing due to antibiotic overuse, posing a major public health threat and causing millions of deaths annually. The present study explored the potential of nanocarriers for delivering novel and alternative antibacterial agents using nanotechnology-based approaches to address the challenge of MDR bacteria. The purpose was to enhance the solubility, stability, and targeted delivery of berberine (BER) and its synthetic derivative NR16 using Styrene-co-Maleic Acid (SMA) nanoparticles. Characterization of the nanoparticles, including dynamic light scattering (DLS) analysis, TEM, and UV/Vis absorption spectroscopy, confirmed their suitability and high stability for passive drug delivery. Antibacterial and antifungal activities were evaluated against a panel of pathogens, revealing significant inhibitory effects on Gram-positive strains; particularly BER, SMA-BER, and NR16 were active against MRSA, MSSA, VR, and VS E. faecalis, and S. epidermidis. Additionally, SMA-BER and SMA-NR16 showed promising activity against biofilm formation of S. epidermidis; while the two free drugs contributed to S. epidermidis biofilm disruption activity. Hemolysis tests and in vitro studies on human embryonic kidney cells (HEK-293) confirmed the safety profiles of the nanoparticles and free drugs. Overall, this research highlighted the potential of nanotechnology in developing effective antibacterial agents with reduced toxicity, addressing the growing threat of MDR bacterial infections.

As an ancient concept and practice, "food as medicine" or "medicine-food homology" is receiving more and more attention these days. It is a tradition in many regions to intake medicinal herbal food for potential health benefits to various organs and systems including the kidney. Kidney diseases usually lack targeted therapy and face irreversible loss of function, leading to dialysis dependence. As the most important organ for endogenous metabolite and exogenous nutrient excretion, the status of the kidney could be closely related to daily diet. Therefore, medicinal herbal food rich in antioxidative, anti-inflammation micronutrients are ideal supplements for kidney protection. Recent studies have also discovered its impact on the "gut-kidney" axis.

Here, we review and highlight the kidney-protective effects of botanicals with medicine-food homology including the most frequently used Astragalus membranaceus and Angelica sinensis (Oliv.) Diels, concerning their micronutrients and mechanism, offering a basis and perspective for utilizing and exploring the key substances in medicinal herbal food to protect the kidney.

The index for medicine-food homology in China contains mostly botanicals while many of them are also consumed by people in other regions. Micronutrients including flavonoids, polysaccharides and others present powerful activities towards renal diseases.

Botanicals with medicine-food homology are widely speeded over multiple regions and incorporating these natural compounds into dietary habits or as supplements shows promising future for renal health.

The rising incidence of fibrosis poses a major threat to global public health, and the continuous exploration of natural products for the effective treatment of fibrotic diseases is crucial. Berberine (BBR), an isoquinoline alkaloid, is widely used clinically for its anti-inflammatory, anti-tumor and anti-fibrotic pharmacological effects. Until now, researchers have worked to explore the mechanisms of BBR for the treatment of fibrosis, and multiple studies have found that BBR attenuates fibrosis through different pathways such as TGF-β/Smad, AMPK, Nrf2, PPAR-γ, NF-κB, and Notch/snail axis. This review describes the anti-fibrotic mechanism of BBR and its derivatives, and the safety evaluation and toxicity studies of BBR. This provides important therapeutic clues and strategies for exploring new drugs for the treatment of fibrosis. Nevertheless, more studies, especially clinical studies, are still needed. We believe that with the continuous implementation of high-quality studies, significant progress will be made in the treatment of fibrosis.

The gastrointestinal tract is where the majority of gut microbiota settles; therefore, the composition of the gut microbiota and the changes in metabolites, as well as their modulatory effects on the immune system, have a very important impact on the development of gastrointestinal diseases. The purpose of this article was to review the role of the gut microbiota in the host environment and immunometabolic system and to summarize the beneficial effects of botanical active ingredients on gastrointestinal cancer, so as to provide prospective insights for the prevention and treatment of gastrointestinal diseases. A literature search was performed on the PubMed database with the keywords "gastrointestinal cancer", "gut microbiota", "immunometabolism", "SCFAs", "bile acids", "polyamines", "tryptophan", "bacteriocins", "immune cells", "energy metabolism", "polyphenols", "polysaccharides", "alkaloids", and "triterpenes". The changes in the composition of the gut microbiota influenced gastrointestinal disorders, whereas their metabolites, such as SCFAs, bacteriocins, and botanical metabolites, could impede gastrointestinal cancers and polyamine-, tryptophan-, and bile acid-induced carcinogenic mechanisms. GPRCs, HDACs, FXRs, and AHRs were important receptor signals for the gut microbial metabolites in influencing the development of gastrointestinal cancer. Botanical active ingredients exerted positive effects on gastrointestinal cancer by influencing the composition of gut microbes and modulating immune metabolism. Gastrointestinal cancer could be ameliorated by altering the gut microbial environment, administering botanical active ingredients for treatment, and stimulating or blocking the immune metabolism signaling molecules. Despite extensive and growing research on the microbiota, it appeared to represent more of an indicator of the gut health status associated with adequate fiber intake than an autonomous causative factor in the prevention of gastrointestinal diseases. This study detailed the pathogenesis of gastrointestinal cancers and the botanical active ingredients used for their treatment in the hope of providing inspiration for research into simpler, safer, and more effective treatment pathways or therapeutic agents in the field.

Mounting evidence implicates the gut microbiota as a possible key susceptibility factor for atherosclerosis (AS). The employment of dietary phytochemicals that strive to target the gut microbiota has gained scientific support for treating AS. This study conducted a general overview of the links between the gut microbiota and AS, and summarized available evidence that dietary phytochemicals improve AS via manipulating gut microbiota. Then, the microbial metabolism of several dietary phytochemicals was summarized, along with a discussion on the metabolites formed and the biotransformation pathways involving key gut bacteria and enzymes. This study additionally focused on the anti-atherosclerotic potential of representative metabolites from dietary phytochemicals, and investigated their underlying molecular mechanisms. In summary, microbiota-dependent dietary phytochemical therapy is a promising strategy for AS management, and knowledge of "phytochemical-microbiota-biotransformation" may be a breakthrough in the search for novel anti-atherogenic agents.

Background: Metabolic imbalance is the common basis of many diseases. As natural isoquinoline alkaloid, berberine (BBR) has shown great promise in regulating glucose and lipids metabolism and treating metabolic disorders. However, the related mechanism still lacks systematic research. Aim: To discuss the role of BBR in the whole body's systemic metabolic regulation and further explore its therapeutic potential and targets. Method: Based on animal and cell experiments, the mechanism of BBR regulating systemic metabolic processes is reviewed. Potential metabolism-related targets were summarized using Therapeutic Target Database (TTD), DrugBank, GeneCards, and cutting-edge literature. Molecular modeling was applied to explore BBR binding to the potential targets. Results: BBR regulates the whole-body metabolic response including digestive, circulatory, immune, endocrine, and motor systems through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), sirtuin (SIRT)1/forkhead box O (FOXO)1/sterol regulatory element-binding protein (SREBP)2, nuclear factor erythroid 2-related factor (Nrf) 2/heme oxygenase (HO)-1, and other signaling pathways. Through these reactions, BBR exerts hypoglycemic, lipid-regulating, anti-inflammatory, anti-oxidation, and immune regulation. Molecular docking results showed that BBR could regulate metabolism targeting FOXO3, Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (Gpx) 4 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). Evaluating the target clinical effects, we found that BBR has the therapeutic potential of anti-aging, anti-cancer, relieving kidney disease, regulating the nervous system, and alleviating other chronic diseases. Conclusion: This review elucidates the interaction between potential targets and small molecular metabolites by exploring the mechanism of BBR regulating metabolism. That will help pharmacologists to identify new promising metabolites interacting with these targets.

We investigated the pharmacokinetic pathway of berberine and its metabolites in vitro, in Caco-2 cells, and in human participants following the administration of dihydroberberine (DHB) and micellar berberine (LipoMicel®, LMB) formulations. A pilot trial involving nine healthy volunteers was conducted over a 24 h period; blood samples were collected and subjected to Ultra High-Performance Liquid Chromatography-High Resolution Mass Spectrometry (UHPLC-HRMS) analyses to quantify the concentrations of berberine and its metabolites. Pharmacokinetic correlations indicated that berberrubine and thalifendine follow distinct metabolic pathways. Additionally, jatrorrhizine sulfate appeared to undergo metabolism differently compared to the other sulfated metabolites. Moreover, berberrubine glucuronide likely has a unique metabolic pathway distinct from other glucuronides. The human trial revealed significantly higher blood concentrations of berberine metabolites in participants of the DHB treatment group compared to the LMB treatment group-except for berberrubine glucuronide, which was only detected in the LMB treatment group. Similarly, results from in vitro investigations showed significant differences in berberine metabolite profiles between DHB and LMB. Dihydroberberine, dihydroxy-berberrubine/thalifendine and jatrorrhizine sulfate were detected in LMB-treated cells, but not in DHB-treated cells; thalifendine and jatrorrhizine-glucuronide were detected in DHB-treated cells only. While DHB treatment provided higher blood concentrations of berberine and most berberine metabolites, both in vitro (Caco-2 cells) and in vivo human studies showed that treatment with LMB resulted in a higher proportion of unmetabolized berberine compared to DHB. These findings suggest potential clinical implications that merit further investigation in future large-scale trials.

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.

Stomach diseases have become global health concerns. Protoberberine alkaloids (PBAs) are a group of quaternary isoquinoline alkaloids from abundant natural sources and have been shown to improve gastric disorders in preclinical and clinical studies. The finding that PBAs exhibit low oral bioavailability but potent pharmacological activity has attracted great interest.

This review aims to provide a systematic review of the molecular mechanisms of PBAs in the treatment of gastric disorders and to discuss the current understanding of the pharmacokinetics and toxicity of PBAs.

The articles related to PBAs were collected from the Web of Science, Pubmed, and China National Knowledge Infrastructure databases using relevant keywords. The collected articles were screened and categorized according to their research content to focus on the gastroprotective effects, pharmacokinetics, and toxicity of PBAs.

Based on the results of preclinical studies, PBAs have demonstrated therapeutic effects on chronic atrophic gastritis and gastric cancer by activating interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (STAT6) pathway and suppressing transforming growth factor-beta 1 (TGF-β1)/phosphoinositide 3-kinase (PI3K), Janus kinase-2 (JAK2)/signal transducers and activators of transcription 3 (STAT3), and mitogen-activated protein kinase (MAPK) pathways. The major PBAs exhibit similar pharmacokinetic properties, including rapid absorption, slow elimination, and low bioavailability. Notably, the natural organ-targeting property of PBAs may account for the finding of their low blood levels and high pharmacological activity. PBAs interact with other compounds, including conventional drugs and natural products, by modulation of metabolic enzymes and transporters. The potential tissue toxicity of PBAs should be emphasized due to their high tissue accumulation.

This review highlights the gastroprotective effects, pharmacokinetics, and toxicity of PBAs and will contribute to the evaluation of drug properties and clinical translational studies of PBAs, accelerating their transfer from the laboratory to the bedside.

Over the past decade, colorectal cancer has reported a higher incidence in younger adults and a lower mortality rate. Recently, the influence of the intestinal flora in the initiation, progression, and treatment of colorectal cancer has been extensively studied, as well as their positive therapeutic impact on inflammation and the cancer microenvironment. Historically, traditional Chinese medicine (TCM) has been widely used in the treatment of colorectal cancer via promoted cancer cell apoptosis, inhibited cancer metastasis, and reduced drug resistance and side effects. The present research is more on the effect of either herbal medicine or intestinal flora on colorectal cancer. The interactions between TCM and intestinal flora are bidirectional and the combined impacts of TCM and gut microbiota in the treatment of colon cancer should not be neglected. Therefore, this review discusses the role of intestinal bacteria in the progression and treatment of colorectal cancer by inhibiting carcinogenesis, participating in therapy, and assisting in healing. Then the complex anticolon cancer effects of different kinds of TCM monomers, TCM drug pairs, and traditional Chinese prescriptions embodied in apoptosis, metastasis, immune suppression, and drug resistance are summarized separately. In addition, the interaction between TCM and intestinal flora and the combined effect on cancer treatment were analyzed. This review provides a mechanistic reference for the application of TCM and intestinal flora in the clinical treatment of colorectal cancer and paves the way for the combined development and application of microbiome and TCM.

The gut microbiota, known as the second human genome, plays a vital role in modulating drug metabolism, significantly impacting therapeutic outcomes and adverse effects. Emerging research has elucidated that the microbiota mediates a range of modifications of drugs, leading to their activation, inactivation, or even toxication. In diverse individuals, variations in the gut microbiota can result in differences in microbe-drug interactions, underscoring the importance of personalized approaches in pharmacotherapy. However, previous studies on drug metabolism in the gut microbiota have been hampered by technical limitations. Nowadays, advances in biotechnological tools, such as microbially derived metabolism screening and microbial gene editing, have provided a deeper insight into the mechanism of drug metabolism by gut microbiota, moving us toward personalized therapeutic interventions. Given this situation, our review summarizes recent advances in the study of gut-microbiota-mediated drug metabolism and showcases techniques and models developed to navigate the challenges posed by the microbial involvement in drug action. Therefore, we not only aim at understanding the complex interaction between the gut microbiota and drugs and outline the development of research techniques and models, but we also summarize the specific applications of new techniques and models in researching gut-microbiota-mediated drug metabolism, with the expectation of providing new insights on how to study drug metabolism by gut microbiota.

Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.

The human gut microbiota, comprising trillions of microorganisms residing in the gastrointestinal tract, has emerged as a pivotal player in modulating various aspects of human health and disease. Recent research has shed light on the intricate relationship between the gut microbiota and pharmaceuticals, uncovering profound implications for drug metabolism, efficacy, and safety. This review depicted the landscape of molecular mechanisms and clinical implications of dynamic human gut Microbiota-Drug Interactions (MDI), with an emphasis on the impact of MDI on drug responses and individual variations. This review also discussed the therapeutic potential of modulating the gut microbiota or harnessing its metabolic capabilities to optimize clinical treatments and advance personalized medicine, as well as the challenges and future directions in this emerging field.

Diabetes mellitus is a chronic, multi-factorial metabolic disorder and also an important public health issue that requires multi-dimensional therapeutic strategies for effective control. Unani herbs have long been used to effectively mitigate diabetes through various mechanisms. In recent years, it has been speculated that the alteration of gut microbiome ecology is potentially one of the important mechanisms through which the Unani drugs exert hypoglycemic action. This review aims at the trans-disciplinary interpretation of the holistic concepts of the Unani system of medicine and the molecular insights of contemporary medicine for novel strategies for diabetes management.

We searched scientific databases such as PubMed, Google Scholar, and Science-Direct, etc. Unani classical texts (Urdu, Arabic, and Persian), and medical books, for diabetic control with Unani medicine through the gut microbiome.

Unani medicine defines, diabetes as a urinary system disorder disrupting the transformational faculty (Quwwat Mughayyira) in the gastrointestinal tract. The Unani system and contemporary biomedicine use different epistemology and ontology for describing diabetes through gutderived factors in whole-body glucose homeostasis. Unani Pharmaceutics have reported in clinical and preclinical (in vitro/ in vivo) trials in improving diabetes by altering gut microbiota composition, microvascular dysfunction, and inflammation. However, the preventive plan is the preservance of six essential factors (Asbāb Sitta Ḍarūriyya) as a lifestyle plan.

This is the first study on the integrative strategy about the hypoglycemic effects of Unani herbs that could serve as a prerogative novel approach for cost-effective, holistic, rationalistic, and multi-targeted diabetes management.

Berberine is an isoquinoline alkaloid found in plants. It presents a wide range of pharmacological activities, including anti-inflammatory and antioxidant properties, despite a low oral bioavailability. Growing evidence suggests that the gut microbiota is the target of berberine, and that the microbiota metabolizes berberine to active metabolites, although little evidence exists in the specific species involved in its therapeutic effects. This study was performed to detail the bidirectional interactions of berberine with the broiler chicken gut microbiota, including the regulation of gut microbiota composition and metabolism by berberine and metabolization of berberine by the gut microbiota, and how they contribute to berberine-mediated effects on gut health. As previous evidence showed that high concentrations of berberine may induce dysbiosis, low (0.1 g/kg feed), middle (0.5 g/kg feed) and high (1 g/kg feed) doses were here investigated. Low and middle doses of in-feed berberine stimulated potent beneficial bacteria from the Lachnospiraceae family in the large intestine of chickens, while middle and high doses tended to increase villus length in the small intestine. Plasma levels of the berberine-derived metabolites berberrubine, thalifendine and demethyleneberberine were positively correlated with the villus length of chickens. Berberrubine and thalifendine were the main metabolites of berberine in the caecum, and they were produced in vitro by the caecal microbiota, confirming their microbial origin. We show that members of the genus Blautia could demethylate berberine into mainly thalifendine, and that this reaction may stimulate the production of short-chain fatty acids (SCFAs) acetate and butyrate, via acetogenesis and cross-feeding respectively. We hypothesize that acetogens such as Blautia spp. are key bacteria in the metabolization of berberine, and that berberrubine, thalifendine and SCFAs play a significant role in the biological effect of berberine.

Traumatic brain injury (TBI) is known as a silent epidemic that causes many deaths and disabilities worldwide. We examined the response of oxyberberine (OBB) in lipopolysaccharide-stimulated BV2 microglial cells and a controlled-cortical impact (CCI) mouse model of TBI.

We synthesized OBB from berberine, and also prepared OBB-nanocrystals (OBB-NC). Male C57BL/6 mice were used for CCI surgery, and post-CCI neurobehavioral deficits were assessed from 1 h after injury through 21 days post-injury (dpi).

OBB treatment reduced the lipopolysaccharide-triggered elevated levels of reactive oxygen species, nitric oxide, and nuclear factor kappa B (NF-κB) in BV2 microglial cells, indicating a neuroprotective potential. CCI-operated mice exhibited significant neurological deficits on 1, 3, and 5 dpi in neurological severity scoring and rotarod assay. OBB (25 and 50 mg/kg/day) and OBB-NC (3 mg/kg/day) ameliorated these neurological aberrations. Mice subjected to CCI surgery also displayed anxiogenic- and depression-like behaviours, and cognitive impairments in forced-swimming test and elevated-zero maze, and novel object recognition task, respectively. Administration of OBB reduced these long-term neuropsychiatric complications, and also levels of toll-like receptor 4 (TLR4), high-motility group protein 1 (HMGB1), NF-κB, tumour necrosis factor-alpha and interleukin 6 cytokines in the ipsilateral cortex of mice.

We suggest that the administration of OBB offers neuroprotective effects via inhibition of HMGB1-mediated TLR4/NFκB pathway.

Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment. Our previous clinical trial demonstrated that berberine (BBR) hydrochloride might reduce the recurrence and canceration of colorectal adenoma (CRA). The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer (CRC).

We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial, and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction. We further performed ApcMin/+ animal intervention tests, RNA sequencing, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assays.

The abundance of fecal Veillonella parvula ( V . parvula ) decreased significantly after BBR administration ( P = 0.0016) and increased through the development from CRA to CRC. Patients with CRC with a higher V. parvula abundance had worse tumor staging and a higher lymph node metastasis rate. The intestinal immune pathway of Immunoglobulin A production was activated, and the expression of TNFSF13B (Tumor necrosis factor superfamily 13b, encoding B lymphocyte stimulator [BLyS]), the representative gene of this pathway, and the genes encoding its receptors (interleukin-10 and transforming growth factor beta) were significantly upregulated. Animal experiments revealed that V. parvula promoted colorectal carcinogenesis and increased BLyS levels, while BBR reversed this effect.

BBR might inhibit V. parvula and further weaken the immunomodulatory effect of B cells induced by V. parvula , thereby blocking the development of colorectal tumors.

ClinicalTrials.gov, No. NCT02226185.

Lipid-lowering therapy is an important tool for the treatment of lipid metabolic diseases, which are increasing in prevalence. However, the failure of conventional lipid-lowering drugs to achieve the desired efficacy in some patients, and the side-effects of these drug regimens, highlight the urgent need for novel lipid-lowering drugs. The liver and intestine are important in the production and removal of endogenous and exogenous lipids, respectively, and have an important impact on circulating lipid levels. Elevated circulating lipids predisposes an individual to lipid deposition in the vascular wall, affecting vascular function. Berberine (BBR) modulates liver lipid production and clearance by regulating cellular targets such as cluster of differentiation 36 (CD36), acetyl-CoA carboxylase (ACC), microsomal triglyceride transfer protein (MTTP), scavenger receptor class B type 1 (SR-BI), low-density lipoprotein receptor (LDLR), and ATP-binding cassette transporter A1 (ABCA1). It influences intestinal lipid synthesis and metabolism by modulating gut microbiota composition and metabolism. Finally, BBR maintains vascular function by targeting proteins such as endothelial nitric oxide synthase (eNOS) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). This paper elucidates and summarizes the pharmacological mechanisms of berberine in lipid metabolic diseases from a multi-organ (liver, intestine, and vascular system) and multi-target perspective.

Gentiopicrin, the main component of the famous Chinese patent medicine Long Dan Xie Gan Wan, has the characteristics of fast absorption in vivo and low bioavailability. Intestinal bacteria play an important role in the absorption and pharmacokinetics of oral drugs. In this study, the metabolic transformation of gentiopicrin by intestinal bacteria was examined. High-performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry (LC/MSn-IT-TOF) and nuclear magnetic resonance (NMR) were used, and six metabolites were identified, including reduction products (G-M1, G-M2, G-M4, and G-M6), a hydrolytic product (G-M3), and a dehydration product (G-M5) of gentiopicrin aglycone after hydrolysis, reduction, and dehydration reactions were performed by the intestinal flora. This is the first time that chiral metabolites of gentiopicrin (G-M1 and G-M2) were found in this study. In addition, the precursors of glucuronic acid conjugates previously reported in vivo may have come from the intestinal bacterial metabolites G-M1, G-M2, and G-M3. In addition, the metabolic transformation of gentiopicrin in liver microsomes was studied in vitro, and it was found that gentiopicrin did not undergo metabolic transformation under the action of liver microsomes. It is suggested that gentiopicroside may be metabolized in the intestine. This study provides both new insight regarding the investigation of effective substances and an exploration of the pharmacodynamic and toxicological properties of gentiopicrin.

Berberine (BBR) is an isoquinoline alkaloid extracted from Chinese medicinal plants showing a tight correlation with gut microbiota. Polycystic ovary syndrome (PCOS) is a prevalent reproductive and endocrine disorder syndrome among women of childbearing age. Dysbiosis, the imbalance of intestinal microorganisms, is a potential factor that takes part in the pathogenesis of PCOS. Recent evidence indicates that berberine offers promise for treating PCOS. Here, we review the recent research on the interaction between berberine and intestinal microorganisms, including the changes in the structure of gut bacteria, the intestinal metabolites after BBR treatment, and the effect of gut microbiota on the bioavailability of BBR. We also discuss the therapeutic effect of BBR on PCOS in terms of gut microbiota and its potential mechanisms.

Berberine, palmatine, physcion, rhein, calycosin-7-O-glucoside, and ferulic acid are six major active consituents that are present in Gushen Jiedu capsule (GSJD) extracts. The aim of this study was to determine the pharmacokinetics of the six active consituents in vivo by a rapid, sensitive, and precise UPLC-MS/MS method, which were compared between normal and diabetic nephropathy (DN) rats. Good separation of the target analytes and internal standards (ketoprofen and puerarin) was obtained on a Waters BEH C18 UPLC column with a mobile phase of 0.1 % formic acid acetonitrile-0.1 % formic acid water. All the calibration curves showed good linearity with a regression coefficient (r2) of ≥ 0.9908. The lower limits of quantification (LLOQ) for berberine, palmatine, physcion, rhein, calycosin-7-O-glucoside, and ferulic acid were 20, 2.5, 20, 20, 2.5, and 2.5 ng/mL, respectively. The relative standard deviations (RSDs) of intra-day and inter-day precision were all within 12.66 %, and the relative errors of intra-day and inter-day accuracy ranged from - 15.00 to 14.93 %. Good extraction recovery and matrix effects were obtained. The stability study confirmed the stability of the six analytes (RSD < 15 %). Finally, the data showed that the pharmacokinetic parameters (especially CLz/F, AUC and Tmax) of the six target analytes in DN rats were significantly different from those in normal rats. PK studies under pathological conditions could provide new thoughts to elucidate the underlying mechanism of GSJD and promote the clinical development of GSJD to treat DN.

The gut microbiome is a diverse system within the gastrointestinal tract composed of trillions of microorganisms (gut microbiota), along with their genomes. Accumulated evidence has revealed the significance of the gut microbiome in human health and disease. Due to its ability to alter drug/xenobiotic pharmacokinetics and therapeutic outcomes, this once-forgotten "metabolic organ" is receiving increasing attention. In parallel with the growing microbiome-driven studies, traditional analytical techniques and technologies have also evolved, allowing researchers to gain a deeper understanding of the functional and mechanistic effects of gut microbiome.

From a drug development perspective, microbial drug metabolism is becoming increasingly critical as new modalities (e.g., degradation peptides) with potential microbial metabolism implications emerge. The pharmaceutical industry thus has a pressing need to stay up-to-date with, and continue pursuing, research efforts investigating clinical impact of the gut microbiome on drug actions whilst integrating advances in analytical technology and gut microbiome models. Our review aims to practically address this need by comprehensively introducing the latest innovations in microbial drug metabolism research- including strengths and limitations, to aid in mechanistically dissecting the impact of the gut microbiome on drug metabolism and therapeutic impact, and to develop informed strategies to address microbiome-related drug liability and minimize clinical risk.

We present comprehensive mechanisms and co-contributing factors by which the gut microbiome influences drug therapeutic outcomes. We highlight in vitro, in vivo, and in silico models for elucidating the mechanistic role and clinical impact of the gut microbiome on drugs in combination with high-throughput, functionally oriented, and physiologically relevant techniques. Integrating pharmaceutical knowledge and insight, we provide practical suggestions to pharmaceutical scientists for when, why, how, and what is next in microbial studies for improved drug efficacy and safety, and ultimately, support precision medicine formulation for personalized and efficacious therapies.

The composition, viability and metabolic functionality of intestinal microbiota play an important role in human health and disease. Studies on intestinal microbiota are often based on fecal samples, because these can be sampled in a non-invasive way, although procedures for sampling, processing and storage vary. This review presents factors to consider when developing an automated protocol for sampling, processing and storing fecal samples: donor inclusion criteria, urine-feces separation in smart toilets, homogenization, aliquoting, usage or type of buffer to dissolve and store fecal material, temperature and time for processing and storage and quality control. The lack of standardization and low-throughput of state-of-the-art fecal collection procedures promote a more automated protocol. Based on this review, an automated protocol is proposed. Fecal samples should be collected and immediately processed under anaerobic conditions at either room temperature (RT) for a maximum of 4 h or at 4 °C for no more than 24 h. Upon homogenization, preferably in the absence of added solvent to allow addition of a buffer of choice at a later stage, aliquots obtained should be stored at either -20 °C for up to a few months or -80 °C for a longer period-up to 2 years. Protocols for quality control should characterize microbial composition and viability as well as metabolic functionality.

Intestinal inflammation is a chronic gastrointestinal disorder with uncertain pathophysiology and causation that has significantly impacted both the physical and mental health of both people and animals. An increasing body of research has demonstrated the critical role of cellular signaling pathways in initiating and managing intestinal inflammation. This review focuses on the interactions of three cellular signaling pathways (TLR4/NF-κB, PI3K-AKT, MAPKs) with immunity and gut microbiota to explain the possible pathogenesis of intestinal inflammation. Traditional medicinal drugs frequently have drawbacks and negative side effects. This paper also summarizes the pharmacological mechanism and application of Chinese herbal compounds (Berberine, Sanguinarine, Astragalus polysaccharide, Curcumin, and Cannabinoids) and formulae (Wumei Wan, Gegen-Qinlian decoction, Banxia xiexin decoction) against intestinal inflammation. We show that the herbal compounds and formulae may influence the interactions among cell signaling pathways, immune function, and gut microbiota in humans and animals, exerting their immunomodulatory capacity and anti-inflammatory and antimicrobial effects. This demonstrates their strong potential to improve gut inflammation. We aim to promote herbal medicine and apply it to multispecies animals to achieve better health.

Berberine, an isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been gaining interest due to anti-inflammatory and antioxidant activities, as well as neuro and cardiovascular protective effects in animal models. Recently, photodynamic therapy demonstrated successful application in many fields of medicine. This innovative, non-invasive treatment modality requires a photosensitizer, light, and oxygen. In particular, the photosensitizer can selectively accumulate in diseased tissues without damaging healthy cells. Berberine's physicochemical properties allow its use as a photosensitising agent for photodynamic therapy, enabling reactive oxygen species production and thus potentiating treatment efficacy. However, berberine exhibits poor aqueous solubility, low oral bioavailability, poor cellular permeability, and poor gastrointestinal absorption that hamper its therapeutic and photodynamic efficacy. Nanotechnology has been used to minimize berberine's limitations with the design of drug delivery systems. Different nanoparticulate delivery systems for berberine have been used, as lipid-, inorganic- and polymeric-based nanoparticles. These berberine nanocarriers improve its therapeutic properties and photodynamic potential. More specifically, they extend its half-life, increase solubility, and allow a high permeation and targeted delivery. This review describes different nano strategies designed for berberine delivery as well as berberine's potential as a photosensitizer for photodynamic therapy. To benefit from berberine's overall potential, nanotechnology has been applied for berberine-mediated photodynamic therapy.

Deaths from bacterial infections have risen year by year. This trend is further aggravated as the overuse antibiotics and the bacterial resistance to all known antibacterial agents. Therefore, new therapeutic alternatives are urgently needed.

Enlightenment the combination usage of traditional herb medicine, one carrier-free binary nanoparticles (GA-BBR NPs) was discovered, which was self-assembled from gallic acid and berberine through electrostatic interaction, π-π stacking and hydrophobic interaction; and it could be successfully prepared by a green, cost-effective and "one-pot" preparation process.

The nanoparticles exhibited strong antibacterial activity and biofilm removal ability against multidrug-resistant S. aureus (MRSA) by downregulating mRNA expression of rpsF, rplC, rplN, rplX, rpsC, rpmC and rpsH to block bacterial translation mechanisms in vitro and in vivo, and it had well anti-inflammatory activity and a promising role in promoting angiogenesis to accelerate the wound healing on MRSA-infected wounds model in vivo. Additionally, the nanoparticles displayed well biocompatibility without cytotoxicity, hemolytic activity, and tissue or organ toxicity.

GA-BBR NPs originated from the drug combination has potential clinical transformation value, and this study provides a new idea for the design of carrier-free nanomedicine derived from natural herbals.