CircPTEN suppresses human clear cell renal carcinoma progression and resistance to mTOR inhibitors by targeting epigenetic modification.

Renal cell carcinoma (RCC) is known to be the most commonly diagnosed kidney cancer. Clear cell RCC (ccRCC) represents approximately 85 % of diagnosed RCC cases. Targeted therapeutics, such as multi-targeted tyrosine kinase inhibitors (TKI) and mTOR inhibitors, are widely used in ccRCC therapy. However, patients treated with mTOR and TKI inhibitors easily acquire drug resistance, making the therapy less effective. Here, we demonstrated that circPTEN inhibits the expression of its parental gene PTEN by reducing methylation of the PTEN promotor and inhibits GLUT1 expression by reducing m6A methylation of GLUT1, which suppresses ccRCC progression and resistance to mTOR inhibitors.

N6-methyladenosine-modified circular RNA QSOX1 promotes colorectal cancer resistance to anti-CTLA-4 therapy through induction of intratumoral regulatory T cells.

BACKGROUND: Colorectal cancer (CRC) is the 3rd most common cancer worldwide. CircRNAs are promising novel biomarkers for CRC. T regulatory (Treg) cells express the immune checkpoint receptor of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and promote tumor immunological tolerance. We therefore investigate the biological functions and mechanisms of circQSOX1 in CRC tumorigenesis; involvement of circQSOX1 in promoting Treg cell-mediated CRC immune escape in anti-CTLA-4 therapy. METHODS: Bioinformatics analyses were performed for circQSOX1expressions, specific binding sites, and N6-methyladenosine (m6A) motifs of circQSOX1, thatwere further validated with a series of experiments. Functions of circQSOX1 in promoting CRC development, Treg cells-based immune escape, and anti-CTLA-4 therapy response were investigated both in vitro and in vivo. RESULTS: High circQSOX1 expression was associated with carcinogenesis and poor clinical outcome of CRC patients. METTL3-mediated RNA m6A modification on circQSOX1 could be read by IGF2BP2 in CRC cells. CircQSOX1 promoted CRC development by regulating miR-326/miR-330-5p/PGAM1 axis. CircQSOX1 regulated glycolysis and promoted immune escape of CRC cells, and inhibits anti-CTLA-4 therapy response in CRC patients. CONCLUSION: m6A-modified circQSOX1 facilitated CRC tumorigenesis by sponging miR-326 and miR-330-5p to promotes PGAM1 expression, which further promoted CRC immune escape by activating glycolysis and inactivating the anti-CTLA-4 therapy response of CRC. Combined treatment with sh-circQSOX1 and anti-CTLA-4 could be a strategy to overcome Treg cell-mediated CRC immune therapy resistance.

Physical therapy in diabetic foot ulcer: Research progress and clinical application.

Diabetes foot ulcer (DFU) is one of the most intractable complications of diabetes and is related to a number of risk factors. DFU therapy is difficult and involves long-term interdisciplinary collaboration, causing patients physical and emotional pain and increasing medical costs. With a rising number of diabetes patients, it is vital to figure out the causes and treatment techniques of DFU in a precise and complete manner, which will assist alleviate patients' suffering and decrease excessive medical expenditure. Here, we summarised the characteristics and progress of the physical therapy methods for the DFU, emphasised the important role of appropriate exercise and nutritional supplementation in the treatment of DFU, and discussed the application prospects of non-traditional physical therapy such as electrical stimulation (ES), and photobiomodulation therapy (PBMT) in the treatment of DFU based on clinical experimental records in ClinicalTrials.gov.

MicroRNA-500a Promotes the Progression of Hepatocellular Carcinoma by Post-Transcriptionally Targeting BID.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is one of the most common human malignant diseases in the world, and the mechanisms underlying HCC carcinogenesis and progression need further investigation. MicroRNAs play important roles in the development of cancer, and miR-500a is suggested to be deregulated in some types of cancer. However, the underlying molecular mechanisms of miR-500a in HCC remain unknown. METHODS: The expression of miR-500a in HCC was analyzed in The Cancer Genome Atlas (TCGA) database and examined in 33 pairs of HCC tissues and matched nontumor tissues. The correlation between miR-500a expression and prognosis of HCC patients was analyzed from the survival data in TCGA. The mechanism of miR-500a upregulation in HCC was detected using chromatin immunoprecipitation-quantitative real-time PCR. The roles of miR-500a in HCC development were examined using a cell counting kit-8 assay in vitro and growth of transplanted tumors in nude mice in vivo. Apoptosis of HCC was detected using Annexin V/propidium iodide staining. The expression of BH3-interacting death agonist (BID) protein was examined using western blot analysis. RESULTS: miR-500a expression was upregulated in HCC tissues, and high miR-500a expression was significantly correlated with the poor prognosis of HCC patients. Histone modifications in the promoter region of miR-500a may be responsible for its increased expression. Inhibition of miR-500a in HCC cell lines significantly promoted apoptosis, as well as inhibiting the proliferation of HCC cells and growth of transplanted tumors in nude mice. miR-500a directly targeted the 3' untranslated region of BID mRNA, and inhibition of miR-500a-promoted apoptosis was almost completely abolished by the administration of ABT-199 via the BID-mitochondria pathway. CONCLUSION: Our results suggest that histone modifications in the promoter region of miR-500a may be responsible for the increased expression of miR-500a in HCC, which promotes cancer progression by targeting BID, indicating that miR-500a may be a potential prognostic predictor and therapeutic target for HCC patients.

Inhibition of Laser-Induced Choroidal Neovascularization by Hematoporphyrin Dimethylether-Mediated Photodynamic Therapy in Rats.

This study aimed to investigate the effect of hematoporphyrin dimethylether (HDME)-mediated photodynamic therapy for laser-induced choroidal neovascularization (CNV) in adult Brown Norway rats. HDME was administered via tail vein at 14 d after the laser photocoagulation, and the rats received irradiance with a laser light at 570 nm at 15 min after injection. CNV was evaluated by fundus photography, fundus fluorescein angiography, optical coherence tomography, and hematoxylin and eosin staining. We found that CNV was occurred at 7 d after photocoagulation and reaching peak activity at 14 d after photocoagulation. There is a significant reduction in the total area of the fluorescein leakage and the number of strong fluorescein leakage spots on 7 d after HDME-mediated photodynamic therapy (PDT). The results suggest that HDME-mediated PDT inhibits laser-induced CNV in rats, representing a promising therapy for wet age-related macular degeneration.

Immunogenic cell death-based cancer vaccines: promising prospect in cancer therapy.

Tumor immunotherapy is a promising approach for addressing the limitations of conventional tumor treatments, such as chemotherapy and radiotherapy, which often have side effects and fail to prevent recurrence and metastasis. However, the effectiveness and sustainability of immune activation in tumor immunotherapy remain challenging. Tumor immunogenic cell death, characterized by the release of immunogenic substances, damage associated molecular patterns (DAMPs), and tumor associated antigens, from dying tumor cells (DTCs), offers a potential solution. By enhancing the immunogenicity of DTCs through the inclusion of more immunogenic antigens and stimulating factors, immunogenic cell death (ICD) based cancer vaccines can be developed as a powerful tool for immunotherapy. Integrating ICD nanoinducers into conventional treatments like chemotherapy, photodynamic therapy, photothermal therapy, sonodynamic therapy, and radiotherapy presents a novel strategy to enhance treatment efficacy and potentially improve patient outcomes. Preclinical research has identified numerous potential ICD inducers. However, effectively translating these findings into clinically relevant applications remains a critical challenge. This review aims to contribute to this endeavor by providing valuable insights into the in vitro preparation of ICD-based cancer vaccines. We explored established tools for ICD induction, followed by an exploration of personalized ICD induction strategies and vaccine designs. By sharing this knowledge, we hope to stimulate further development and advancement in the field of ICD-based cancer vaccines.

Antibacterial and anticancer activities of green-synthesized silver nanoparticles using Photinia glabra fruit extract.

Aims: We prepared Photinia glabra (PG) aqueous fruit extract, utilized it to synthesize silver nanoparticles (PG-Ag NPs) and evaluated the antibacterial and anticancer activities of the nanoparticles (NPs). Materials & methods: Silver nitrate aqueous solution was reduced to PG-Ag NPs using aqueous PG fruit extract. NP shape, size, composition and functionalization were determined using transmission electron microscopy, x-ray photoelectron spectroscopy, Fourier transform infrared and x-ray diffraction. Results & conclusions: PG-Ag NPs were spherical, approximately 39-77 nm-sized, functionalized surfaces with notable antibacterial activity against both Escherichia coli and Staphylococcus aureus, with an MIC <30 ug/ml and cytotoxicity toward esophageal cancer cells, with IC50 values less than 20 ug/ml. PG-Ag@rt NPs have been shown to be a potent antibacterial and anticancer agent, and their enriched particle surfaces can be conjugated with other compounds for multibiomedical applications.

The present study reports for the first time the preparation of Photinia glabra (PG) aqueous fruit extract and its use for the synthesis of smaller silver particles (PG-Ag NPs) from bulk aqueous silver nitrate solution (AgNO₃). The preparation followed the reduction ability of PG fruit extract phytochemical under different preparation conditions: at room temperature (PG-Ag@rt), at 70°C (PG-Ag@70) and in the presence of cerium oxide at 70°C (PG-Ag+CeO₂@70). The prepared smaller particles were found using transmission electron microscopy to be spherical in shape with sizes 39, 77 and 44 nm for PG-Ag@rt, PG-Ag@70 and PG-Ag+CeO₂@70, respectively. The NPs contained different functional groups on their surfaces due to the capping ability of PG fruit extract components. Among all, PG-Ag@rt NPs showed strongest antibacterial activity against Escherichia coli and Staphylococcus aureus with MIC 7.0 µg/ml and 28.0 µg/ml, respectively, and commendable anticancer activity toward Eca-109 cancer cells with IC₅₀ less than 20 ug/ml.

Nanocarrier-Mediated Immunogenic Cell Death for Melanoma Treatment.

Melanoma, a highly aggressive skin tumor, exhibits notable features including heterogeneity, a high mutational load, and innate immune escape. Despite advancements in melanoma treatment, current immunotherapies fail to fully exploit the immune system's maximum potential. Activating immunogenic cell death (ICD) holds promise in enhancing tumor cell immunogenicity, stimulating immune amplification response, improving drug sensitivity, and eliminating tumors. Nanotechnology-enabled ICD has emerged as a compelling therapeutic strategy for augmenting cancer immunotherapy. Nanoparticles possess versatile attributes, such as prolonged blood circulation, stability, and tumor-targeting capabilities, rendering them ideal for drug delivery. In this review, we elucidate the mechanisms underlying ICD induction and associated therapeutic strategies. Additionally, we provide a concise overview of the immune stress response associated with ICD and explore the potential synergistic benefits of combining ICD induction methods with the utilization of nanocarriers.

Anti-SARS-CoV-2 IgM/IgG antibodies detection using a patch sensor containing porous microneedles and a paper-based immunoassay.

Infectious diseases are among the leading causes of mortality worldwide. A new coronavirus named severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) was identified in Wuhan, China in 2019, and the World Health Organization (WHO) declared its outbreak, coronavirus disease 2019 (COVID-19), as a global pandemic in 2020. COVID-19 can spread quickly from person to person. One of the most challenging issues is to identify the infected individuals and prevent potential spread of SARS-CoV-2. Recently, anti-SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody tests using immunochromatographic methods have been used as a complement to current detection methods and have provided information of the approximate course of COVID-19 infection. However, blood sampling causes pain and poses risks of infection at the needle puncture site. In this study, a novel patch sensor integrating porous microneedles and an immunochromatographic assay (PMNIA) was developed for the rapid detection of anti-SARS-CoV-2 IgM/IgG in dermal interstitial fluid (ISF), which is a rich source of protein biomarkers, such as antibodies. Biodegradable porous microneedles (MNs) made of polylactic acid were fabricated to extract ISF from human skin by capillary effect. The extracted ISF was vertically transported and flowed into the affixed immunoassay biosensor, where specific antibodies could be detected colorimetrically on-site. Anti-SARS-CoV-2 IgM/IgG antibodies were simultaneously detected within 3 min in vitro. Moreover, the limit of detection of anti-SARS-CoV-2 IgM and IgG concentrations was as low as 3 and 7 ng/mL, respectively. The developed device integrating porous MNs and immunochromatographic biosensors is expected to enable minimally invasive, simple, and rapid anti-SARS-CoV-2 IgM/IgG antibody testing. Furthermore, the compact size of the MN and biosensor-integrated device is advantageous for its widespread use. The proposed device has great potential for rapid screening of various infectious diseases in addition to COVID-19 as an effective complementary method with other diagnostic tests.

Recent advances in porous microneedles: materials, fabrication, and transdermal applications.

In the past two decades, microneedles (MNs), as a painless and simple drug delivery system, have received increasing attention for various biomedical applications such as transdermal drug delivery, interstitial fluid (ISF) extraction, and biosensing. Among the various types of MNs, porous MNs have been recently researched owing to their distinctive and unique characteristics, where porous structures inside MNs with continuous nano- or micro-sized pores can transport drugs or biofluids by capillary action. In addition, a wide range of materials, including non-polymers and polymers, were researched and used to form the porous structures of porous MNs. Adjustable porosity by different fabrication methods enables the achievement of sufficient mechanical strength by optimising fluid flows inside MNs. Moreover, biocompatible porous MNs integrated with biosensors can offer portable detection and rapid measurement of biomarkers in a minimally invasive manner. This review focuses on several aspects of current porous MN technology, including material selection, fabrication processes, biomedical applications, primarily covering transdermal drug delivery, ISF extraction, and biosensing, along with future prospects as well as challenges.

Exosomes as drug delivery system in gastrointestinal cancer.

Gastrointestinal cancer is one of the most common malignancies with relatively high morbidity and mortality. Exosomes are nanosized extracellular vesicles derived from most cells and widely distributed in body fluids. They are natural endogenous nanocarriers with low immunogenicity, high biocompatibility, and natural targeting, and can transport lipids, proteins, DNA, and RNA. Exosomes contain DNA, RNA, proteins, lipids, and other bioactive components, which can play a role in information transmission and regulation of cellular physiological and pathological processes during the progression of gastrointestinal cancer. In this paper, the role of exosomes in gastrointestinal cancers is briefly reviewed, with emphasis on the application of exosomes as drug delivery systems for gastrointestinal cancers. Finally, the challenges faced by exosome-based drug delivery systems are discussed.

Clinical significance and immunogenomic landscape analysis of glycolysis-associated prognostic model to guide clinical therapy in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor with a poor prognosis and high mortality rate worldwide. Glucose metabolism disorder is one of the most important characteristics of HCC. However, as the primary risk factors for the prognosis of HCC patients are unclear, the survival prognosis and therapy response of patients cannot be accurately predicted. Methods: First, gene sets of 29 cancer hallmarks were collected from public databases. The z-score of various cancer hallmarks were quantitively analyzed by a single-sample gene set enrichment analysis (ssGSEA) of HCC patients. Next, a glycolysis-related gene signature (GRS) was constructed using a series of bioinformatics methods, which were used to predict the survival prognosis of HCC patients and the immunotherapy benefits. The prediction accuracy of the GRS was validated in different HCC cohorts and clinical subgroups. Additionally, a decision tree and nomogram were also established based on the GRS and other clinical variables. Finally, the genomic alterations and tumor immune microenvironment of the HCC patients were examined. Results: Among the 29 cancer hallmarks, glycolysis was the most predominant risk factor for a poor prognosis in HCC. We subsequently constructed a novel GRS comprising 12 glycolysis-related genes. The high-GRS patients had a poorer survival prognosis than the low-GRS patients. The GRS exhibited a powerful ability to predict survival prognosis in different HCC cohorts and clinical feature subgroups. Additionally, the decision tree and nomogram aided in the risk stratification and prognosis evaluations of HCC patients. Further, we found that a high GRS was characterized by a severe tumor stage, pathological grade, and other clinical features. There were significant differences in the genomic alterations, immune cells, and immune checkpoints between the low- and high-GRS patients, especially in relation to the tumor protein p53 mutation and immunosuppressive cells. Notably, we also found that the GRS could be used to identify HCC patients who are more sensitive to chemotherapy and immunotherapy. Conclusions: In summary, the GRS may be a useful tool for predicting the prognosis and guiding the clinical therapy of HCC patients.

The improvement of biocompatibility by incorporating porphyrins into carbon dots with photodynamic effects and pH sensitivities.

Photodynamic therapy (PDT) is a promising new treatment for cancer; however, the hydrophobic interactions and poor solubility in water of photosensitizers limit the use in clinic. Nanoparticles especially carbon dots have attracted the attention of the world's scientists because of their unique properties such as good solubility and biocompatibility. In this paper, we integrated carbon dots with different porphyrins to improve the properties of porphyrins and evaluated their efficacy as PDT drugs. The spectroscopic characteristics of porphyrins nano-conjugates were studied. Singlet oxygen generation rate and the light- and dark-induced toxicity of the conjugates were studied. Our results showed that the covalent interaction between CDs and porphyrins has improved the biocompatibility. The synthesized conjugates also inherit the pH sensitivity of the carbon dots, while the conjugation also decreases the hemolysis ratio making them a promising candidate for PDT. The incorporation of carbon dots into porphyrins improved their biocompatibility by reducing toxicity.

Metabolism heterogeneity in melanoma fuels deactivation of immunotherapy: Predict before protect.

Malignant melanoma is widely acknowledged as the most lethal skin malignancy. The metabolic reprogramming in melanoma leads to alterations in glycolysis and oxidative phosphorylation (OXPHOS), forming a hypoxic, glucose-deficient and acidic tumor microenvironment which inhibits the function of immune cells, resulting in a low response rate to immunotherapy. Therefore, improving the tumor microenvironment by regulating the metabolism can be used to improve the efficacy of immunotherapy. However, the tumor microenvironment (TME) and the metabolism of malignant melanoma are highly heterogeneous. Therefore, understanding and predicting how melanoma regulates metabolism is important to improve the local immune microenvironment of the tumor, and metabolism regulators are expected to increase treatment efficacy in combination with immunotherapy. This article reviews the energy metabolism in melanoma and its regulation and prediction, the integration of immunotherapy and metabolism regulators, and provides a comprehensive overview of future research focal points in this field and their potential application in clinical treatment.

Macrophage Membrane-Derived Biomimetic Nanoparticles for Treatment of Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is a severe complication of infectious diseases like Coronavirus disease 2019 (COVID-19) that cause serious damage to public health. Currently, supportive therapy is still the main therapeutic strategy exists for CRS treatment. Here, we show the potential of macrophage membrane-derived biomimetic nanoparticles for CRS treatment. By fusing macrophage membrane on the surface of the PLGA nano core, we constructed biomimetic nanoparticles that inherited the membrane receptors from the "parental" macrophages, enabling the neutralization of CRS-related cytokines. We compared three types of macrophage membranes to screen out more effective biomimetic nanoparticles for CRS treatment. Our results show that M0 macrophage membrane-derived biomimetic nanoparticles could neutralize pro-inflammatory cytokines involved in CRS to the greatest extent and reduce organ damage in a mouse model.

Incorporation of green emission polymer dots into pyropheophorbide-α enhance the PDT effect and biocompatibility.

BACKGROUND: A green emission up-conversion carbon-based polymer dots (CPDs) owned excellent photophysical properties and good solubility. Most photosensitizers (PS) are hydrophobic which limits their application in biomedicine. Herein we synthesized and integrated green emitting CPDs into pyropheophorbide-α (PPa) to improve the overall properties of the PS. MATERIAL AND METHODS: The nano-agent was incorporated through amide condensation and electrostatic interaction. The structure, size and morphology of the prepared conjugates were determined by FTIR, TEM, DLS, TGA, 1HNMR, Uv-vis, and fluorescence spectrophotometry. The dark and light toxicity, as well as cellular uptake, was also monitored on the human esophageal cancer cell line (Eca-109). RESULTS: Our results illustrate that the conjugation improved the PDT efficacy by increasing the ROS generation. The nano-hybrids showed pH sensitivity as well as good hemocompatibility as the hemolysis ratio was decreased when treated with nano-conjugates. PPa-CPD1 and PPa-CPD2 had the pH response and stronger ability to absorb light and produce fluorescence in an acidic environment (pH 4.0 and pH 5.0) The synthesized nano-hybrids doesnot affect the clotting time. An increase in the absorbance wavelengths was observed. The results of MTT assay showed that dark toxicity was reduced after conjugation. CONCLUSION: This CPDs-based drug enhanced tumor-inhibition efficiency as well as low dark toxicity in vitro, showing significant application potential for PDT-based treatment.

Gold nanoparticle-directed autophagy intervention for antitumor immunotherapy via inhibiting tumor-associated macrophage M2 polarization.

Tumor-associated macrophages (TAMs), one of the dominating constituents of tumor microenvironment, are important contributors to cancer progression and treatment resistance. Therefore, regulation of TAMs polarization from M2 phenotype towards M1 phenotype has emerged as a new strategy for tumor immunotherapy. Herein, we successfully initiated antitumor immunotherapy by inhibiting TAMs M2 polarization via autophagy intervention with polyethylene glycol-conjugated gold nanoparticles (PEG-AuNPs). PEG-AuNPs suppressed TAMs M2 polarization in both in vitro and in vivo models, elicited antitumor immunotherapy and inhibited subcutaneous tumor growth in mice. As demonstrated by the mRFP-GFP-LC3 assay and analyzing the autophagy-related proteins (LC3, beclin1 and P62), PEG-AuNPs induced autophagic flux inhibition in TAMs, which is attributed to the PEG-AuNPs induced lysosome alkalization and membrane permeabilization. Besides, TAMs were prone to polarize towards M2 phenotype following autophagy activation, whereas inhibition of autophagic flux could reduce the M2 polarization of TAMs. Our results revealed a mechanism underlying PEG-AuNPs induced antitumor immunotherapy, where PEG-AuNPs reduce TAMs M2 polarization via induction of lysosome dysfunction and autophagic flux inhibition. This study elucidated the biological effects of nanomaterials on TAMs polarization and provided insight into harnessing the intrinsic immunomodulation capacity of nanomaterials for effective cancer treatment.

Clinical applicability of renin-angiotensin system inhibitors in cancer treatment.

The renin-angiotensin system (RAS) regulates physiological functions of the cardiovascular system, kidneys, and other tissues. Various in vivo and in vitro studies have shown that RAS plays a pivotal role in the development of malignant tumors, while several retrospective studies have confirmed that patients undergoing long-term RAS inhibitors (RASi) treatment have a lowered risk of cancer. Moreover, blocking RAS has been shown to inhibit tumor growth, metastasis, and angiogenesis in various experimental models of malignant tumors. Herein, we review the available RASi-related literature and provide an analysis using the scientific atlas software VOSviewer. We observed that recent studies have primarily focused on gene expression, tumor biology, and survival analysis. Through an in-depth data analysis from the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx), we identified the impact of AGTR1, an essential component of RAS, on tumors, and we discuss the underlying biological mechanism of RASi. Furthermore, we outline the research progress and potential use of RASi in tumor treatment. Overall, RASi may be a promising adjunct in cancer therapy.

Research Progress on the Antiosteoarthritic Mechanism of Action of Natural Products.

BACKGROUND: Osteoarthritis (OA) is a clinical joint degenerative disease, the pathogenic factors of which include age, obesity, and mechanical injury. Its main pathological features include cartilage loss, narrowing of joint space, and osteophyte formation. At present, there are a variety of treatment methods for OA. Natural products, which are gradually being applied in the treatment of OA, are advantageous as they present with low toxicity and low costs and act on multiple targets. METHODS: The terms "natural products," "osteoarthritis," and "chondrocytes" were searched in PubMed to screen the related literature in the recent 10 years. RESULTS: We comprehensively introduced 62 published papers on 48 natural products involving 6, 3, 5, 12, 4, and 5 kinds of terpenoids, polysaccharides, polyphenols, flavonoids, alkaloids, and saponins, respectively (and others). CONCLUSION: The mechanisms of their anti-OA action mainly involve reducing the production of inflammatory factors, reducing oxidative stress, regulating the metabolism of chondrocytes, promoting the proliferation of chondrocytes, or inhibiting chondrocyte apoptosis. This article summarizes the anti-OA activity of natural products in the last 10 years and provides candidate monomers for further study for use in OA treatment.

Schisandrin B regulates macrophage polarization and alleviates liver fibrosis via activation of PPARγ.

BACKGROUND: Schisandrin B (Sch B), the main ingredient of Schisandra chinensis, displays many bioactivities. This study aimed to identify the drug target of Sch B against liver fibrosis and describe the related molecular mechanisms. METHODS: The effects of Sch B on liver fibrosis and macrophage polarization was investigated in vivo and in vitro. Furthermore, we analyzed the regulatory effect of Sch B on peroxisome proliferator-activated receptor gamma (PPARγ). RESULTS: Our data showed that Sch B dramatically alleviated liver inflammation and fibrosis and inhibited macrophage activation via PPARγ. Sch B binds with PPARγ by molecular docking. Immunofluorescence double staining showed that PPARγ was mainly expressed in macrophages rather than hepatic stellate cells (HSCs) in liver fibrosis. Importantly, Sch B strongly inhibited macrophage polarization in fibrotic livers compared with the model group. Further, the results revealed that Sch B efficiently inhibited macrophage polarization and also decreased the levels of inflammatory cytokines in vitro. Knockdown of PPARγ by small interfering RNA (siRNA) inhibited the effect of Sch B on macrophage polarization. Mechanistically, Sch B regulated macrophage polarization through inhibition of the nuclear factor (NF)-κB signaling pathway via PPARγ both in vivo and in vitro. CONCLUSIONS: These results suggested that Sch B alleviated carbon tetrachloride (CCl4)-induced liver inflammation and fibrosis by inhibiting macrophage polarization via targeting PPARγ.