Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Knockout of C6orf120 in Rats Alleviates Concanavalin A-induced Autoimmune Hepatitis by Regulating Macrophage Polarization

Objective The effect of the functionally unknown gene C6orf120 on autoimmune hepatitis was investigated on C6orf120 knockout rats(C6orf120^(-/-))and THP-1 cells.Method Six–eight-week-old C6orf120^(-/-)and wild-type(WT)SD rats were injected with Con A(16 mg/kg),and euthanized after 24 h.The sera,livers,and spleens were collected.THP-1 cells and the recombinant protein(rC6ORF120)were used to explore the mechanism in vitro.The frequency of M1 and M2 macrophages was analyzed using flow cytometry.Western blotting and PCR were used to detect macrophage polarization-associated factors.Results C6orf120 knockout attenuated Con A-induced autoimmune hepatitis.Flow cytometry indicated that the proportion of CD68^(+)CD86^(+)M1 macrophages from the liver and spleen in the C6orf120^(-/-)rats decreased.C6orf120 knockout induced downregulation of CD86 protein and the mRNA levels of related inflammatory factors TNF-α,IL-1β,and IL-6 in the liver.C6orf120 knockout did not affect the polarization of THP-1 cells.However,rC6ORF120 promoted the THP-1 cells toward CD68^(+)CD80^(+)M1 macrophages and inhibited the CD68^(+)CD206^(+)M2 phenotype.Conclusion C6orf120 knockout alleviates Con A-induced autoimmune hepatitis by inhibiting macrophage polarization toward M1 macrophages and reducing the expression of related inflammatory factors in C6orf120^(-/-)rats.

Macrophage polarization or repolarization in tuberculosis

Tuberculosis caused by Mycobacterium(M.)tuberculosis remains a global public health threat.Over the last few decades,anti-tubercular research mainly focused on mechanisms of identifying by which activated macrophages can slaughter or the proliferation of M.tuberculosis bacilli prevented in a cell-dependent manner.In this regard,for disease resolution,inflammatory cytokines are very crucial.Here,we demonstrate how macrophages act as the first line of defense against the M.tuberculosis.Studies have revealed a dual role in M.tuberculosis infection played by macrophages.It is worth mentioning that the macrophages are the crucial immune effector and antigen-presenting cells that play the anti-tubercular response,which is the habitat of M.tuberculosis,hence,followed by progressing the disease protecting M.tuberculosis.This dual role can be correlated with the different macrophage polarization statuses,namely,M1 and M2.Herein,we have stated how the several polarization conditions of macrophages are directly linked to the immune responses during host and M.tuberculosis pathogen interactions.We have proposed that macrophage polarization and repolarization are of paramount significance for the anti-tubercular immune response that may involve a sterile cure of the disease.This article summarizes the immune response to M.tuberculosis,the polarization states of macrophages during M.tuberculosis and the repolarization of macrophages by some agents during some diseases including M.tuberculosis,which may be an important factor in the World Health Organization's target to cure tuberculosis by 2035.

Atorvastatin ameliorated myocardial fibrosis in db/db mice by inhibiting oxidative stress and modulating macrophage polarization

BACKGROUND People with diabetes mellitus(DM)suffer from multiple chronic complications due to sustained hyperglycemia,especially diabetic cardiomyopathy(DCM).Oxidative stress and inflammatory cells play crucial roles in the occurrence and progression of myocardial remodeling.Macrophages polarize to two distinct phenotypes:M1 and M2,and such plasticity in phenotypes provide macrophages various biological functions.AIM To investigate the effect of atorvastatin on cardiac function of DCM in db/db mice and its underlying mechanisms.METHODS DCM mouse models were established and randomly divided into DM,atorvastatin,and metformin groups.C57BL/6 mice were used as the control.Cardiac function was evaluated by echocardiography.Hematoxylin and eosin and Masson staining was used to examine the morphology and collagen fibers in myocardial tissues.The expression of transforming growth factor-β1(TGF-β1),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),M1 macrophages(iNOS^(+)),and M2 macrophages(CD206^(+))were demonstrated by immunohistochemistry and immunofluorescence staining.The levels of TGF-β1,IL-1β,and TNF-αwere detected by ELISA and real-time quantitative polymerase chain reaction.Malondialdehyde(MDA)concentrations and superoxide dismutase(SOD)activities were also measured.RESULTS Treatment with atorvastatin alleviated cardiac dysfunction and decreased db/db mice. The broken myocardialfibers and deposition of collagen in the myocardial interstitium were relieved especially by atorvastatin treatment.Atorvastatin also reduced the levels of serum lactate dehydrogenase, creatine kinase isoenzyme, and troponin;lowered the levels of TGF-β1, TNF-α and IL-1β in serum and myocardium;decreased the concentration of MDAand increased SOD activity in myocardium of db/db mice;inhibited M1 macrophages;and promoted M2macrophages.CONCLUSION Administration of atorvastatin attenuates myocardial fibrosis in db/db mice, which may be associated with theantioxidative stress and anti-inflammatory effects of atorvastatin on diabetic myocardium through modulatingmacrophage polarization.

Exploration of the molecular mechanism of Qishen decoction in regulating miR-495/FTO pathway mediated macrophage polarization to improve insulin resistance therapy of type 2 diabetes

Objective:To observe the effect of Qishen decoction on macrophage polarization mediated by miR-495/FTO signaling pathway,and to clarify the molecular mechanism of Qishen decoction in improving insulin resistance in the treatment of type 2 diabetes.Methods:THP-1 was induced to differentiate macrophages with phorbol ester.It was divided into the control group,the model group,the Qishen decoction group,the miR-495 inhibitor group,and the Qishen decoction+miR-495 inhibitor group.Except for the control group,the remaining groups were stimulated with 30 mmol/L glucose to construct a macrophage polarization model,and corresponding drugs were given for intervention.Cells were collected from each group for 24 hours and the content of inflammatory factors(IL-6,IL-1β,IL-4,and IL-10)were detected using enzyme-linked immunosorbent assay.The expression of macrophage polarization marker molecules,miR-495,and FTO were detected by flow cytometry,qPCR,and Western blot to detect.Results:Compared with the control group,there was no significant change in the activity of macrophages in the control serum,Qishen decoction containing serum,and miR-495 inhibitor transfected serum,and the difference was not statistically significant(P>0.05).In addition,compared to the control group,the content of IL-6 and IL-1β,the expression levels of CD68,iNOS,COX-2,miR-495,and the ratio of CD68/CD206,were significantly increased(P<0.01).While the content of IL-4 and IL-10,as well as the expression of CD206,Arg-1,YM-1,and FTO were significantly reduced(P<0.01).Compared with the model group,the QiShen decoction significantly reduced the contents of IL-6 and IL-1β,and the expression levels of CD68,iNOS,COX-2,and miR-495,as well as the ratio of CD68/CD206,while the content of IL-4 and IL-10,as well as the expression of CD206,Arg-1,YM-1,and FTO were significantly increased(P<0.01).Conclusion:Qishen decoction upregulate the expression of FTO to promote M2 type polarization of macrophages,thereby inhibiting inflammation and improving insulin resistance by inhibiting the expression of miR-495.

The mechanism of regulating macrophage polarization based on Notch1 signaling pathway to improve joint inflammation in adjuvant arthritis rats

Objective:To study the impact of the Notch1/Jagged1/RBP-Jκ/Hes1 signaling pathway on macrophage polarization and its role in modulating the inflammatory response in rats with adjuvant arthritis(AA).Methods:The rats were randomly divided into three groups(6 rats):the healthy group(NC),the model group(MC),and the Notch1 inhibitor group(FLI).Medication was administered after 12 days of inducing inflammation.After 30 days,the arthritis index(AI)and degree of swelling in the right hind foot joint(E)were measured in each group.The expression levels of CD80^(+)and CD163^(+)cells in peripheral blood macrophages of rats were analyzed by flow cytometry.The standards of IL-4,IL-10,IL-1β,and TNF-α in rat serum were gauged by Enzyme-linked immunosorbent assay.The expression of Notch1,Jagged1,RBP-Jκ,and Hes1 proteins in rat synovial tissue was detected using Western blot.Results:The degree of swelling(E)and arthritis index(AI)in the MC group rats with AA were significantly higher than those in the NC group(P<0.01).CD80^(+)cell expression was significantly higher compared to the control group(P<0.01),while CD163^(+)cell expression was significantly lower than the control group(P<0.01).IL-1βand TNF-α expression levels were significantly elevated(P<0.01),whereas IL-4 and IL-10 expression levels were significantly decreased(P<0.01).Notch1,RBP-Jκ,Jagged1,and Hes1 protein expression levels were significantly increased(P<0.01).In comparison to the MC group,the rats in the Notch1 inhibitor group exhibited a significant reduction in toe swelling and arthritis index(P<0.01).CD80^(+)cell expression was significantly decreased(P<0.01),while CD163+cell expression was significantly increased(P<0.01).IL-1β and TNF-α expression levels were significantly decreased(P<0.05),whereas IL-4 and IL-10 levels were significantly increased(P<0.01).Notch1,Jagged1,Hes1,and RBP-Jκ protein expression levels were significantly decreased(P<0.05).Correlation analysis revealed a positive association between CD80^(+)and Notch1,Jagged1,Hes1,and RBP-Jκ(P<0.01),while CD163^(+)showed a negative correlation with the expression of these proteins(P<0.01).Conclusion:The Notch1/Jagged1/RBP-Jκ/Hes1 signaling axis regulates macrophage polarization to M2 type and reduces inflammation in AA rats.

Xiaochaihu decoction alleviates viral pneumonia by regulating macrophage polarization

Background:In this investigation,we sought to evaluate the benefits of Xiaochaihu decoction(XCHD)on polyinosinic:polycytidylic acid-induced viral pneumonia in mice and elucidate its mechanisms of action.Method:A viral pneumonia model was established in mice using polyinosinic:polycytidylic acid,with mice being intragastrically administered different doses of XCHD.The benefits of XCHD therapy for mice with viral pneumonia were assessed by determining the weight ratio of lung tissue,wet-to-dry,overall protein concentrations,and total cell counts in bronchoalveolar lavage fluid,and hematoxylin and eosin staining of lung tissues.By determining the interleukin-1βlevels,interleukin-6,tumor necrosis factor-alpha,nitric oxide,interleukin-10,and interleukin-4,and the mRNA and protein expression of nitric oxide synthase 2,arginase-1,and macrophage mannose receptor 1 in bronchoalveolar lavage fluid,we assessed consequences of XCHD on macrophage polarization with mice suffering from viral pneumonia.Results:XCHD was found to significantly reduce lung tissue wet-to-dry and the total protein content and total number of cells of bronchoalveolar lavage fluid,while ameliorating pathological modifications to the lung tissues of rodents suffering from viral pneumonia,thereby indicating that this medicinal preparation has a healing impact on model mice with viral pneumonia.In addition,XCHD was found to reduce the magnitudes of interleukin-1β,interleukin-6,tumor necrosis factor-alpha,and nitric oxide and the mRNA and protein manifestation of nitric oxide synthase 2,and promote an increase in the levels of interleukin-10 and interleukin-4 and the mRNA and protein expression of arginase-1 and macrophage mannose receptor 1,thereby indicating that XCHD can favorably mediate polarization of macrophages in mice with viral pneumonia.Conclusion:XCHD has notable therapeutic effects on viral pneumonia in mice,the fundamental workings of action of which may be connected to regulation of macrophage polarization.

Macrophage membrane-mediated targeted drug delivery for treatment of spinal cord injury regardless of the macrophage polarization states

Targeted delivery of therapeutics for spinal cord injury(SCI)has been a long-term challenge due to the complexity of the pathological procession.Macrophage,as an immune cell,can selectively accumulate at the trauma site after SCI.This intrinsic targeting,coupled with good immune-escaping capacity makes macrophages an ideal source of biomimetic delivery carrier for SCI.Worth mentioning,macrophages have multiple polarization states,which may not be ignored when designing macrophage-based delivery systems.Herein,we fabricated macrophage membrane-camouflaged liposomes(RM-LIPs)and evaluated their abilities to extend drug circulation time and target the injured spinal cord.Specially,we detected the expression levels of the two main targeted receptors Mac-1 and integrinα4 in three macrophage subtypes,including unactivated(M0)macrophages,classically activated(M1)macrophages and alternatively activated(M2)macrophages,and compared targeting of these macrophage membrane-coated nanoparticles for SCI.The macrophage membrane camouflage decreased cellular uptake of liposomes in RAW264.7 immune cells and strengthened binding of the nanoparticle to the damaged endothelial cells in vitro.RM-LIPs can prolong drug circulation time and actively accumulate at the trauma site of the spinal cord in vivo.Besides,RM-LIPs loaded with minocycline(RM-LIP/MC)showed a comprehensive therapeutic effect on SCI mice,and the anti-pyroptosis was found to be a novel mechanism of RM-LIP/MC treatment of SCI.Moreover,the levels of Mac-1 and integrinα4 in macrophages and the targeting of RM-LIP for SCI were found to be independent of macrophage polarization states.Our study provided a biomimetic strategy via the biological properties of macrophages for SCI targeting and treatment.

Regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease

BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).Various studies have shown that PPAR-γexerts potent anti-inflammatory and immunomodulatory properties.However,little is known about the regulation of PPAR-γactivity in modulating cell crosstalk in NAFLD.AIM To investigate whether the regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation.METHODS Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocytespecific PPAR-γknockout mice and incubated with free fatty acids(FFAs).Macrophages were incubated with conditioned medium(CM)from lipid-laden hepatocytes with or without a PPAR-γagonist.Wild-type C57BL/6J mice were fed a high-fat(HF)diet and administered rosiglitazone.RESULTS Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs.CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway.A PPAR-γagonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization.Hepatocyte-specific PPAR-γdeficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes,which further promoted M1 macrophage polarization.Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.CONCLUSION Upregulation of PPAR-γactivity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1βpathway.

Experimental study of TGF-β1/Smads pathway inhibition of macrophage polarization based on miR145-5P negative feedback regulation

imbalance of synovial macrophages in patients with rheumatoid arthritis(RA).Methods:Human mononuclear cells(THP‑1)at logarithmic growth stage were induced into M1‑type macrophages,and RA synovial fibroblasts M1‑type macrophages were co‑cultured into synovial macrophages.Synovial macrophages were divided into four groups:RA group(blank group),TGF‑β1 group(model group)and miR145‑5P overexpression group(TGF‑β1+miR145‑5P mimics group)and miR145‑5P overexpression negative control group(TGF‑β1+miR145‑5P‑mimics‑NC group).The blank group did not receive any treatment,and the other three groups were induced by TGF‑β1 in the medium for 48 h.Transfection miR145‑5p mimic and miR145‑5P‑mimics‑NC were added to co‑culture medium,and IL‑6,IL‑6 and IL‑6 of synovial macrophages were detected by ELISA.CD163 expression.Rt‑qpcr was used to detect miR145‑5p mRNA,TGF‑β1mRNA,Smad3mRNA,Smad7mRNA expression level.The expression of TGF‑β1/Smads pathway related proteins was detected by Western Blotting.Results:Compared with blank group,IL‑6 level was up‑regulated(P<0.01),and CD163 level was down‑regulated in model group(P<0.05),suggesting that TGF‑β1 could induce intensified immune inflammatory response.Compared with the negative miR145‑5P overexpression control group and model group,The expression of miR145‑5P overexpression group molecule CD163 was significantly increased by ELISA(P<0.01),and the expression of inflammatory factor IL‑6 was decreased(P<0.05).PCR showed that miR145‑5P mRNA expression level was significantly increased in miR145‑5P overexpression group,Smad3 mRNA and TGF‑β1 mRNA were significantly decreased,and Smad7 mRNA was significantly increased(P<0.01).WB method showed that the anti‑inflammatory protein Smad7 was significantly increased,while TGF‑β1 and Smad3 were significantly decreased(P<0.01).Transwell chamber results confirmed that miR145‑5P overexpression group significantly reduced macrophage invasion(P<0.01).Correlation analysis showed that miR145‑5P was negatively correlated with Smad3 and positively correlated with Smad7(P<0.01).Conclusion:miR145‑5P may inhibit macrophage polarization in RA patients by targeting Smad3 protein,negatively regulating TGF‑β1/Smads pathway,and alleviating immune inflammation.

Correlation analysis of changes in miR145‑5p/Smads pathway and macrophage polarization in adjuvant arthritis rats

Objective:To explore the relationship between the changes of miR145‑5p/Smads pathway and macrophage polarization in adjuvant arthritis rats.Methods:Twelve rats were divided into normal group and model group induced by freund's complete adjuvant(0.1 mL/mouse)by random number table method,with 6 rats in each group.The expression of inflammatory polarization markers IL‑8 and CD206 in synovial tissue was detected by enzyme‑linked immunosorbent assay on the 12th day after the formation of arthritis in rats.Western blotting was used to detect the expression of TGF‑β1/Smads pathway factors in synovial tissues.The expression of miR145‑5P,Smads3 and Smads7 in synovial tissue was detected by RT‑qPCR.Results:Compared with normal group,the expression levels of IL‑8,TGF‑β1 and Smad3 in model group were significantly increased(P<0.05);The expression levels of CD206,Smad7 and miR145‑5P were significantly decreased(P<0.01).The correlation results showed that IL‑8 was positively correlated with Smad3(P<0.01),IL‑8 was negatively correlated with Smad7(P<0.05),CD206 was negatively correlated with Smad3(P<0.01)and positively correlated with Smad7(P<0.05).miR145‑5p was negatively correlated with Smad3(P<0.01)and positively correlated with Smad7(P<0.01).Conclusion:miR145‑5p may inhibit the overactivation of TGF‑β1/Smads pathway,regulate macrophage polarization,and inhibit the development of adjuvant arthritis by inhibiting Smad3 expression.

Macrophage polarization in nerve injury： do Schwann cells play a role？

In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in peripheral nerve injury, clearing debris and regulating the microenvironment to allow for efficient regeneration. There are several cells within the microenvironment that likely interact with macrophages to support their function – most notably the Schwann cell, the glial cell of the peripheral nervous system. Schwann cells express several ligands that are known to interact with receptors expressed by macrophages, yet the effects of Schwann cells in regulating macrophage phenotype remains largely unexplored. This review discusses macrophages in peripheral nerve injury and how Schwann cells may regulate their behavior.

Sequential dual-locking strategy using photoactivated Pt(Ⅳ)-based metallo-nano prodrug for enhanced chemotherapy and photodynamic efficacy by triggering ferroptosis and macrophage polarization

Selective activation of Pt(Ⅳ)prodrugs within tumors has emerged as a promising strategy in tumor treatment.Although progress has been made with photo-and ultrasound-activated Pt(Ⅳ)prodrugs,concerns remain over the non-specific activation of photosensitizers(PS)and the potential for phototoxicity and chemical toxicity.In this study,a sequential dual-locked Pt(Ⅳ)nano-prodrug that can be activated by both the acidic tumor microenvironment and light was developed.The Pt(Ⅳ)prodrug was prepared by conjugating PS-locked Pt(Ⅳ)to a polymeric core,which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug.Under acidic tumor microenvironment conditions,the metallo-nano prodrug undergoes dissociation of iron,triggering a reduction process in oxaliplatin under light irradiation,resulting in the activation of both chemotherapy and photodynamic therapy(PDT).Additionally,the prodrug could induce metallo-triggered ferroptosis and polarization of tumorassociated macrophages(TAM),thereby enhancing tumor inhibition.The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs,making it a promising new direction in cancer treatment.

Metal-organic framework and its composites modulate macrophage polarization in the treatment of inflammatory diseases

Metal-organic framework(MOF)is a periodic sexual network structure with large surface area and high porosity,which is assembled by inorganic nodes and organic ligands through coordinate covalent bond.MOFs have the advantages of controllable pore size and shape,large specific surface area,easy modification and more active sites.In addition,MOF based nanoenzymes display excellent enzyme catalytic activity due to their special structure and multiple exposed metal active sites,controlling the production of reactive oxygen species(ROS)in cells or the body,and thus regulating the polarization of macrophage.This article reviews the mechanism of MOF material regulating macrophage polarization and the function of macrophages with different phenotypes.By utilizing the excellent properties of MOFs and the advantages of combining them with bioactive materials,we have discovered their excellent applications in the treatment of inflammatory diseases.Finally,we discussed the current challenges and prospects faced by MOF based composite materials.We expect that the research in this developing field will play a more important role in combating inflammatory diseases in the field of nanomedicine.

Inhibition of M2 tumor-associated macrophages polarization by modulating the Wnt/β-catenin pathway as a possible liver cancer therapy method

The problem of liver cancer is becoming increasingly important due to the epi-demic of metabolic diseases and persistent high alcohol consumption.This deter-mines great attention to the development and improvement of methods for early diagnosis and treatment of liver cancer.Huang et al presented a study in the World Journal of Gastroenterology,in which they showed that the use of the traditional Chinese medicine Calculus bovis(CB)can suppress tumor growth in mice by inhibiting M2 tumor-associated macrophages(TAM)through modulating the activity of the Wnt/β-catenin pathway.The interaction of CB components with the Wnt/β-catenin pathway,M2 TAM polarization,and tumor dynamics were studied using network pharmacology,transcriptomics,and molecular docking.It is now generally accepted that the polarization of TAM and the differentiation of the functions of M1 and M2 phagocytes are of great importance for the progression of neoplasms.It is assumed that M2 TAM promote proliferation and migration of tumor cells.Attempts to medicinally influence the Wnt/β-catenin pathway in order to modulate phagocyte polarization now belong to one of the most promising areas of immunotherapy of oncological diseases.Undoubtedly,the work of the Chinese authors deserves attention and further development.

Mesenchymal Stem Cells Alleviate Acute Liver Failure through Regulating Hepatocyte Apoptosis and Macrophage Polarization

Background and Aims:Acute liver failure(ALF)is a life-threatening clinical problem with limited treatment options.Administration of human umbilical cord mesenchymal stem cells(hUC-MSCs)may be a promising approach for ALF.This study aimed to explore the role of hUC-MSCs in the treat-ment of ALF and the underlying mechanisms.Methods:A mouse model of ALF was induced by lipopolysaccharide and d-galactosamine administration.The therapeutic effects of hUC-MSCs were evaluated by assessing serum enzyme activity,histological appearance,and cell apoptosis in liver tissues.The apoptosis rate was analyzed in AML12 cells.The levels of inflammatory cytokines and the phenotype of RAW264.7 cells co-cultured with hUC-MSCs were detected.The C-Jun N-terminal kinase/nuclear factor-kappa B signal-ing pathway was studied.Results:The hUC-MSCstreatment decreased the levels of serum alanine aminotransferase and aspartate aminotransferase,reduced pathological damage,alleviated hepatocyte apoptosis,and reduced mortality in vivo.The hUC-MSCs co-culture reduced the apoptosis rate of AML12 cells in vitro.Moreover,lipopolysaccharide-stimulated RAW264.7 cells had higher levels of tumor necrosis factor-α,interleukin-6,and interleukin-1β and showed more CD86-positive cells,whereas the hUC-MSCs co-culture reduced the levels of the three inflammatory cytokines and increased the ratio of CD206-positive cells.The hUC-MSCs treatment inhibited the activation of phosphorylated(p)-C-Jun N-terminal kinase and p-nuclear factor-kappa B not only in liver tissues but also in AML12and RAW264.7 cells co-cultured with hUC-MSCs.Conclusions:hUC-MSCs could alleviate ALF by regulating hepatocyte apoptosis and macrophage polarization,thus hUC-MSC-based cell therapy may be an alternative option for patients with ALF.

FAM53B promotes pancreatic ductal adenocarcinoma metastasis by regulating macrophage M2 polarization

BACKGROUND Our study investigated the role of FAM53B in regulating macrophage M2 polarization and its potential mechanisms in promoting pancreatic ductal adenocarcinoma(PDAC)metastasis.AIM To further investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism in promoting PDAC metastasis.Our goal is to determine how FAM53B affects macrophage M2 polarization and to define its underlying mechanism in PDAC metastasis.METHODS Cell culture and various experiments,including protein analysis,immunohisto-chemistry,and animal model experiments,were conducted.We compared FAM53B expression between PDAC tissues and healthy tissues and assessed the correlation of FAM53B expression with clinical features.Our study analyzed the role of FAM53B in macrophage M2 polarization in vitro by examining the expression of relevant markers.Finally,we used a murine model to study the role of FAM53B in PDAC metastasis and analyzed the potential underlying mechanisms.RESULTS Our research showed that there was a significant increase in FAM53B levels in PDAC tissues,which was linked to adverse tumor features.Experimental findings indicated that FAM53B can enhance macrophage M2 polarization,leading to increased anti-inflammatory factor release.The results from the mouse model further supported the role of FAM53B in PDAC metastasis,as blocking FAM53B prevented tumor cell invasion and metastasis.CONCLUSION FAM53B promotes PDAC metastasis by regulating macrophage M2 polarization.This discovery could lead to the development of new strategies for treating PDAC.For example,interfering with the FAM53B signaling pathway may prevent cancer spread.Our research findings also provide important information for expanding our understanding of PDAC pathogenesis.

Wedelolactone attenuates sepsis-associated acute liver injury by regulating the macrophage M1/M2 polarization balance through the PI3K/AKT/NF-κB signalling pathway

Background:Liver injury caused by sepsis seriously impairs the normal physiology of the liver.Wedelactone(WED)has an obvious anti-inflammatory effect against liver damage caused by various factors.Nevertheless,further research is needed to determine if WED might mitigate acute liver damage linked to sepsis by influencing macrophage polarization.Methods:We first assessed the effect of WED on lipopolysaccharides-triggered liver injury by biochemistry assay and tissue staining.Inflammatory factors were assessed using the ELISA kits.The expression of Cluster of Differentiation 86(CD86)and Cluster of Differentiation 206(CD206)was measured by immunofluorescence assay.The protein levels of inducible nitric oxide sythase(iNOS),Arginase 1(Arg-1),phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT),PI3K phosphorylation(p-PI3K),AKT phosphorylation(p-AKT),inhibitor of kappa B kinase(IKK),inhibitor of kappa B(IκB),and nuclear factor kappa-B(NF-κB)p65 were quantified by western blot analysis.Results:WED decreased the level of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP)and malondialdehyde,and increased the activity of superoxide dismutase(SOD)and glutathione peroxidase(GSH-PX).Moreover,WED exerted effective anti-inflammatory effects by decreasing the level of Tumor necrosis factor-α(TNF-α)and Interleukin 6(IL-6)and increasing the level of Interleukin 10(IL-10)in serum and cells.WED not only decreased CD86 and iNOS expression but also increased CD206 and Arg-1 expression.WED also downregulated the increased expression of PI3K,AKT,p-PI3K,p-AKT,IKK,and NF-κB p65 induced by lipopolysaccharides,while up-regulated the decreased expression of IκB.Besides,LY294002 with WED decreased the expression of protein PI3K,AKT,p-PI3K,p-AKT,IKK and NF-κB p65,and raised the expression of IκBα.Conclusion:Wedelolactone could attenuate sepsis-associated acute liver injury,and its mechanism may be associated with balancing pro-inflammatory and anti-inflammatory by the regulation of M1/M2 macrophage polarization via the PI3K/AKT/NF-κB signaling pathway.

Electrospun naringin-loaded microsphere/sucrose acetate isobutyrate system promotes macrophage polarization toward M2 and facilitates osteoporotic bone defect repair

Repairing osteoporotic bone defects is still a major clinical challenge.Recent studies have revealed that immune response is also essential in osteogenesis.The intrinsic inflammatory response of the host,especially the M1/M2 polarization status and inflammatory secretory function of macrophages,can directly affect osteogenic differentiation.Therefore,in this study,an electrospun naringin-loaded microspheres/sucrose acetate isobutyrate(Ng-m-SAIB)system was constructed to investigate its effect on the polarization of macrophage and osteoporotic bone defects.The results of both in vitro and in vivo experiments showed that Ng-m-SAIB had good biocompatibility and could promote the polarization of macrophage toward M2,thereby forming a favorable microenvironment for osteogenesis.The animal experiments also showed that Ng-m-SAIB could promote the osteogenesis of critical size defects in the skull of the osteoporotic model mouse(the senescence-accelerated mouse-strain P6).Together,these results collectively suggested that Ng-m-SAIB might be a promising biomaterial to treat osteoporotic bone defects with favorable osteo-immunomodulatory effects.

Discovery of novel aporphine alkaloid derivative as potent TLR2 antagonist reversing macrophage polarization and neutrophil infiltration against acute inflammation

Toll-like receptor 2(TLR2)mediated macrophages regulate the protective immune response to infectious microorganisms,but the aberrant activation of macrophages often leads to pathological inflammation,including tissue damage.In this study,we identified antagonists of TLR2 by screening2100 natural products and subsequently identified Taspine,an aporphine alkaloid,as an excellent candidate.Furthermore,analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6,which has higher activity,better solubility,and improved drug-feasible property.Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs,hindered the formation of TLR2/MyD88 complex,and blocked the downstream NF-κB and MAPK signaling pathway,thus suppressing the release of inflammatory cytokines.SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kdof 0.18μmol/L.Additionally,SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization,reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis.Collectively,we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property,thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.