Ming Yang

Bio: Ming Yang is an academic researcher from University of Missouri. The author has contributed to research in topics: Nonalcoholic fatty liver disease & Hepatic stellate cell. The author has an hindex of 2, co-authored 5 publications receiving 16 citations.

Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response.

Abstract: Background Minimally invasive radiofrequency ablation (RFA) is used as a first-line treatment option for hepatocellular cancer (HCC) with the weaknesses of incomplete ablation, tumor recurrence, and inferior outcomes. To overcome this limitation, we proposed to develop sunitinib-RFA integrated therapy with a potential of activating anti-HCC immune response. Methods Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib–RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by HE immune reaction was defined by flow cytometry; and signaling molecules were examined with real-time PCR (qPCR), western blot, and immunohistochemical staining. Results A significantly reduced tumor growth and extended lift span were observed in the mice receiving combined treatment with RFA and sunitinib. This combined treatment significantly increased the frequency of CD8+ T cell, memory CD8+ T cell, and dendritic cells (DCs); decreased the frequency of regulatory T cells; and activated tumor-specific antigen (TSA) immune response in tumor microenvironment. We found that RFA caused PD-1 upregulation in tumor-infiltrated T cells by boosting hepatocyte growth factor (HGF) expression, which was suppressed by sunitinib treatment. We have also demonstrated that sunitinib suppressed VEGF’s effect in enhancing PD-L1 expression in DCs and attenuated heat-sink effect. The results indicate that RFA induced tumor destruction and release of in situ TSAs which can activate a tumoricidal immune response in sunitinib-treated mice, significantly improving anti-HCC therapeutic efficacy. Conclusions Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib–RFA as a synergistic therapeutic approach significantly suppresses HCC growth.

Current Options and Future Directions for NAFLD and NASH Treatment

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, there is no currently approved treatment. NAFLD accounts as a major causing factor for the development of hepatocellular carcinoma (HCC), and its incidence rises accompanying the prevalence of obesity and diabetes. Reprogramming of antidiabetic and anti-obesity medicine is a major treatment option for NAFLD and NASH. Liver inflammation and cellular death, with or without fibrosis account for the progression of NAFLD to NASH. Therefore, molecules and signaling pathways involved in hepatic inflammation, fibrosis, and cell death are critically important targets for the therapy of NAFLD and NASH. In addition, the avoidance of aberrant infiltration of inflammatory cytokines by treating with CCR antagonists also provides a therapeutic option. Currently, there is an increasing number of pre-clinical and clinical trials undergoing to evaluate the effects of antidiabetic and anti-obesity drugs, antibiotics, pan-caspase inhibitors, CCR2/5 antagonists, and others on NAFLD, NASH, and liver fibrosis. Non-invasive serum diagnostic markers are developed for fulfilling the need of diagnostic testing in a large amount of NAFLD cases. Overall, a better understanding of the underlying mechanism of the pathogenesis of NAFLD is helpful to choose an optimized treatment.

G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a broad-spectrum disease, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and liver cancer. Abnormal hepatic lipid accumulation is the major manifestation of this disease, and lipotoxicity promotes NAFLD progression. In addition, intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins, resulting in progression of NAFLD to fibrosis and even cirrhosis. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD and obesity, through their function as receptors for bile acids and free fatty acids. In addition, GPCRs link gut microbiota-mediated connections in a variety of diseases, such as intestinal diseases, hepatic steatosis, diabetes, and cardiovascular diseases. The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids. GPCR agonists, including peptides and natural products like docosahexaenoic acid, have been applied to investigate their role in liver diseases. Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome. This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment. Overall, understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.

Gut microbiota mediated molecular events and therapy in liver diseases

Abstract: Gut microbiota is a community of microorganisms that reside in the gastrointestinal tract. An increasing number of studies has demonstrated that the gut-liver axis plays a critical role in liver homeostasis. Dysbiosis of gut microbiota can cause liver diseases, including nonalcoholic fatty liver disease and alcoholic liver disease. Preclinical and clinical investigations have substantiated that the metabolites and other molecules derived from gut microbiota and diet interaction function as mediators to cause liver fibrosis, cirrhosis, and final cancer. This effect has been demonstrated to be associated with dysregulation of intrahepatic immunity and liver metabolism. Targeting these findings have led to the development of novel preventive and therapeutic strategies. Here, we review the cellular and molecular mechanisms underlying gut microbiota-mediated impact on liver disease. We also summarize the advancement of gut microbiota-based therapeutic strategies in the control of liver diseases.

Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity

Abstract: Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD and identifying therapeutic targets, no therapeutic agent has been approved. Astaxanthin (ASTN), a natural antioxidant product, exerts an anti-inflammation and anti-fibrotic effect in mice induced with carbon tetrachloride (CCl4) and bile duct ligation (BDL); thus, we proposed to further investigate the potential effect of ASTN on a diet-induced mouse NASH and liver fibrosis, as well as the underlying cellular and molecular mechanisms. By treating pre-development of NASH in mice induced with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), we have demonstrated that oral administration ASTN preventively ameliorated NASH development and liver fibrosis by modulating the hepatic immune response, liver inflammation, and oxidative stress. Specifically, ASTN treatment led to the reduction in liver infiltration of monocyte-derived macrophages, hepatic stellate cell (HSC) activation, oxidative stress response, and hepatocyte death, accompanied by the decreased hepatic gene expression of proinflammatory cytokines such as TNF-α, TGF-β1, and IL-1β. In vitro studies also demonstrated that ASTN significantly inhibited the expression of proinflammatory cytokines and chemokine CCL2 in macrophages in response to lipopolysaccharide (LPS) stimulation. Overall, in vivo and in vitro studies suggest that ASTN functions as a promising therapeutic agent to suppress NASH and liver fibrosis via modulating intrahepatic immunity.

Turning cold tumors into hot tumors by improving T-cell infiltration.

Abstract: Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has greatly improved the clinical efficacy of malignant tumor therapy. ICI-mediated antitumor responses depend on the infiltration of T cells capable of recognizing and killing tumor cells. ICIs are not effective in "cold tumors", which are characterized by the lack of T-cell infiltration. To realize the full potential of immunotherapy and solve this obstacle, it is essential to understand the drivers of T-cell infiltration into tumors. We present a critical review of our understanding of the mechanisms underlying "cold tumors", including impaired T-cell priming and deficient T-cell homing to tumor beds. "Hot tumors" with significant T-cell infiltration are associated with better ICI efficacy. In this review, we summarize multiple strategies that promote the transformation of "cold tumors" into "hot tumors" and discuss the mechanisms by which these strategies lead to increased T-cell infiltration. Finally, we discuss the application of nanomaterials to tumor immunotherapy and provide an outlook on the future of this emerging field. The combination of nanomedicines and immunotherapy enhances cross-presentation of tumor antigens and promotes T-cell priming and infiltration. A deeper understanding of these mechanisms opens new possibilities for the development of multiple T cell-based combination therapies to improve ICI effectiveness.

Impact of COVID-19 in liver disease progression

Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus disease 19 (COVID-19), which has infected millions of people worldwide in only a few months. A minority, but significant number, of infected individuals require hospitalization and intensive care. From the start of this new virus pandemic, it was apparent that obese and/or diabetic individuals had a bad prognosis for COVID-19 progression, strongly suggesting an association between liver disease and severe COVID-19. Because chronic liver disease (CLD) is associated with immune dysregulation and inflammation, it is unsurprising that patients with CLD may carry a greater risk of adverse outcomes following SARS-CoV-2 infection. Initial COVID-19 data have also indicated that healthy infected individuals display abnormal liver function tests, suggesting a possible direct implication of SARS-CoV-2 in liver damage. Here we show that COVID-19 affects the liver metabolism and increases the morbidity and mortality of individuals with underlying CLD.

Cancer Immunology and Immunotherapy

Abstract: The study of molecular and cellular interplays between immune system and cancerous cells is gaining tremendous momentum across the globe. Concomitantly, with the better insight into the intricacies of cancer immunology, immunotherapeutic approaches to deal with cancer have garnered tremendous boost in the recent past; reckoning with these, it is timely to analyse their potentialities either as standalone stratagem or in conjunction with traditional cancer therapeutic modalities. The comprehensive review by M. L. Santangelo et al. entitled “Immunosuppression and Multiple Primary Malignancies in Kidney-Transplanted Patients: A Single-Institute Study” provides an overview of immunotherapeutic interventions for metastatic renal cell carcinoma (RCC) as well as updating the readers on the recent developments in the field. Further, the article entitled “Immunotherapy for Bone and Soft Tissue Sarcomas” by T. Uehara et al. enlightens the readers on immunotherapeutic strategies against bone and soft tissue sarcomas and metastatic prostate cancer under various stages of trials, besides highlighting their roles as an adjunct to traditional therapeutic modalities. Natural killer (NK) cells have long been hypothesized to play a pivotal role in the development of new immunotherapeutic strategies to combat variety of cancers. In this regard, the article titled “‘Adherent' versus Other Isolation Strategies for Expanding Purified, Potent, and Activated Human NK Cells for Cancer Immunotherapy” by S. R. Selvan and J. P. Dowling introduces a simple methodology for isolation and expansion of NK cells for adoptive cell therapies. Moreover, the researchers also equate potentialities of the newly introduced method with various published protocols to underline its effectiveness thereof. In the arena of NK cell based immunotherapies, the article “NKG2D and DNAM-1 Ligands: Molecular Targets for NK Cell-Mediated Immunotherapeutic Intervention in Multiple Myeloma” by C. Fionda et al. has come up with satisfactory results to further potentiate NK cell based immunotherapies. In their article of this special issue, the authors collate and discuss the molecular pathways whereby various chemotherapeutic agents could regulate the expression of NK cell activating ligands in multiple myeloma cells. Further, in a manner similar to NK cells, dendritic cells are also exploited in adoptive cell therapies; the manuscript “Dendritic Cell-Based Immunotherapy Treatment for Glioblastoma Multiforme” by L. Yang et al. discusses DCs based immunotherapeutic interventions for glioblastoma multiforme. It is in general consensus that immunodeficiencies are associated with higher risk of cancer susceptibility; nevertheless, there remains paucity of reports on the association of immunodeficiencies with the development of multiple primary malignancies. In this regard, the study by R. Raman and D. Vaena illuminated the relationship between immunodeficiency status of the patient, related to kidney transplant in particular, and occurrence of multiple primary malignancies; nonetheless, further evidences are required to firmly establish the linkages between immune status of the recipient and its correlation with incidences of malignancy. With continuous efforts laid down to better dissect the interplay between immune system and tumors, significant progresses have been made in the recent past, albeit much have been unveiled; nevertheless, the drive continues to explore more and more. To this end, the manuscript by N. Vigneron provides a better insight into the ins and outs of tumor-immune system interrelationships highlighting the recent understandings gained in the field. Further, the article by S. Stigliani et al. suggests that expressions of FOXP3, CD14, and ARG1 in neuroblastoma tumor tissue from high-risk patients are significantly associated with event-free and overall survival. Besides, C. Li et al. investigate the association of CXCL13 (C-X-C motif chemokine 13) with hepatocellular carcinoma (HCC) and the authors further suggest that the correlation of CXCL13 with progression of HCC is related to the activation of Wnt/β-catenin pathway and the facilitation of IL-12, IL-17, and IgG4. Ascertaining their role in progression of HCC, the authors anticipate that CXCL13 could be a potential target for the diagnosis and treatment of HCC. Further, the report by A. Curioni-Fontecedro et al. highlights the intratumoral heterogeneity of MAGE-C1/CT7 and MAGE-C2/CT10 expression in mucosal melanoma. The article by Y. Nishimura et al. investigates the immunological effects of asbestos exposure and analyzes immune functions of patients with mesothelioma, thereby signifying that there occurs functional alteration in natural killer cells and cytotoxic T lymphocytes upon asbestos exposure as well as in malignant mesothelioma patients, while the manuscript by Z. Liu et al. investigates the regulative effects of microRNA-451a (miR-451a) on cell proliferation and sensitivity to tamoxifen in breast cancer cells. Further, P. Johnson et. al. from Cancer Research UK Clinical Centre have highlighted that it is equally important to delineate the metrics that are appropriate to annotate the significance of new cancer therapeutics modalities. The study also provided an insight into the intricacies that are the same and further ascertains that the mean overall survival, cure fraction, and overall survival rate at landmark time points represent the more appropriate endpoints. The recent conceptual and technical footing of cancer immunology has paved ways to discover innovative cancer immunotherapies to treat and retard progression of the disease. It is widely accepted that the gamut of genetics and epigenetics changes occurring in tumors provides diverse set of antigenic repertoire that the immune system can exploit to distinguish tumor cells from their normal healthy counterparts. Moreover, studies continue to explore various genetic factors that increase the risk for cancer; the article by Y. Liu et al. studied the polymorphisms of nuclear factor-kappa B (NFκB) and its inhibitor (IκBα) and their synergistic outcome on nasopharyngeal carcinoma (NPC) predisposition. From their study, authors anticipate that genetic variants in NFκB1 (rs28362491del>ins ATTG) and IκBα (rs696G>A) and their synergistic outcome contribute to NPC susceptibility. Further, the manuscript by I. Silvestri et al. embarks on the importance of insight into the intricacies of antigenic peptide presentation in immunotherapy as well as in vaccine delivery. Reckoning with the recent efforts devoted to developing superior strategies to fight against various diseases, over the years, there has been great wave of enthusiasm regarding employment of immunomodulators to combat various untamed diseases. In fact the strategy is high on pharma agenda and various immunomodulators especially naturally derived agents have been explored against various ailments including cancer. Considering the impact of immunomodulators in the field on cancer immunotherapies, W.-J. Wang et al. illuminated the role of mushroom β-Glucan to immunomodulate tumor associated macrophages in Lewis Lung Carcinoma. Moreover, the article by A. Ito et al. updates the readers on the clinical development of immunomodulators or immune checkpoint inhibitors. Further, the manuscript by Q. Guo et al. delineates the effect and molecular mechanisms of traditional Chinese medicine (TCM) on regulating tumor immunosuppressive microenvironment (TIM) revealing bidirectional and multitargeting features of TCM on TIM. Finally, the pioneer work by O. Kurtenkov et al. for the first time revealed the fact that increased sialylation of anti-Thomsen-Friedenreich (TF) Antigen (CD176) antibodies is strongly linked to gastric cancer; reckoning with this, the authors anticipate that the important biomolecule can be employed as a novel biomarker for cancer detection and prognosis. Besides active regimens to control and cure one of the most dreadful diseases across the world, the immunological intervention to dissipate various forms of the cancer seems to be the promising ordeal. The timely coverage of the various cancer cells versus host immune system interplay by some of the leading experts of the field will certainly take us to the state of affairs that will offer a great input to control this important ailment. Mohammad Owais Swaleha Zubair Anshu Agrawal Yung-Fu Chang

Current Options and Future Directions for NAFLD and NASH Treatment

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, there is no currently approved treatment. NAFLD accounts as a major causing factor for the development of hepatocellular carcinoma (HCC), and its incidence rises accompanying the prevalence of obesity and diabetes. Reprogramming of antidiabetic and anti-obesity medicine is a major treatment option for NAFLD and NASH. Liver inflammation and cellular death, with or without fibrosis account for the progression of NAFLD to NASH. Therefore, molecules and signaling pathways involved in hepatic inflammation, fibrosis, and cell death are critically important targets for the therapy of NAFLD and NASH. In addition, the avoidance of aberrant infiltration of inflammatory cytokines by treating with CCR antagonists also provides a therapeutic option. Currently, there is an increasing number of pre-clinical and clinical trials undergoing to evaluate the effects of antidiabetic and anti-obesity drugs, antibiotics, pan-caspase inhibitors, CCR2/5 antagonists, and others on NAFLD, NASH, and liver fibrosis. Non-invasive serum diagnostic markers are developed for fulfilling the need of diagnostic testing in a large amount of NAFLD cases. Overall, a better understanding of the underlying mechanism of the pathogenesis of NAFLD is helpful to choose an optimized treatment.

Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies

Abstract: Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.