Pyroptosis in acute pancreatitis and its therapeutic regulation.

Pyroptosis defines a new type of GSDMs-mediated programmed cell death, distinguishes from the classical concepts of apoptosis and necrosis-mediated cell death and is prescribed by cell swelling and membrane denaturation, leading to the extensive secretion of cellular components and low-grade inflammatory response. However, NLRP3 inflammasome activation can trigger its downstream inflammatory cytokines, leading to the activation of pyroptosis-regulated cell death. Current studies reveal that activation of caspase-4/5/11-driven non-canonical inflammasome signaling pathways facilitates the pathogenesis and progression of acute pancreatitis (AP). In addition, a large number of studies have reported that NLRP3 inflammasome-dependent pyroptosis is a crucial player in driving the course of the pathogenesis of AP. Excessive uncontrolled GSDMD-mediated pyroptosis has been implicated in AP. Therefore, the pyroptosis-related molecule GSDMD may be an independent prognostic biomarker for AP. The present review paper summarizes the molecular mechanisms of pyroptotic signaling pathways and their pathophysiological impacts on the progress of AP. Moreover, we briefly present some experimental compounds targeting pyroptosis-regulated cell death for exploring novel therapeutic directions for the treatment and management of AP. Our review investigations strongly suggest that targeting pyroptosis could be an ideal therapeutic approach in AP.

Pyroptosis in diabetic nephropathy.

Diabetic nephropathy (DN), a sterile inflammatory disease, is a serious complication of diabetes mellitus. However, recent evidence indicates that pyroptosis, a new term for pro-inflammatory cell death featured by gasdermin D (GSDMD)-stimulated plasma membrane pore generation, cell expansion and rapid lysis with the extensive secretion of pro-inflammatory factors, including interleukin-1ß (IL-1ß) and -18 (IL-18) may be involved in DN. Caspase-1-induced canonical and caspase-4/5/11-induced non-canonical inflammasome-signaling pathways are mainly believed to participate in pyroptosis-mediated cell death. Further research has uncovered that activation of the caspase-3/8 signaling pathway may also activate pyroptosis. Accumulating evidence has shown that NLRP3 inflammasome activation plays a critical role in promoting the pathogenesis of DN. In addition, current studies have suggested that pyroptosis-induced cell death promotes several diabetic complications that include DN. Our present study briefs the cellular mechanisms of pyroptosis-related signaling pathways and their impact on the promotion of DN. In this review, several investigational compounds suppressing pyroptosis-mediated cell death are explored as promising therapeutics in DN.

Role of pyroptosis in cancer and its therapeutic regulation.

Pyroptosis is mainly considered a gasdermin-regulated cell death mechanism characterized by cellular lysis and the release of several pro-inflammatory factors. Nowadays, pyroptosis has notably been gained extensive attention from clinicians and researchers. However, current studies report that downregulation of pyroptosis-mediated cell death plays a significant role in developing multiple cancers. Increasing studies also suggest that pyroptosis can impact all stages of carcinogenesis. Inducing pyroptotic cellular death could be a promising therapeutic option for managing and regulating multiple cancers in the near future. Our current review highlights the molecular and morphological features of pyroptosis and its potential roles in various cancers. In addition, we have also highlighted the biological characteristics and significances of GSDMD and GSDME and their critical functions in cancer progression, management and regulation.

Cisplatin's potential for type 2 diabetes repositioning by inhibiting CDKN1A, FAS, and SESN1.

Cisplatin is a DNA-damaging chemotherapeutic agent used for treating cancer. Based on cDNA dataset analysis, we investigated how cisplatin modified gene expression and observed cisplatin-induced dysregulation and system-level variations relating to insulin resistance and type 2 diabetes mellitus (T2DM). T2DM is a multifactorial disease affecting 462 million people in the world, and drug-induced T2DM is a serious issue. To understand this etiology, we designed an integrative, system-level study to identify associations between cisplatin-induced differentially expressed genes (DEGs) and T2DM. From a list of differential expressed genes, cisplatin downregulated the cyclin-dependent kinase inhibitor 1 (CDKN1A), tumor necrosis factor (FAS), and sestrin-1 (SESN1) genes responsible for modifying signaling pathways, including the p53, JAK-STAT, FOXO, MAPK, mTOR, P13-AKT, Toll-like receptor (TLR), adipocytokine, and insulin signaling pathways. These enriched pathways were expressively associated with the disease. We observed significant gene signatures, including SMAD3, IRS, PDK1, PRKAA1, AKT, SOS, RAS, GRB2, MEK1/2, and ERK, interacting with source genes. This study revealed the value of system genetics for identifying the cisplatin-induced genetic variants responsible for the progression of T2DM. Also, by cross-validating gene expression data for T2DM islets, we found that downregulating IRS and PRK families is critical in insulin and T2DM signaling pathways. Cisplatin, by inhibiting CDKN1A, FAS, and SESN1, promotes IRS and PRK activity in a similar way to rosiglitazone (a popular drug used for T2DM treatment). Our integrative, network-based approach can help in understanding the drug-induced pathophysiological mechanisms of diabetes.

Designing of Potential Polyvalent Vaccine Model for Respiratory Syncytial Virus by System Level Immunoinformatics Approaches.

BACKGROUND: Respiratory syncytial virus (RSV) infection is a public health epidemic, leading to around 3 million hospitalization and about 66,000 deaths each year. It is a life-threatening condition exclusive to children with no effective treatment. METHODS: In this study, we used system-level and vaccinomics approaches to design a polyvalent vaccine for RSV, which could stimulate the immune components of the host to manage this infection. Our framework involves data accession, antigenicity and subcellular localization analysis, T cell epitope prediction, proteasomal and conservancy evaluation, host-pathogen-protein interactions, pathway studies, and in silico binding affinity analysis. RESULTS: We found glycoprotein (G), fusion protein (F), and small hydrophobic protein (SH) of RSV as potential vaccine candidates. Of these proteins (G, F, and SH), we found 9 epitopes for multiple alleles of MHC classes I and II bear significant binding affinity. These potential epitopes were linked to form a polyvalent construct using AAY, GPGPG linkers, and cholera toxin B adjuvant at N-terminal with a 23.9 kDa molecular weight of 224 amino acid residues. The final construct was a stable, immunogenic, and nonallergenic protein containing cleavage sites, TAP transport efficiency, posttranslation shifts, and CTL epitopes. The molecular docking indicated the optimum binding affinity of RSV polyvalent construct with MHC molecules (-12.49 and -10.48 kcal/mol for MHC classes I and II, respectively). This interaction showed that a polyvalent construct could manage and control this disease. CONCLUSION: Our vaccinomics and system-level investigation could be appropriate to trigger the host immune system to prevent RSV infection.

Role of Pyroptosis in Diabetes and Its Therapeutic Implications.

Pyroptosis is mainly considered as a new pro-inflammatory mediated-programmed cell death. In addition, pyroptosis is described by gasdermin-induced pore formation on the membrane, cell swelling and rapid lysis, and several pro-inflammatory mediators interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) release. Extensive studies have shown that pyroptosis is commonly involved by activating the caspase-1-dependent canonical pathway and caspase-4/5/11-dependent non-canonical pathway. However, pyroptosis facilitates local inflammation and inflammatory responses. Current researches have reported that pyroptosis promotes the progression of several diabetic complications. Emerging studies have suggested that some potential molecules targeting the pyroptosis and inflammasome signaling pathways could be a novel therapeutic avenue for managing and treating diabetes and its complications in the near future. Our narrative review concisely describes the possible mechanism of pyroptosis and its progressive understanding of the development of diabetic complications.

Role of pyroptosis in diabetic retinopathy and its therapeutic implications.

Pyroptosis has recently been established as a term of programmed-inflammatory cell death. Pyroptosis is mainly divided into two molecular signaling pathways, including caspase-1-dependent canonical and caspase-4/5/11-dependent non-canonical inflammasome pathways. Extensive investigations have reported inflammasome activation facilitates the maturation and secretion of the inflammatory factors interleukin-1ß/18 (IL-1ß/18), cleavage of gasdermin D (GSDMD), and leading to the stimulation of pyroptosis-mediated cell death. Furthermore, accumulating studies report NLRP3 inflammasome activation plays a significant role in triggering the pyroptosis-mediated cell death and promotes the pathogenesis of diabetic retinopathy (DR). Our current review elaborates on the molecular mechanisms of pyroptosis-signaling pathways and their potential roles in the pathogenesis and impact of DR development. We also emphasize several investigational molecules regulating key steps in pyroptotic-cell death to create new comprehensions and findings to explore the pathogenesis of DR advancement. Our narrative review concisely suggests these potential pharmacological agents could be promising therapies to treat and manage DR in the future.

Advances in immunotherapy for the treatment of spinal cord injury.

Spinal cord injury (SCI) is a leading cause of morbidity and disability in the world. Over the past few decades, the exact molecular mechanisms describing secondary, persistent injuries, as well as primary and transient injuries, have attracted massive attention to the clinicians and researchers. Recent investigations have distinctly shown the critical roles of innate and adaptive immune responses in regulating sterile neuroinflammation and functional outcomes after SCI. In past years, some promising advances in immunotherapeutic options have efficaciously been identified for the treatment of SCI. In our narrative review, we have mainly focused on the new therapeutic strategies such as the maturation and apoptosis of immune cells by several agents, mesenchymal stem cells (MSCs) as well as multi-factor combination therapy, which have recently provided novel ideas and prospects for the future treatment of SCI. This article also illustrates the latest progress in clarifying the potential roles of innate and adaptive immune responses in SCI, the progression and specification of prospective immunotherapy and outstanding issues in the area.

Role of pyroptosis in spinal cord injury and its therapeutic implications.

BACKGROUND: Currently, spinal cord injury (SCI) is a pathological incident that triggers several neuropathological conditions, leading to the initiation of neuronal damage with several pro-inflammatory mediators' release. However, pyroptosis is recognized as a new programmed cell death mechanism regulated by the stimulation of caspase-1 and/or caspase-11/-4/-5 signaling pathways with a series of inflammatory responses. AIM: Our current review concisely summarizes the potential role of pyroptosis-regulated programmed cell death in SCI, according to several molecular and pathophysiological mechanisms. This review also highlights the targeting of pyroptosis signaling pathways and inflammasome components and its therapeutic implications for the treatment of SCI. KEY SCIENTIFIC CONCEPTS: Multiple pieces of evidence have illustrated that pyroptosis plays significant roles in cell swelling, plasma membrane lysis, chromatin fragmentation and intracellular pro-inflammatory factors including IL-18 and IL-1ß release. In addition, pyroptosis is directly mediated by the recently discovered family of pore-forming protein known as GSDMD. Current investigations have documented that pyroptosis-regulated cell death plays a critical role in the pathogenesis of multiple neurological disorders as well as SCI. Our narrative article suggests that inhibiting the pyroptosis-regulated cell death and inflammasome components could be a promising therapeutic approach for the treatment of SCI in the near future.

Polyvalent therapeutic vaccine for type 2 diabetes mellitus: Immunoinformatics approach to study co-stimulation of cytokines and GLUT1 receptors.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a worldwide disease that have an impact on individuals of all ages causing micro and macro vascular impairments due to hyperglycemic internal environment. For ultimate treatment to cure T2DM, association of diabetes with immune components provides a strong basis for immunotherapies and vaccines developments that could stimulate the immune cells to minimize the insulin resistance and initiate gluconeogenesis through an insulin independent route. METHODOLOGY: Immunoinformatics based approach was used to design a polyvalent vaccine for T2DM that involved data accession, antigenicity analysis, T-cell epitopes prediction, conservation and proteasomal evaluation, functional annotation, interactomic and in silico binding affinity analysis. RESULTS: We found the binding affinity of antigenic peptides with major histocompatibility complex (MHC) Class-I molecules for immune activation to control T2DM. We found 13-epitopes of 9 amino acid residues for multiple alleles of MHC class-I bears significant binding affinity. The downstream signaling resulted by T-cell activation is directly regulated by the molecular weight, amino acid properties and affinity of these epitopes. Each epitope has important percentile rank with significant ANN IC50 values. These high score potential epitopes were linked using AAY, EAAAK linkers and HBHA adjuvant to generate T-cell polyvalent vaccine with a molecular weight of 35.6 kDa containing 322 amino acids residues. In silico analysis of polyvalent construct showed the significant binding affinity (- 15.34 Kcal/mol) with MHC Class-I. This interaction would help to understand our hypothesis, potential activation of T-cells and stimulatory factor of cytokines and GLUT1 receptors. CONCLUSION: Our system-level immunoinformatics approach is suitable for designing potential polyvalent therapeutic vaccine candidates for T2DM by reducing hyperglycemia and enhancing metabolic activities through the immune system.

Role of NLRP3 inflammasome in liver disease.

Inflammasomes have become an important natural sensor of host immunity, and can protect various organs against pathogenic infections, metabolic syndromes, cellular stress and cancer metastasis. Inflammasomes are intracellular multi-protein complexes found in both parenchymal and non-parenchymal cells, stimulating the initiation of caspase-1 and interleukin (IL)-1ß and IL-18 in response to cell danger signals. Inflammasomes induce cell death mechanisms. The potential role of NOD-like receptor protein 3 (NLRP3) inflammasome in alcoholic and non-alcoholic steatohepatitis, hepatitis, nanoparticle-induced liver injury and other liver diseases has recently attracted widespread attention from clinicians and researchers. In this review we summarize the role played by the NLRP3 inflammasome in molecular and pathophysiological mechanisms in the pathogenesis and progression of liver disease. This article aims to establish that targeting the NLRP3 inflammasome and other inflammasome components may make a significant therapeutic approach to the treatment of liver disease.

Experimental analysis of T cell epitopes for designing liver cancer vaccine predicted by system-level immunoinformatics approach.

Liver cancer is a worldwide disease, and, currently, due to the poor prognostic and therapeutic options of liver cancer, we investigated the T cell epitopes as potential therapeutic vaccine candidates to get the benefit of experimental processes and utilize the complete ability of the immune system compared with other artificial ex vivo proliferation of T cells. Activation of T cells targets and kills several tumors, developing a strong rationale for the improvement of immunotherapeutic strategies to cancer therapy. To predict T cell epitopes for liver cancer, we designed a comprehensive immunoinformatics framework involving data mining, immunogenicity prediction, functional proteomic analysis, conservation studies, molecular modeling, and in vivo validation analysis. We found the binding affinity of antigenic peptides with major histocompatibility complex (MHC) I molecules to control the cancerous activity. Five extracellular antigenic proteins, including complement protein (C6), serotransferrin, coagulation factor XIII B, serum albumin (ALB), and prothrombin, were identified. We predicted and synthesized T cell epitopes to human leukocytes antigen-A*01:01 allele of MHC class I molecule. The hematological assay and IgG ELISA showed that C6 and ALB epitopes induced the production of lymphocytes, granulocytes, and peptide-specific IgG in immunized rats. We observed substantial high levels of granzymes B in serum samples of C6 and ALB compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.NEW & NOTEWORTHY We observed substantial high levels of granzymes B in serum samples of component C6 (C6) and albumin (ALB) compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.

Role of pyroptosis in liver diseases.

Pyroptosis is known as a novel form of pro-inflammatory cell death program, which is exceptional from other types of cell death programs. Particularly, pyroptosis is characterized by Gasdermin family-mediated pore formation and subsequently cellular lysis, also release of several pro-inflammatory intracellular cytokines. In terms of mechanism, there are two signaling pathways involved in pyroptosis, including caspase-1, and caspase-4/5/11 mediated pathways. However, pyroptosis plays important roles in immune defense mechanisms. Recent studies have demonstrated that pyroptosis plays significant roles in the development of liver diseases. In our review, we have focused on the role of pyroptosis based on the molecular and pathophysiological mechanisms in the development of liver diseases. We have also highlighted targeting of pyroptosis for the therapeutic implications in liver diseases in the near future.

Antitumor activity and combined inhibitory effect of ceritinib with gemcitabine in pancreatic cancer.

Pancreatic cancer (PC) is predominantly incurable and is primarily treated with gemcitabine, but drug resistance commonly develops. Thus, new medicines are needed. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) with antitumor activity in various cancers. However, studies involving ceritinib for the treatment of PC are inadequate. We analyzed the combined effects of ceritinib and gemcitabine on PC and their mechanism of action. Three PC cell lines were used to evaluate the antitumor effects of ceritinib combined with gemcitabine. We analyzed cell viability using CCK-8 assays, determined apoptosis levels through flow cytometry, and analyzed autophagy and cell signaling pathways by Western blotting and tissue array analysis with samples from xenograft models. Ceritinib strongly inhibited the proliferation of PC cells in a dose-dependent manner, induced apoptosis, and inhibited autophagy and cell migration by regulating relevant factors. Ceritinib in combination with gemcitabine exhibited significant growth inhibition and additive antitumor effects in vitro. In vivo, gemcitabine and ceritinib reduced tumor size by up to 30%. In our study, ALK was shown to be highly expressed in various PC cells and tissues. Ceritinib strongly inhibited the levels of activated ALK in PC cells with subsequent effects on the downstream mediators STAT3, AKT, and ERK. In addition, ceritinib inhibited tumor progression in xenograft models. Overall, our research shows that ceritinib inhibits the ALK signaling pathway, leading to cell growth/angiogenesis inhibition in PC and the induction of apoptosis. We recommend using ceritinib as a new treatment for PC.NEW & NOTEWORTHY These data proved that ceritinib inhibits the anaplastic lymphoma kinase signaling pathway, leading to cell growth/angiogenesis inhibition and the induction of apoptosis by inhibiting STAT3, AKT, and ERK pathway in pancreatic cancer (PC). We recommend using ceritinib as a new treatment for PC.

Advances in immunomodulatory therapy for severe acute pancreatitis.

Severe acute pancreatitis (SAP) has a complex course and a worse prognosis. Immune response imbalance is an important cause of severe pancreatitis or even death in patients. Immunomodulation therapy can regulate the imbalance of inflammatory response, alleviate SAP-related organ damage and improve the prognosis of patients. There are some problems in early immune regulation measures, such as single target and simple way. In recent years, new treatment methods, such as regulating the maturation and apoptosis of immune cells, the application of mesenchymal stem cells (MSCs) and multifactor combination therapy, have provided new ideas and hope for the future treatment of SAP. This article reviews the development of SAP immunoregulation and its recent progress.

Current status of diagnosis and Mesenchymal stem cells therapy for acute pancreatitis.

Acute pancreatitis (AP) is an acute gastrointestinal disorder that is the most common and requiring emergency hospitalization. Its incidence is increasing worldwide, thus increasing the burden of medical services. Approximately 20% of the patients develop moderate to severe necrotizing pancreatitis associated with pancreatic or peri-pancreatic tissue necrosis and multiple organ failure. There are many reports about the anti-inflammatory effect of mesenchymal stem cells (MSCs) on pancreatitis and the repair of tissue damage. MSCs cells come from a wide range of sources, autologous MSCs come from bone marrow and allogeneic MSCs such as umbilical cord blood MSCs, placenta-derived MSCs, etc. The wide source is not only an advantage of MSCs but also a disadvantage of MSCs. Because of different cell sources and different methods of collection and preparation, it is impossible to establish a unified standard method for evaluation of efficacy. The biggest advantage of iMSCs is that it can be prepared by a standardized process, and can be prepared on a large scale, which makes it easier to commercialize. This paper reviews the present status of diagnosis and progress of MSCs therapy for AP.

Protective effects of maresin 1 against inflammation in experimentally induced acute pancreatitis and related lung injury.

Severe acute pancreatitis (SAP) is an inflammatory disorder that progresses with local and systemic difficulties accompanied by a relatively high mortality rate. In recent years, maresin 1 (MaR1) has been shown to be a macrophage mediator with effective proresolving and anti-inflammatory properties that prevents the occurrence of various inflammatory conditions. The purpose of this study was to investigate the role of MaR1 in SAP and related lung injury. Experimental SAP was induced in mice with a combination of cerulean and lipopolysaccharide. MaR1 was administered 30 min before the primary injection of cerulean. Biochemical markers and histological injury scores were used to evaluate the severity of acute pancreatitis. To determine the degree of inflammation, serum cytokines and myeloperoxidase activity in pancreas and lung tissues were measured. Western blot analysis detected the activation of NF-κB. After MaR1 pretreatment, the activities of amylase, lipase, TNF-α, IL-1ß, and IL-6 were decreased in serum, and the myeloperoxidase activity both in pancreas and in lung tissues significantly decreased, whereas the activity of anti-inflammatory cytokine IL-10 in serum was increased. MaR1-pretreated mice reduced the activation of pancreatic NF-κB and decreased the severity of pancreatic and lung-related injuries. These results confirm that MaR1 alleviated inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimentally induced acute pancreatitis and exerted anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of SAP.NEW & NOTEWORTHY These results provided us evidence to confirm that maresin 1 (MaR1) can alleviate inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimental induced acute pancreatitis and exerts certain anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of severe acute pancreatitis.

Autophagy regulates proliferation and biliary differentiation of hepatic oval cells via the MAPK/ERK signaling pathway.

Hepatic oval cells (HOCs) are thought to possess self­renewal ability and a bipotential capacity for differentiation, which allows them to differentiate into hepatocytes and cholangiocytes. Autophagy serves an important role in self­renewal and differentiation of stem cells; however, how autophagy contributes to proliferation and differentiation of hepatic progenitor cells has yet to be elucidated. In the present study, autophagy was regulated by rapamycin (Rapa) and chloroquine (Chlo) administration. The results demonstrated that Chlo­treated HOCs exhibited decreased autophagic activity alongside a decreased tendency to proliferate, as determined by Cell Counting Kit­8. In addition, activation of autophagy by Rapa enhanced the biliary differentiation of HOCs. Furthermore, increased phosphorylated (p)­extracellular signal­regulated kinase (ERK)/p­p38 expression was observed following the induction of autophagy, thus indicating that the mitogen­activated protein kinase (MAPK)/ERK signaling pathway was activated by autophagy to exert effects on the stimulation of HOC proliferation and differentiation. In conclusion, the present study demonstrated that autophagy regulates proliferation and biliary differentiation of HOCs via the MAPK/ERK signaling pathway. These results suggest a role for autophagy in stimulating the proliferation and differentiation of HOCs.