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Background Endoplasmic reticulum (ER) perturbations are novel subcellular effectors involved in the ischaemia‐reperfusion injury. As an ER stress‐inducible protein, mesencephalic astrocyte‐derived neurotrophic factor (MANF) has been proven to be increased during ischaemic brain injury. However, the role of MANF in liver ischaemia reperfusion (I/R) injury has not yet been studied. Methods To investigate the role of MANF in the process of liver ischaemia‐reperfusion, Hepatocyte‐specific MANF knockout (MANFhep−/−) mice and their wild‐type (WT) littermates were used in our research. Mice partial (70%) warm hepatic I/R model was established by vascular occlusion. We detected the serum levels of MANF in both liver transplant patients and WT mice before and after liver I/R injury. Recombinant human MANF (rhMANF) was injected into the tail vein before 1 hour occlusion. AST, ALT and Suzuki score were used to evaluate the extent of I/R injury. OGD/R test was performed on primary hepatocytes to simulate IRI in vitro. RNA sequence and RT‐PCR were used to detect the cellular signal pathway activation while MANF knockout. Results We found that MANF expression and secretion are dramatically up‐regulated during hepatic I/R. Hepatocyte‐specific MANF knockout aggravates the I/R injury through the over‐activated ER stress. The systemic administration of rhMANF before ischaemia has the potential to ameliorate I/R‐triggered UPR and liver injury. Further study showed that MANF deficiency activated ATF4/CHOP and JNK/c‐JUN/CHOP pathways, and rhMANF inhibited the activation of the two proapoptotic pathways caused by MANF deletion. Conclusion Collectively, our study unravels a previously unknown relationship among MANF, UPR and hepatic I/R injury.

Lung cancer is the leading cause of cancer death worldwide. Although diagnostic methods and targeted drugs have been rapidly developed in recent years, the underlying molecular mechanisms in the pathogenesis of lung cancer remain enigmatic. The N6‐methyladenosine (m6A) modification is the most common modification of messenger RNA in eukaryotes and plays critical roles in many diseases, especially cancers. Ectopic m6A modification is associated with human carcinogenesis, including lung cancer. The m6A modification is mediated by methyltransferases (writers) and demethylases (erasers) and indirectly affects biological processes through the recruitment of specific reader proteins (readers). Many studies have shown that m6A writers, erasers, and readers serve as specific and sensitive biomarkers for lung cancer diagnosis, prognosis, and therapy. This review summarizes recent studies on the biological functions of the m6A modification in lung cancer and discusses the potential application of m6A regulators in lung cancer diagnosis and therapeutics.

Long noncoding RNAs (lncRNAs) are defined as transcripts with more than 200 nucleotides that have little or no coding potential. In recent years, due to the development of next-generation sequencing (NGS), a large number of studies have revealed that lncRNAs function as key regulators to maintain immune balance and participate in diverse physiological and pathological processes in the human body. Notably, overwhelming evidence suggests that lncRNAs can regulate innate immune responses, the differentiation and development of immune cells, inflammatory autoimmune diseases, and many other immunological processes with distinct regulatory mechanisms. In this review, we summarized the emerging roles of lncRNAs in macrophage development and polarization. In addition, the potential value of lncRNAs as diagnostic biomarkers and novel therapeutic targets for the treatment of aberrant immune responses and inflammatory diseases are discussed.

Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible secreting protein, has evolutionarily conserved immune-regulatory function that contributes to the negative regulation of inflammation in macrophages. In this study, we investigated the profiles of MANF in the macrophages of the patients with active inflammatory bowel disease (IBD) and the mice with experimental colitis, which was induced in both myeloid cell-specific MANF knockout mice and wild-type mice by 3% dextran sodium sulfate (DSS) for 7 days. We found that MANF expression was significantly increased in intestinal macrophages from both the mice with experimental colitis and patients with active IBD. DSS-induced colitis was exacerbated in myeloid cell-specific MANF knockout mice. Injection of recombinant human MANF (rhMANF, 10 mg·kg–1·d–1, i.v.) from D4 to D6 significantly ameliorated experimental colitis in DSS-treated mice. More importantly, MANF deficiency in myeloid cells resulted in a dramatic increase in the number of Ly6ChiCX3CRint proinflammatory macrophages in colon lamina propria of DSS-treated mice, and the proinflammatory cytokines and chemokines were upregulated as well. Meanwhile, we demonstrated that MANF attenuated Th17-mediated immunopathology by inhibiting BATF2-mediated innate immune response and downregulating CXCL9, CXCL10, CXCL11 and IL-12p40; MANF functioned as a negative regulator in inflammatory macrophages via inhibiting CHOP-BATF2 signaling pathway, thereby protecting against DSS-induced mouse colitis. These results suggest that MANF ameliorates colon injury by negatively regulating inflammatory macrophage transformation, which shed light on a potential therapeutic target for IBD.