Gliomas are the most prevalent primary neoplasms of the central nervous system and arise from glial cells present in the brain or spinal cord. N6-methyladenosine (m6A) is one of the most frequently occurring modifications in RNA, and its potential implications in glioma have received widespread attention in recent years. In glioma, m6A-related enzymes are capable of modifying target RNAs, influencing their translation, degradation, and splicing, which can promote or inhibit biological processes such as ferroptosis and glycolysis, ultimately impacting the progression of glioma. Furthermore, upstream modulators are capable of regulating the expression of m6A-associated enzymes, ultimately affecting glioma development by modulating m6A modification on target RNAs. In addition, the m6A modification influences glioma resistance to temozolomide, resulting in an impact on glioma patient survival. This review comprehensively delineates the molecular mechanisms by which m6A and its upstream signaling molecules regulate glioma development, emphasizing their potential value in exploring new therapeutic approaches and improving patient prognosis.

Programmed cell death (PCD) refers to a form of cell death governed by genetic regulation, and consists of several distinct pathways, including apoptosis, autophagy, cuproptosis, ferroptosis, necroptosis, paraptosis and pyroptosis. These pathways are crucial for maintaining intracellular stability and homeostasis, which are involved in the pathogenesis of various diseases. This review innovatively proposes an integrated framework classified by death patterns, and systematically expounds the strategic significance of targeting PCD in cancer treatment. Based on this framework, we conduct an in-depth analysis of how to design corresponding therapeutic strategies for different death patterns, with a particular emphasis on the complex cross-talk and synergistic effects among different PCD pathways. Moreover, we demonstrate that this interaction is the cornerstone for designing the next generation of combination treatment regimens. The aim is to lay a foundation and point out the future direction for the development of more effective and targeted cancer treatment strategies based on the regulation of PCD networks.

Signal Transducer and Activator of Transcription 3 (STAT3), a significant component of the STAT family, is vital for cellular signal transduction and gene expression regulation. STAT3 is capable of interacting with cytokine receptors, facilitating signal transduction to the nucleus, where it modulates the transcriptional activity of downstream target genes. Notably, STAT3 exhibits dual roles depending on its activation state: physiologically activated STAT3 contributes to neuroprotection, promotes neurogenesis, and inhibits inflammation, whereas under pathological conditions, overactivated STAT3 exacerbates neuroinflammation, induces apoptosis, and disrupts synaptic function. Recent research has discovered that the STAT3 signaling pathway is crucial in the occurrence and development of depression. This article reviews the mechanism of the STAT3 signaling pathway in depression, including its regulatory role in neuroinflammation, neurogenesis, apoptosis, synaptic function, and hormone regulation. In particular, the article analyzed in detail the activation of STAT3 in the JAK/STAT pathway, which has a crucial impact on cell proliferation, differentiation, survival, and apoptosis, and thus regulates neuronal survival and function in the nervous system. In addition, we highlighted the potential advantages of STAT3 as a multi-target regulatory center in anti- inflammation, the promotion of neural regeneration, and the improvement of synaptic function, and suggested that combining it with conventional antidepressants may enhance the therapeutic effect, thus paving a new way for personalized and precise treatment. We have reviewed previous studies on the link between STAT3 signaling and depression and evaluated the value of STAT3 signaling as a therapeutic target for depression, with a view to providing a novel direction for the development of treatment strategies for depression.

Celastrol (CEL), a quinonic methyl triterpenoid extracted from the rootstock of the plant Tripterygium wilfordii, which shows therapeutic potential in improving inflammatory diseases, tumor, metabolic diseases and neurodegenerative diseases. However, the role of CEL in acute inflammatory pain is still unclear. In our experiment, the inflammatory pain model induced by formalin was used to explore the mechanism and effect of CEL on pain regulation. The results showed that intraperitoneal injection (i.p.) or intragastric gavage (i.g.) of CEL (0.5 mg/kg and 1.0 mg/kg) obviously reduced the time of licking/biting the right hind paw in the formalin test, without affecting normal motor function or voluntary activity. Moreover, both naloxone (NLX, 1.0 mg/kg, co-injected with CEL) and nor-binaltorphimine (nor-BNI, 10 mg/kg, administrated 24 h prior to CEL) significantly antagonized the antinociceptive effect of CEL, indicating that the κ-opioid receptor was involved in the antinociceptive effect of CEL. In addition, CEL significantly up-regulated the gene expression and protein levels of dynorphin mRNA and Oprk1, while did not influence the expression of Penk, Pomc, Oprm1 and Oprd1. The protein expression levels of p-CaMKII, p-ERK and p-CREB were also significantly decreased in the CEL treated group. Moreover, the immunohistochemistry and immunofluorescence results demonstrated the numbers of positive c-Fos and GFAP in the dorsal horn (L4-6) were obviously reduced. However, all of these protein’s expression change induced by CEL were blocked by nor-BNI. Thus, our results indicate that CEL may produce analgesic effect through activating KOR, which subsequently reduce the expression of p-CaMKII/ERK/CREB and inhibit the activation of neural cells in the dorsal horn (L4-6).

Correction for 'A bottlebrush-architectured dextran polyprodrug as an acidity-responsive vector for enhanced chemotherapy efficiency' by Tian Zhang, et al., Biomater. Sci., 2020, 8, 473-484, https://doi.org/10.1039/C9BM01692A.

Celastrol is one of the main active ingredients extracted from the plant Tripterygium wilfordii Hook F. A growing number of studies have shown that celastrol has various pharmacological effects, including anti-inflammation, anti-rheumatism, treatment of neurodegenerative diseases, and anti-tumor. This article systematically summarized the mechanism and role of celastrol in lipid metabolism and obesity, rheumatoid arthritis (RA), osteoarthritis (OA), gouty arthritis, inflammatory bowel disease, neurodegenerative diseases, and cancer and other diseases (such as diabetes, respiratory-related diseases, atherosclerosis, psoriasis, hearing loss, etc.). The celastrol played roles in inflammation response, cell apoptosis, autophagy, ferroptosis, and lipid metabolism mainly by acting on chondrocytes, macrophages, mitochondria, and endoplasmic reticulum (ER) through NF-κB, STAT, MAPK, TLR, PI3K-AKT-mTOR, and other signal pathways. This review could provide a reference for the clinical application and further development and utilization of celastrol.

Orexin – a neuropeptide – is extensively distributed in the central nervous system and is involved in the regulation of diverse physiological functions and behaviors. Orexin is strongly associated with the onset and development of depression. The most important function of orexin is to interact with the transport system, mediating arousal, and energy homeostasis. Hypothalamic-ventral tegmental and hypothalamic-ventral thalamic pathways provide clues for understanding the function of orexin and related disorders, such as sleep disorders, eating disorders, and substance abuse. This article summarizes the basic and clinical studies on the role of the orexin system in regulating and treating depression, including the relationship between the expression level of orexin in specific brain areas and diseases, relationship between adolescent depression and orexin, orexin receptor antagonists as a treatment for depression, and narcolepsy, which is closely associated with depression. Research progress on the role of orexin in depression and recent relevant studies are summarized, providing novel directions for developing depression treatment strategies.

PEST-containing nuclear protein (PCNP), a short-lived small nuclear protein with 178 amino acids, is a nuclear protein containing two PEST sequences. PCNP is highly expressed in several malignant tumors such as cervical cancer, rectal cancer, and lung cancer. It is also associated with cell cycle regulation and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and Wnt signaling pathways during tumor growth. The present article discuss how PCNP regulates the PI3K/AKT/mTOR and Wnt signaling pathways and related proteins, and the ubiquitination of PCNP regulates tumor cell cycle as well as the progress of the application of PCNP in the pathophysiology and treatment of colon cancer, human ovarian cancer, thyroid cancer, lung adenocarcinoma and oral squamous cell carcinoma. The main relevant articles were retrieved from PubMed, with keywords such as PEST-containing nuclear protein (PCNP), cancer (tumor), and signaling pathways as inclusion/exclusion criteria. Relevant references has been included and cited in the manuscript.

Ghrelin is a hormone consisting of 28 amino acids. Growth hormone secretagogue receptor (GHSR) is a receptor for ghrelin, which is expressed in the brain, pituitary gland, and adrenal glands, especially in the hypothalamus. The binding of ghrelin to the receptor 1a subtype mediates most of the biological effects of ghrelin. Ghrelin has a close relationship with the onset of psychosis. Ghrelin can affect the onset of psychosis by regulating neurotransmitters such as dopamine, γ-aminobutyric acid (GABA), and 5-hydroxytryptamine (5-HT) through the hypothalamus-pituitary-adrenal (HPA) axis, brain-gut axis, the mesolimbic dopamine system, and other ways. Ghrelin activates neuropeptide Y (NPY) in the hypothalamic arcuate nucleus (ARC) through the GHSR. Ghrelin binds to neurons in the ventral tegmental area (VTA), where it promotes the activity of dopamine neurons in the nucleus accumbens (NAcs) in a GHSR-dependent way, increasing dopamine levels and the reward system. This article summarized the recent research progress of ghrelin in depression, anxiety, schizophrenia, anorexia nervosa (AN), and bulimia nervosa (BN), and emphasized its potential application for psychiatric disorders treatment.

Major depressive disorder (MDD) is a psychiatric disorder with increasing prevalence worldwide. It is a leading cause of disability and suicide, severely affecting physical and mental health. However, the study of depression remains at an exploratory stage in terms of diagnostics and treatment due to the complexity of its pathogenesis. MicroRNAs are endogenous short-stranded non-coding RNAs capable of binding to the 3'untranslated region of mRNAs. Because of their ability to repress translation process of genes and are found at high levels in brain tissues, investigation of their role in depression has gradually increased recently. This article summarizes recent research progress on the relationship between microRNAs and depression. The microRNAs play a regulatory role in the pathophysiology of depression, involving dysregulation of monoamines, abnormalities in neuroplasticity and neurogenesis, hyperactivity of the HPA axis, and dysregulation of inflammatory responses. These microRNAs might provide new clue for the diagnosis and treatment of MDD, and the development of antidepressant drugs.

Cancer is a public health problem that is extremely harmful to people’s health. Most cancer patients experience severe pain in the advanced stage, which will seriously affect their prognosis. At present, opioids, such as morphine, have been used as the drug of choice for treating moderate to severe cancer-related pain. Mu (μ)-opioid receptor (MOR) is expressed in many different cancer cells. In this article, we present the relationship between MOR and tumor pathophysiology; summarize the molecular mechanism and effect of MOR on tumor proliferation and progression, tumor angiogenesis, tumor immunity, and cancer therapy; and propose the future research direction of MOR for cancer treatment. MOR could be as a promising prognostic biomarker and immune checkpoint in cancer therapy.

Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN/APLNR system was involved in a variety of pathological and physiological functions, such as tumorigenesis and development. However, its prognostic roles in patients with central nervous system (CNS) cancers remain unknown. The present study was designed to explore the expression profile, prognostic significance, and interaction network of APLN/APLNR by integrating data from Oncomine, GEPIA, LOGpc, STRING, GeneMANIA, and immunohistochemical staining. The results demonstrated that APLN and APLNR mRNA expression were significantly increased in CNS cancers, including both low-grade glioma (LGG) and glioblastoma (GBM), when compared with normal CNS tissues. The high APLN, but not APLNR, expression was significantly correlated with overall survival (OS), recurrence free survival (RFS), and progression free survival (PFS) of LGG patients. However, neither APLN nor APLNR expression was significantly related to prognostic value in terms of OS, disease free interval (DFI), disease specific survival (DSS), or progression free interval (PFI) for GBM patients. Additionally, immunohistochemistry staining confirmed the increased APLN expression in tissues of LGG patients with grade II than grade I. These results showed that an elevated APLN level could predict poor OS, RFS, and PFS for LGG patients, and it could be a promising prognostic biomarker for LGG.

Phoenixin is a newly discovered neuropeptide generated from small integral membrane protein 20. Phoenixin is a ligand for the G protein-coupled receptor 173 (GPR173) and has been detected in central and peripheral tissues of human, rats, mice, bovine, and zebrafish. It was initially involved in regulating reproductive function by stimulating the luteinizing hormone release from pituitary cells by increasing the level of gonadotropin-releasing hormone. Recently, many functions of phoenixin have been generalized, including regulation of food intake, memory, Alzheimer's disease, anxiety, inflammation, neuronal and microglial activity, energy metabolism and body fluid balance, cardiovascular function, and endocrine activity. In addition, the interaction between phoenixin and nesfatin-1 have been revealed. The present article summarized the latest research progress on physiological function of phoenixin, suggesting that it is a potential target for novel drug development and clinical application.

Ischemia/reperfusion (I/R) injury is characterized by limiting blood supply to organs, then restoring blood flow and reoxygenation. It leads to many diseases, including acute kidney injury, myocardial infarction, circulatory arrest, ischemic stroke, trauma, and sickle cell disease. Autophagy is an important and conserved cellular pathway, in which cells transfer the cytoplasmic contents to lysosomes for degradation. It plays an important role in maintaining the balance of cell synthesis, decomposition and reuse, and participates in a variety of physiological and pathological processes. Hydrogen sulfide (H2S), along with carbon monoxide (CO) and nitric oxide (NO), is an important gas signal molecule and regulates various physiological and pathological processes. In recent years, there are many studies on the improvement of I/R injury by H2S through regulating autophagy, but the related mechanisms are not completely clear. Therefore, we summarize the related research in the above aspects to provide theoretical reference for future in-depth research.

Ischemia/reperfusion (I/R) injury is characterized by a limited blood supply to organs, followed by the restoration of blood flow and reoxygenation. In addition to ischemia, blood flow recovery can also lead to very harmful injury, especially inflammatory injury. Autophagy refers to the transport of cellular materials to the lysosomes for degradation, leading to the conversion of cellular components and offering energy and macromolecular precursors. It can maintain the balance of synthesis, decomposition and reuse of the intracellular components, and participate in many physiological processes and diseases. Inflammasomes are a kind of protein complex. Under physiological and pathological conditions, as the cellular innate immune signal receptors, inflammasomes sense pathogens to trigger an inflammatory response. TheNLRP3 inflammasome is the most deeply studied inflammasome and is composed of NLRP3, the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18 mediated by caspase-1 and promotes a further inflammatory process. Studies have shown that autophagy and the NLRP3 inflammasome play an important role in the process of I/R injury, but the relevant mechanisms have not been fully explained, especially how the interaction between autophagy and the NLRP3 inflammasome participates in I/R injury, which remains to be further studied. Therefore, we reviewed the recent studies about the interplay between autophagy and the NLRP3 inflammasome in I/R injury and analyzed the mechanisms to provide the theoretical references for further research in the future.

RNA interference (RNAi), also known as gene silencing, is a biological process that prevents gene expression in certain diseases such as cancer. It can be used to improve the accuracy, efficiency, and stability of treatments, particularly genetic therapies. However, challenges such as delivery of oligonucleotide drug to less accessible parts of the body and the high incidence of toxic side effects are encountered. It is therefore imperative to improve their delivery to target sites and reduce their harmful effects on noncancerous cells to harness their full potential. In this study, the role of RNAi in the treatment of COVID-19, the novel coronavirus disease plaguing many countries, has been discussed. This review aims to ascertain the mechanism and application of RNAi and explore the current challenges of RNAi therapy by identifying some of the cancer delivery systems and providing drug information for their improvement. It is worth mentioning that delivery systems such as lipid-based delivery systems and exosomes have revolutionized RNAi therapy by reducing their immunogenicity and improving their cellular affinity. A deeper understanding of the mechanism and challenges associated with RNAi in cancer therapy can provide new insights into RNAi drug development.

Ischemia/reperfusion (I/R) injury refers to the functional and structural changes in the process of blood flow recovery after ischemia. In addition to ischemia, the blood flow recovery can also lead to very harmful damage, such as the obvious cell swelling and the irreversible cell necrosis. I/R injury is related with many diseases, including myocardial I/R injury. Myocardial I/R injury refers to the aggravation of ischemic myocardial tissue injury due to sudden disorder of blood circulation. Although there are many studies on myocardial I/R injury, the exact mechanism is not fully understood. Hydrogen sulfide (H2S), like carbon monoxide and nitric oxide, is an important gas signal molecule. It plays an important role in many physiological and pathological processes. Recent studies indicate that H2S can improve myocardial I/R injury, however, its mechanism is not fully understood, especially the involved signal pathways. In this review, we summarize the related researches about the role of the signaling pathways involved in the protective effects of exogenous H2S on myocardial I/R injury, so as to provide theoretical reference for the future in-depth researches.

Apelin, a peptide hormone, is an endogenous ligand for G protein-coupled receptor and has been shown to be widely expressed in human and animal tissues, such as the central nervous system and adipose tissue. Recent studies indicate that the apelin/APJ system is involved in the regulation of multiple physiological and pathological processes, and it is associated with cardiovascular diseases, metabolic disorders, neurological diseases, ischemia-reperfusion injury, aging, eclampsia, deafness, and tumors. The occurrence and development of these diseases are closely related to the local inflammatory response. Oxidative stress is that the balance between oxidation and antioxidant is broken, and reactive oxygen species are produced in large quantities, causing cell or molecular damage, which leads to vascular damage and a series of inflammatory reactions. Hence, this article reviewed recent advances in the relationship between apelin/APJ and oxidative stress, and inflammation-related diseases, and highlights them as potential therapeutic targets for oxidative stress-related inflammatory diseases.

Βeta-cyclodextrin (β-CD) with a hydrophobic cavity enables the formation of inclusion complexes with organic molecules. The formation of host–guest complexes makes the application of β-CD popular in many fields, but their interaction with organisms is poorly understood. In the present study, the effect of β-CD on gut microbiota (16S rRNA gene sequencing), serum metabolites (gas chromatography–mass spectrometry platform), and their correlation (Pearson correlation analysis) was investigated after 14 days repeated oral exposure in mice. β-CD did not significantly affect the α-diversity indexes, including Richness, Chao1, Shannon and Simpson indexes, but disturbed the structure of the gut bacteria according to the result of principal component analysis (PCA). After taxonomic assignment, 1 in 27 phyla, 2 in 48 classes, 3 in 107 orders, 6 in 192 families, and 8 in 332 genera were significantly different between control and β-CD treated groups. The serum metabolites were significantly changed after β-CD treatment according to the result of unsupervized PCA and supervised partial least squares-discriminant analysis (PLS-DA). A total of 112 differential metabolites (89 downregulated and 23 upregulated) were identified based on the VIP >1 from orthogonal PLS-DA and p <0.05 from Student’s t -test. The metabolic pathways, including ABC transporters, pyrimidine metabolism, purine metabolism, glucagon signaling pathway, insulin signaling pathway, and glycolysis/gluconeogenesis, were enriched by KEGG pathway analysis. Our study provides a general observation of gut microbiota, serum metabolites and their correlation after exposure to β-CD in mice, which will be helpful for future research and application of β-CD.

Autophagy is a vital cell mechanism which plays an important role in many physiological processes including clearing long-lived, accumulated and misfolded proteins, removing damaged organelles and regulating growth and aging. Autophagy also participates in a variety of biological functions, such as development, cell differentiation, resistance to pathogens and nutritional hunger. Recently, autophagy has been reported to be involved in diabetes, but the mechanism is not fully understood. Hydrogen sulfide (H2S) is a colorless, water-soluble, flammable gas with the typical odor of rotten eggs, which has been known as a highly toxic gas for many years. However, it has been reported recently that H2S, together with nitric oxide and carbon monoxide, is an important gas signal transduction molecule. H2S has been reported to play a protective role in many diabetes-related diseases, but the mechanism is not fully clear. Recent studies indicate that H2S plays an important role by regulating autophagy in many diseases including cancer, tissue fibrosis diseases and glycometabolic diseases; however, the related mechanism has not been fully studied. In this review, we summarize recent research on the role of H2S in regulating autophagy in diabetic-related diseases to provide references for future related research.