Enhancing anti-tumor immune responses through combination therapies: epigenetic drugs and immune checkpoint inhibitors

Epigenetic mechanisms are processes that affect gene expression and cellular functions without involving changes in the DNA sequence. This abnormal or unstable expression of genes regulated by epigenetics can trigger cancer and other various diseases. The immune cells involved in anti-tumor responses and the immunogenicity of tumors may also be affected by epigenomic changes. This holds significant implications for the development and application of cancer immunotherapy, epigenetic therapy, and their combined treatments in the fight against cancer. We provide an overview of recent research literature focusing on how epigenomic changes in immune cells influence immune cell behavior and function, as well as the immunogenicity of cancer cells. And the combined utilization of epigenetic medications with immune checkpoint inhibitors that focus on immune checkpoint molecules [e.g., Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), T cell Immunoglobulin and Mucin Domain (TIM-3), Lymphocyte Activation Gene-3 (LAG-3)] present in immune cells and stromal cells associated with tumors. We highlight the potential of small-molecule inhibitors targeting epigenetic regulators to amplify anti-tumor immune responses. Moreover, we discuss how to leverage the intricate relationship between cancer epigenetics and cancer immunology to create treatment regimens that integrate epigenetic therapies with immunotherapies

Synthesis and Biological Evaluation of 4β-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents

A series of novel podophyllotoxin derivatives obtained by 4β-N-acetylamino substitution at C-4 position was designed, synthesized, and evaluated for in vitro cytotoxicity against four human cancer cell lines (EC-9706, HeLA, T-24 and H460) and a normal human epidermal cell line (HaCaT). The cytotoxicity test indicated that most of the derivatives displayed potent anticancer activities. In particular, compound 12h showed high activity with IC50 values ranging from 1.2 to 22.8 μM, with much better cytotoxic activity than the control drug etoposide (IC50: 8.4 to 78.2 μM). Compound 12j exhibited a promising cytotoxicity and selectivity profile against T24 and HaCaT cell lines with IC50 values of 2.7 and 49.1 μM, respectively. Compound 12g displayed potent cytotoxicity against HeLA and T24 cells with low activity against HaCaT cells. According to the results of fluorescence-activated cell sorting (FACS) analysis, 12g induced cell cycle arrest in the G2/M phase accompanied by apoptosis in T24 and HeLA cells. Furthermore, the docking studies showed possible interactions between human DNA topoisomerase IIα and 12g. These results suggest that 12g merits further optimization and development as a new podophyllotoxin-derived lead compound

Clonal analysis for elucidating the lineage potential of embryonic NG2+ cells

Background aims. The widespread NG2-expressing neural progenitors in the central nervous system (CNS) are considered to be multifunctional cells with lineage plasticity, thereby possessing the potential for treating CNS diseases. Their lineages and functional characteristics have not been completely unraveled. The present study aimed to disclose the lineage potential of clonal NG2+ populations in vitro and in vivo. Methods. Twenty-four clones from embryonic cerebral cortex-derived NG2+ cells were induced for oligodendrocyte, astrocyte, neuronal and chondrocyte differentiation. The expression profiles of neural progenitor markers chondroitin sulfate proteoglycan 4 (NG2), platelet-derived growth factor-α receptor (PDGFαR); nestin and neuronal cell surface antigen (A2B5) were subsequently sorted on cells with distinct differentiation capacity. Transplantation of these NG2+ clones into the spinal cord was used to examine their lineage potential in vivo. Results. In vitro differentiation analysis revealed that all the clones could differentiate into oligodendrocytes, and seven of them were bipotent (oligodendrocytes and astrocytes). Amazingly, one clone exhibited a multipotent capacity of differentiating into not only neuronal–glial lineages but also chondrocytes. These distinct subtypes were further found to exhibit phenotypic heterogeneity based on the examination of a spectrum of neural progenitor markers. Transplanted clones survived, migrated extensively and differentiated into oligodendrocytes, astrocytes or even neurons to integrate with the host spinal cord environment. Conclusions. These results suggest that NG2+ cells contain heterogeneous progenitors with distinct differentiation capacities, and the immortalized clonal NG2+ cell lines might provide a cell source for treating spinal cord disorders

Anti-Melanogenic Activities of Heracleum moellendorffii via ERK1/2-Mediated MITF Downregulation

In this study, the anti-melanogenic effects of Heracleum moellendorffii Hance extract (HmHe) and the mechanisms through which it inhibits melanogenesis in melan-a cells were investigated. Mushroom tyrosinase (TYR) activity and melanin content as well as cellular tyrosinase activity were measured in the cells. mRNA and protein expression of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), TYR-related protein-1 (TYRP-1) and -2 were also examined. The results demonstrate that treatment with HmHe significantly inhibits mushroom tyrosinase activity. Furthermore, HmHe also markedly inhibits melanin production and intracellular tyrosinase activity. By suppressing the expression of TYR, TYRP-1, TYRP-2, and MITF, HmHe treatment antagonized melanin production in melan-a cells. Additionally, HmHe interfered with the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, with reversal of HmHe-induced melanogenesis inhibition after treatment with specific inhibitor U0126. In summary, HmHe can be said to stimulate ERK1/2 phosphorylation and subsequent degradation of MITF, resulting in suppression of melanogenic enzymes and melanin production, possibly due to the presence of polyphenolic compounds

Alteration of faecal microbiota balance related to long-term deep meditation

Background Advancements in research have confirmed that gut microbiota can influence health through the microbiota–gut–brain axis. Meditation, as an inner mental exercise, can positively impact the regulation of an individual’s physical and mental health. However, few studies have comprehensively investigated faecal microbiota following long-term (several years) deep meditation. Therefore, we propose that long-term meditation may regulate gut microbiota homeostasis and, in turn, affect physical and mental health.Aims To investigate the effects of long-term deep meditation on the gut microbiome structure.Methods To examine the intestinal flora, 16S rRNA gene sequencing was performed on faecal samples of 56 Tibetan Buddhist monks and neighbouring residents. Based on the sequencing data, linear discriminant analysis effect size (LEfSe) was employed to identify differential intestinal microbial communities between the two groups. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis was used to predict the function of faecal microbiota. In addition, we evaluated biochemical indices in the plasma.Results The α-diversity indices of the meditation and control groups differed significantly. At the genus level, Prevotella and Bacteroides were significantly enriched in the meditation group. According to the LEfSe analysis, two beneficial bacterial genera (Megamonas and Faecalibacterium) were significantly enriched in the meditation group. Functional predictive analysis further showed that several pathways—including glycan biosynthesis, metabolism and lipopolysaccharide biosynthesis—were significantly enriched in the meditation group. Moreover, plasma levels of clinical risk factors were significantly decreased in the meditation group, including total cholesterol and apolipoprotein B.Conclusions Long-term traditional Tibetan Buddhist meditation may positively impact physical and mental health. We confirmed that the gut microbiota composition differed between the monks and control subjects. The microbiota enriched in monks was associated with a reduced risk of anxiety, depression and cardiovascular disease and could enhance immune function. Overall, these results suggest that meditation plays a positive role in psychosomatic conditions and well-being

Flattening Grain Boundary Grooves for Perovskite Solar Cells with High Optomechanical Reliability

Optomechanical reliability has emerged as an important criterion for evaluating the performance and commercialization potential of perovskite solar cells (PSCs) due to the mechanical property mismatch of metal halide perovskites with other device layer. In this work, grain boundary grooves, a rarely discussed film microstructural characteristic, are found to impart significant effects on the optomechanical reliability of perovskite substrate heterointerfaces and thus PSC performance. By pre burying iso butylammonium chloride additive in the electron transport layer (ETL), GB grooves (GBGs) are flattened and an optomechanically reliable perovskite heterointerface that resists photothermal fatigue is created. The improved mechanical integrity of the ETL perovskite heterointerfaces also benefits the charge transport and chemical stability by facilitating carrier injection and reducing moisture or solvent trapping, respectively. Accordingly, high performance PSCs which exhibit efficiency retentions of 94.8% under 440 h damp heat test (85% RH and 85 degrees C), and 93.0% under 2000 h continuous light soaking are achieved

Loss of Microglia and Impaired Brain-Neurotrophic Factor Signaling Pathway in a Comorbid Model of Chronic Pain and Depression

Major depressive disorder (MDD) and chronic pain are two complex disorders that often coexist. The underlying basis for this comorbidity is unknown. In the current investigation, microglia and the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) pathway were investigated. A comorbidity model, with characteristics of both MDD and chronic pain, was developed by the administration of dextran sodium sulfate (DSS) and the induction of chronic unpredictable psychological stress (CUS). Mechanical threshold sensory testing and the visceromotor response (VMR) were employed to measure mechanical allodynia and visceral hypersensitivity, respectively. RT-qPCR and western blotting were used to assess mRNA and protein levels of ionized calcium-binding adaptor molecule 1 (Iba-1), nuclear factor-kappa B (NF-κB), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBa), BDNF, and CREB. In comorbid animals, mechanical allodynia and visceral hypersensitivities were significant with increased mRNA and protein levels for NF-κB-p65 and IκBa. Furthermore, the comorbid animals had deceased mRNA and protein levels for Iba-1, BDNF, and CREB as well as a reduced number and density of microglia in the medial prefrontal cortex (mPFC). These results together suggest that DSS and CUS can induce the comorbidities of chronic pain and depression-like behavior. The pathology of this comorbidity involves loss of microglia within the mPFC with subsequent activation of NF-κB-p65 and down-regulation of BDNF/p-CREB signaling

Intermediary roles of prospective memory and retrospective memory in the comorbidity of depression and pain

Background Patients who suffer comorbidity of major depressive disorder (MDD) and chronic pain (CP) maintain a complex interplay between maladaptive prospective memory (PM) and retrospective memory (RM) with physical pain, and their complications are still unknown.Aims We aimed to focus on the full cognitive performance and memory complaints in patients with MDD and CP, patients with depression without CP, and control subjects, considering the possible influence of depressed affect and chronic pain severity.Methods According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders and the criteria given by the International Association of Pain, a total of 124 participants were included in this cross-sectional cohort study. Among them, 82 depressed inpatients and outpatients from Anhui Mental Health centre were divided into two groups: a comorbidity group(patients with MDD and CP) (n=40) and a depression group (patients with depression without CP) (n=42). Meanwhile, 42 healthy controls were screened from the hospital’s physical examination centre from January 2019 to January 2022. The Hamilton Depression Rating Scale-24 (HAMD-24) and Beck Depression Inventory-II (BDI-II) were used to evaluate the severity of depression. The Pain Intensity Numerical Rating Scale (PI-NRS), Short-Form McGill Pain Questionnaire-2 Chinese version (SF-MPQ-2-CN), Montreal Cognitive Assessment-Basic Section (MoCA-BC), and Prospective and Retrospective Memory Questionnaire (PRMQ) were used to assess pain-related features and the global cognitive functioning of study participants.Results The impairments in PM and RM differed remarkably among the three groups (F=7.221, p<0.001; F=7.408, p<0.001) and were severe in the comorbidity group. Spearman correlation analysis revealed the PM and RM were positively correlated with continuous pain and neuropathic pain (r=0.431, p<0.001; r=0.253, p=0.022 and r=0.415, p<0.001; r=0.247, p=0.025), respectively. Regression analysis indicated a significant positive relationship between affective descriptors and total BDI-II score (β=0.594, t=6.600, p<0.001). Examining the mediator pathways revealed the indirect role of PM and RM in patients with comorbid MDD and CP.Conclusions Patients with comorbid MDD and CP presented more PM and RM impairments than patients with MDD without CP. PM and RM are possibly mediating factors that affect the aetiology of comorbid MDD and CP.Trial registration number chiCTR2000029917