Changwu Yue

The circadian rhythm system coordinates physiological functions such as gene expression, hormone release, energy consumption, cell growth and metabolism through a multi-level molecular network to maintain homeostasis. Circadian core genes regulate cell cycle checkpoints, metabolic homeostasis, and key signaling pathways through a transcription-translation negative feedback loop, and their dysfunction can drive malignant progression of tumors. At the same time, circadian rhythm affects the immune surveillance and immune escape process in the tumor immune microenvironment by regulating the development, differentiation and effector function of immune cells, and further promotes the occurrence and development of tumors. At present, chronotherapy based on circadian rhythm has shown significant advantages in clinical practice. Optimizing the dosage regimen and implementing the chronotherapy strategy can significantly improve the anti-tumor efficacy and reduce the side effects of drugs. Small molecule modulators targeting the biological clock or novel sequential treatment regimens combined with immune checkpoint inhibitors are being evaluated in a number of clinical trials. In view of the great potential value of circadian rhythm regulation in precision medicine, this paper systematically explores the interaction network of circadian rhythm, tumor and immune response, and provides a new perspective for tumor treatment strategy based on biological clock regulation.

Objective: To explore the effects of probiotic fermentation products of germinated grains on cognitive and sleep improvement in mice with sleep deprivation induced by chlorophenylalanine (PCPA), and to provide theoretical and experimental basis for the development of natural products to alleviate insomnia.Methods: ELISA and high-performance liquid chromatography (HPLC) were used to determine the contents of γ-aminobutyric acid and L-theanine in fermentation products. Open Field Test was used to analyze the changes of emotional behavior between groups before and after intervention. ELISA was used to analyze the changes of hypothalamic serotonin, GABA, glutamate, and serum interleukin 6. 16S rRNA sequencing was used to analyze the changes of intestinal flora before and after the intervention of compound fermentation products. LC–MS/MS was used to analyze the changes of intestinal SCFAs before and after the intervention.Results: The content of GABA and L-theanine in 7 L fermentation products was 12.555 μmol/L (1.295 mg/L) and 0.471 mg/mL by ELISA. Compared with the PCPA-induced Model group, the sleep duration of the KEY group was statistically significant (p < 0.0001). Compared with the PCPA-induced Model group, the number of crossing the central lattice in the KEY group was significantly increased, and the number of grooming was significantly reduced (all p < 0.05), suggesting that the anxiety behavior of the mice was improved. In addition, this study found that the compound fermentation products could significantly increase the content of neurotransmitters such as 5-HT, GABA and Glu in the hypothalamus of mice, reduce the content of inflammatory factors such as IL-6, IL-1β and TNF-α in serum, regulate the structure of intestinal flora and increase the content of short-chain fatty acids.Conclusion: Probiotic fermentation products of germinated grains can significantly improve sleep deprivation in PCPA mice, which may be related to regulating the levels of neurotransmitters and inflammatory factors, improving the structure of intestinal flora, and increasing the content of short-chain fatty acids. This study provides new candidates and research directions for the development of natural drugs to alleviate insomnia.

Natural killer (NK) cells directly lysis the virus-infected cells through rapidly releasing cytotoxic mediators and cytokines. The balance between inhibitory and activated receptors on the surface of NK cells, as well as the corresponding ligands expressed on target cells are involved in the regulation of the cytotoxic function of NK cells. NKG2A is one of the highly anticipated inhibitory receptors expressed on NK cells, which can inhibit the cytotoxicity of NK cells to autologous normal tissue cells through interacting with the ligand HLA-E. The studies have shown that HLA-E is overexpressed on virus-infected cells and forms a complex with peptides derived from viral proteins. The interaction of HLA-E and NKG2A can regulate the functions of NK cells, participateing the pathogenesis process of virus infectious diseases. This review outlines the characteristics of the molecular interaction between NKG2A and HLA-E, as well as the mechanisms of NKG2A-HLA-E axis in regulating NK cell responses.

The global aging situation is severe, and the medical pressures associated with aging issues should not be underestimated. The need and feasibility of studying aging and intervening in aging have been confirmed. Aging is a complex natural physiological progression, which involves the irreversible deterioration of body cells, tissues, and organs with age, leading to enhanced risk of disease and ultimately death. The intestinal microbiota has a significant role in sustaining host dynamic balance, and the study of bidirectional communication networks such as the brain–gut axis provides important directions for human disease research. Moreover, the intestinal microbiota is intimately linked to aging. This review describes the intestinal microbiota changes in human aging and analyzes the causal controversy between gut microbiota changes and aging, which are believed to be mutually causal, mutually reinforcing, and inextricably linked. Finally, from an anti-aging perspective, this study summarizes how to achieve delayed aging by targeting the intestinal microbiota. Accordingly, the study aims to provide guidance for further research on the intestinal microbiota and aging.

Excessive free radicals and iron death lead to oxidative damage, which is one of the main causes of aging and diseases. In this field of antioxidation, developing new, safe, and efficient antioxidants is the main research focus. Lactic acid bacteria (LAB) are natural antioxidants with good antioxidant activity and can regulate gastrointestinal microecological balance and immunity. In this study, 15 LAB strains from fermented foods (“Jiangshui” and pickles) or feces were evaluated in terms of their antioxidant attributes. Strains with strong antioxidant capacity were preliminarily screened by the following tests: 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl radical, superoxide anion radical scavenging capacity; ferrous ion chelating assay; hydrogen peroxide tolerance capacity. Then, the adhesion of the screened strains to the intestinal tract was examined using hydrophobic and auto-aggregation tests. The safety of the strains was analyzed based on their minimum inhibitory concentration and hemolysis, and 16S rRNA was used for molecular biological identification. Antimicrobial activity tests showed them probiotic function. The cell-free supernatant of selected strains were used to explore the protective effect against oxidative damage cells. The scavenging rate of DPPH, hydroxyl radicals, and ferrous ion-chelating of 15 strains ranged from 28.81–82.75%, 6.54–68.52%, and 9.46–17.92%, respectively, the scavenging superoxide anion scavenging activity all exceeded 10%. According to all the antioxidant-related tests, strains possessing high antioxidant activities J2-4, J2-5, J2-9, YP-1, and W-4 were screened, these five strains demonstrated tolerance to 2 mM hydrogen peroxide. J2-4, J2-5, and J2-9 were Lactobacillus fermentans and γ-hemolytic (non-hemolytic). YP-1 and W-4 were Lactobacillus paracasei and α-hemolytic (grass-green hemolytic). Although L. paracasei has been proven as a safe probiotic without hemolytic characteristics, the hemolytic characteristics of YP-1 and W-4 should be further studied. Due to the weak hydrophobicity and antimicrobial activity of J2-4, finally, we selected J2-5, J2-9 for cell experiment, J2-5 and J2-9 showed an excellent ability that resistant to oxidative damage by increasing SOD, CAT, T-AOC activity of 293T cells. Therefore, J2-5, and J2-9 strains from fermented foods “Jiangshui” could be used as potential antioxidants for functional food, health care, and skincare.

Introduction:Phellinus igniarius (P. igniarius) (Sanghuang) is a widely used traditional Chinese medicine fungus, and its natural products have great potential for clinical application in immune enhancement. This study aimed to explore the immune-enhancing activity and underlying mechanisms of the polysaccharides and flavonoids derived from Phellinus igniarius (P. igniarius) and to provide a theoretical and experimental basis for the development of novel drugs.Methods: Wild P. igniarius YASH1 from the Loess Plateau in Yan’an region was collected, and polysaccharides and total flavonoids were extracted, isolated and identified from mycelium and sporophore. In vitro antioxidant activity was detected through the scavenging activity of hydroxyl radicals and total antioxidant capacity. Cell Counting Kit-8 and trypan blue detection kit were used to detect the effect of extract polysaccharides and flavonoids on the proliferation and phagocytosis ability of immune cells. To assess the effect of the drugs on cytokine secretion by immune cells and immune recovery in immunocompromised mice, the expression of interleukin (IL)-2, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were examined at the cellular and animal levels. The species composition, abundance of gut microbiota and the altered content of short-chain fatty acids in the feces were analyzed to elucidate the possible mechanisms of drugs by 16S ribosomal RNA (rRNA) amplifiers sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS).Results: Both polysaccharides and flavonoids derived from mycelium or sporophore had antioxidant activity and may stimulate the expression and secretion of IL-2, IL-6, and IFN-γ in immune cells while inhibiting TNF-α expression and secretion and increasing IL-2, IL-6, and IFN- γ expression levels in mice. Furthermore, polysaccharides and flavonoids from mycelium and sporophore showed different effects on the metabolic response of intestinal short-chain fatty acids (SCFAs) in mice, and the use of these drugs remarkably changed the species composition and abundance of intestinal flora in mice.Discussion: Polysaccharides and flavonoids from P. igniarius YASH1 mycelium and sporophore have in vitro antioxidant activity, and they affect the promotion of cell proliferation, stimulation of IL-2, IL-6, and IFN-γ secretion, and inhibition of TNF-α expression in immune cells. Polysaccharides and flavonoids from P. igniarius YASH1 may enhance immunity in immunocompromised mice and remarkably affect the intestinal flora and content of SCFAs.

The gut microbiota is a complex ecosystem that has coevolved with the human body for hundreds of millions of years. In the past 30 years, with the progress of gene sequencing and omics technology, the research related to gut microbiota has developed rapidly especially in the field of digestive system diseases and systemic metabolic diseases. Mechanical, biological, immune, and other factors make the intestinal flora form a close bidirectional connection with the liver and gallbladder, which can be called the “gut–liver–biliary axis.” Liver and gallbladder, as internal organs of the peritoneum, suffer from insidious onset, which are not easy to detect. The diagnosis is often made through laboratory chemical tests and imaging methods, and intervention measures are usually taken only when organic lesions have occurred. At this time, some people may have entered the irreversible stage of disease development. We reviewed the literature describing the role of intestinal flora in the pathogenesis and biotherapy of hepatobiliary diseases in the past 3–5 years, including the dynamic changes of intestinal flora at different stages of the disease, as well as the signaling pathways involved in intestinal flora and its metabolites, etc. After summarizing the above contents, we hope to highlight the potential of intestinal flora as a new clinical target for early prevention, early diagnosis, timely treatment and prognosis of hepatobiliary diseases.

This study aimed to explore the efficacy of zunyimycin C in the immunological enhancement of hypoimmune mice and improvement of cognitive impairment in a mice model of Alzheimer’s disease (AD). Zunyimycin C was administered intranasally to interfere with AD mouse models or gavage to hypoimmune animals. Results of the Morris water maze (MWM) showed that zunyimycin may improve the learning and memory abilities of the AD mice model. The results of differential expression analysis of mRNA levels of inflammatory factors and pathways in brain tissues of the AD mouse model suggested that differential expression was more obvious under Zun-Int L. Western blot revealed that the relative expression of glial fibrillary acidic protein in the brain tissue of the AD mouse model in the Zun-Pre group was significantly higher than that in the other groups, and the difference was statistically significant. The relative expression of interleukin (IL)-6 protein in the brain tissue of mice in the low-dose intervention group was significantly lower than that in the other groups, and the difference was statistically significant. As for hypoimmune animals, short chain fatty acids (SCFAs) assay and intestinal flora assay results showed that zunyimycin C may change intestinal flora diversity and SCFA biosynthesis. The prophylactic administration of zunyimycin C could not inhibit acute neuroinflammation in AD mice. Zunyimycin C may participate in the immune response by activating the Ras-Raf-MEK-ERK signaling pathway to stimulate microglia to produce more inflammatory factors. Zunyimycin C may inhibit autophagy by activating the PI3K-AKT-mTOR signaling pathway, promote cell survival, mediate neuroprotective effects of reactive microglia and reactive astrocytes, and reduce IL-1β in brain tissue and IL-6 secretion, thereby attenuating neuroinflammation in AD mice and achieving the effect of improving learning and memory impairment. Zunyimycin C may play a role in immunological enhancement by changing intestinal flora diversity and SCFAs.

Exposure of the skin to an external stimulus may lead to a series of irreversible dysfunctions, such as skin aging, refractory wounds, and pigmented dermatosis. Nowadays, many cutaneous treatments have failed to strike a balance between cosmetic needs and medical recovery. Extracellular vesicles (EVs) are one of the most promising therapeutic tools. EVs are cell-derived nanoparticles that can carry a variety of cargoes, such as nucleic acids, lipids, and proteins. They also have the ability to communicate with neighboring or distant cells. A growing body of evidence suggests that EVs play a significant role in skin repair. We summarize the current findings of EV therapy in skin aging, refractory wound, and pigmented dermatosis and also describe the novel engineering strategies for optimizing EV function and therapeutic outcomes.