Sleep Deprivation Impairs Intestinal Mucosal Barrier by Activating Endoplasmic Reticulum Stress in Goblet Cells.

Sleep deficiency is associated with intestinal inflammatory conditions and is increasingly recognized as a public health concern worldwide. However, the effects of sleep deficiency on intestinal goblet cells (GCs), which play a major role in intestinal barrier formation, remain elusive. Herein, the effects of sleep deprivation on intestinal GCs were determined using a sleep-deprivation mouse model. Sleep deprivation impaired the intestinal mucosal barrier and decreased the expression of tight junction proteins. According to single-cell RNA sequencing and histologic assessments, sleep deprivation significantly reduced GC numbers and mucin protein levels in intestinal tissues. Furthermore, sleep deprivation initiated endoplasmic reticulum stress by activating transcription factor 6 and binding Ig protein. Treatment with melatonin, an endoplasmic reticulum stress regulator, significantly alleviated endoplasmic reticulum stress responses in intestinal GCs. In addition, melatonin increased the villus length, reduced the crypt depth, and restored intestinal barrier function in mice with sleep deprivation. Overall, the findings revealed that sleep deprivation could impair intestinal mucosal barrier integrity and GC function. Targeting endoplasmic reticulum stress could represent an ideal strategy for treating sleep deficiency-induced gastrointestinal disorders.

Invariant natural killer T cells drive hepatic homeostasis in nonalcoholic fatty liver disease via sustained IL-10 expression in CD170+ Kupffer cells.

Kupffer cells (KCs) are liver-resident macrophages involved in hepatic inflammatory responses, including nonalcoholic fatty liver disease (NAFLD) development. However, the contribution of KC subsets to liver inflammation remains unclear. Here, using high-dimensional single-cell RNA sequencing, we characterized murine embryo-derived KCs and identified two KC populations with different gene expression profiles: KC-1 and KC-2. KC-1 expressed CD170, exhibiting immunoreactivity and immune-regulatory abilities, while KC-2 highly expressed lipid metabolism-associated genes. In a high-fat diet-induced NAFLD model, KC-1 cells differentiated into pro-inflammatory phenotypes and initiated more frequent communications with invariant natural killer T (iNKT) cells. In KC-1, interleukin (IL)-10 expression was unaffected by the high-fat diet but impaired by iNKT cell ablation and upregulated by iNKT cell adoptive transfer in vivo. Moreover, in a cellular co-culture system, primary hepatic iNKT cells promoted IL-10 expression in RAW264.7 and primary KC-1 cells. CD206 signal blocking in KC-1 or CD206 knockdown in RAW264.7 cells significantly reduced IL-10 expression. In conclusion, we identified two embryo-derived KC subpopulations with distinct transcriptional profiles. The CD206-mediated crosstalk between iNKT and KC-1 cells maintains IL-10 expression in KC-1 cells, affecting hepatic immune balance. Therefore, KC-based therapeutic strategies must consider cellular heterogeneity and the local immune microenvironment for enhanced specificity and efficiency.

[Adoptive bone marrow cells can reduce the liver injury of metabolic-dysfunction-associated fatty liver disease in mice by differentiating into natural killer T (NKT) cells and increasing their own lipid content].

Objective To investigate the therapeutic effect of bone marrow cell adoptive therapy on metabolic-dysfunction-associated fatty liver disease (MAFLD) in mice and its possible cell population. Methods The staining was used to detect the liver lesions of MAFLD in C57BL/6 mice induced by methionine and choline deficiency diet (MCD) and the adoptive therapeutic effect of bone marrow cells on MAFLD was evaluated by detecting the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The mRNA expressions of low density lipoprotein receptor (LDLR) and interleukin-4 (IL-4) in liver immune cells (including T, NKT, Kupffer cells and other cell populations) were detected by real-time quantitative PCR. The bone marrow cells labeled with 5, 6- carboxyfluorescein diacetate succinimidyl ester (CFSE) were injected into the tail vein of mice. The proportion of CFSE positive cells in liver tissue was observed by the frozen section, and the proportion of labeled cells in the liver and spleen was tracked by flow cytometry. The expression of CD3, CD4, CD8, NK1.1, CD11b and Gr-1 in CFSE labeled adoptive cells was detected by flow cytometry. The intracellular lipid content of NKT cells in liver tissue was evaluated by Nile Red lipid staining. Results The injury of liver tissue and the levels of serum ALT and AST in MAFLD mice were significantly reduced. At the same time, liver immune cells up-regulated the expression of IL-4 and LDLR. LDLR knockout mice induced more severe MAFLD after giving MCD diet. Bone marrow adoptive cells had a significant therapeutic effect and differentiated more NKT cells to colonize the liver. At the same time, the intracellular lipids of these NKT cells increased significantly. Conclusion Bone marrow cell adoptive therapy can reduce liver injury in MAFLD mice by differentiating more NKT cells and increasing the intracellular lipid content of these cells.

COVID-19 and Male Reproduction: A Thorny Problem.

With the global epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the increasing number of infections, little is known about how SARS-CoV-2 affects the male reproductive system during infection or after recovery. Based on the existing research data, we reviewed the effects of SARS-CoV-2 on the male reproductive system and discussed its possible mechanism of action. SARS-CoV-2 enters host cells through the angiotensin-converting enzyme 2 (ACE2)/transmembrane serine protease 2 (TMPRSS2) pathway, and males are more susceptible than females. After infection, immunopathological damage is noticed in the testicles, and the semen index is significantly reduced. Second, abnormalities of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were also observed, suggesting that there may be dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. Even after recovery, the effect of SARS-CoV-2 on the male reproductive system can last for at least a period. There are still many unresolved questions about the effect of SARS-CoV-2 infection on the male reproductive tract. Other receptors involved during the invasion of human cells by SARS-CoV-2 remain to be identified. Will the mutation of SARS-CoV-2 increase the diversity of receptors? How does SARS-CoV-2 affect the HPG axis? The long-term effects of SARS-CoV-2 on the male reproductive system remain to be evaluated. SARS-CoV-2 infection can affect male reproductive function. Standard treatment strategies should be developed in time to protect the fertility of infected patients. For recovered patients with fertility requirements, fertility assessments should be performed and professional fertility guidance should be provided at the same time.