Single-cell transcriptome analysis of aging mouse liver.

Aging has a great impact on the liver, which causes a loss of physiological integrity and an increase in susceptibility to injury, but many of the underlying molecular and cellular processes remain unclear. Here, we performed a comprehensive single-cell transcriptional profiling of the liver during aging. Our data showed that aging affected the cellular composition of the liver. The increase in inflammatory cells including neutrophils and monocyte-derived macrophages, as well as in inflammatory cytokines, could indicate an inflammatory tissue microenvironment in aged livers. Moreover, aging drove a distinct transcriptional course in each cell type. The commonly significant up-regulated genes were S100a8, S100a9, and RNA-binding motif protein 3 across all cell types. Aging-related pathways such as biosynthesis, metabolism, and oxidative stress were up-regulated in aged livers. Additionally, key ligand-receptor pairs for intercellular communication, primarily linked to macrophage migration inhibitory factor, transforming growth factor-ß, and complement signaling, were also elevated. Furthermore, hepatic stellate cells (HSCs) serve as the prominent hub for intrahepatic signaling. HSCs acquired an "activated" phenotype, which may be involved in the increased intrahepatic vascular tone and fibrosis with aging. Liver sinusoidal endothelial cells derived from aged livers were pseudocapillarized and procontractile, and exhibited down-regulation of genes involved in vascular development and homeostasis. Moreover, the aging-related changes in cellular composition and gene expression were reversed by caloric restriction. Collectively, the present study suggests liver aging is linked to a significant liver sinusoidal deregulation and a moderate pro-inflammatory state, providing a potential concept for understanding the mechanism of liver aging.

The association between fear of progression and medical coping strategies among people living with HIV: a cross-sectional study.

BACKGROUND: Due to the chronic nature of HIV, mental health has become a critical concern in people living with HIV (PLWHIV). However, little knowledge exists about the association between fear of progression (FoP) and medical coping modes (MCMs) in PLWHIV in China. METHODS: A cohort of 303 PLWHIV were consecutively enrolled and their demographic, clinical and psychological information was collected. The Fear of Progression Questionnaire-Short Form (FoP-Q-SF), Social Support Rating Scale (SSRS), Internalized HIV Stigma Scale (IHSS) and MCMs Questionnaire were utilized. RESULTS: Of the participants, 215 PLWHIV were classified into the low-level FoP group, and 88 were grouped into the high-level FoP group based on their FoP-Q-SF scores, according to the criteria for the classification of dysfunctional FoP in cancer patients. The high-level group had a higher proportion of acquired immunodeficiency syndrome (AIDS) stage (P = 0.005), lower education levels (P = 0.027) and lower income levels (P = 0.031). Additionally, the high-level group had lower scores in social support (P < 0.001) and its three dimensions, with total SSRS scores showing a negative correlation with two dimensions of FoP-Q-SF, namely physical health (r2 = 0.0409, P < 0.001) and social family (r2 = 0.0422, P < 0.001). Further, the high-level group had higher scores in four dimensions of internalized HIV stigma, and a positive relationship was found to exist between IHSS scores and FoP-Q-SF scores for physical health (r2 = 0.0960, P < 0.001) and social family (r2 = 0.0719, P < 0.001). Social support (OR = 0.929, P = 0.001), being at the AIDS stage (OR = 3.795, P = 0.001), and internalized HIV stigma (OR = 1.028, P < 0.001) were independent factors for FoP. Furthermore, intended MCMs were evaluated. FoP were positively correlated with avoidance scores (r2 = 0.0886, P < 0.001) and was validated as the only factor for the mode of confrontation (OR = 0.944, P = 0.001) and avoidance (OR = 1.059, P = 0.001) in multivariate analysis. CONCLUSION: The incidence of dysfunctional FoP in our study population was relatively high. High-level FoP was associated with poor social support, high-level internalized HIV stigma and a negative MCM among PLWHIV.

Simulation and Experimental Study of Non-Resonant Vibration-Assisted Lapping of SiCp/Al.

SiCp/Al is a difficult-to-machine material that makes it easy to produce surface defects during machining, and researchers focus on reducing the surface defects. Vibration-assisted machining technology is considered an effective method to reduce surface defects by changing the trajectory and contact mode of the abrasive. Aiming at the problem of SiCp/Al processing technology, a vibration-assisted lapping device (VLD) is designed, and elliptical motion is synthesized by a set of parallel symmetrical displacement output mechanisms. The working parameters of the device were tested by simulation and experiment, and the lapping performance was verified. Then, the effects of removal characteristics and process parameters on surface roughness and lapping force were analyzed by simulation and experiment. Simulation and experimental results show that frequency and amplitude that are too low or too high are not conducive to the advantages of NVL. The best surface quality was 54 nm, obtained at A = 8 µm and f = 850 Hz.

Autophagy and Senescence: The Molecular Mechanisms and Implications in Liver Diseases.

The liver is the primary organ accountable for complex physiological functions, including lipid metabolism, toxic chemical degradation, bile acid synthesis, and glucose metabolism. Liver function homeostasis is essential for the stability of bodily functions and is involved in the complex regulation of the balance between cell proliferation and cell death. Cell proliferation-halting mechanisms, including autophagy and senescence, are implicated in the development of several liver diseases, such as cholestasis, viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Among various cell death mechanisms, autophagy is a highly conserved and self-degradative cellular process that recycles damaged organelles, cellular debris, and proteins. This process also provides the substrate for further metabolism. A defect in the autophagy machinery can lead to premature diseases, accelerated aging, inflammatory state, tumorigenesis, and cellular senescence. Senescence, another cell death type, is an active player in eliminating premalignant cells. At the same time, senescent cells can affect the function of neighboring cells by secreting the senescence-associated secretory phenotype and induce paracrine senescence. Autophagy can promote and delay cellular senescence under different contexts. This review decodes the roles of autophagy and senescence in multiple liver diseases to achieve a better understanding of the regulatory mechanisms and implications of autophagy and senescence in various liver diseases.

Nicotinamide N-methyltransferase and liver diseases.

Cellular metabolism-induced epigenetic regulation is essential for the maintenance of cellular homeostasis. Nicotinamide N-methyltransferase (NNMT) is emerging as a key point of intersection between cellular metabolism and epigenetic regulation and has a central role in various physiological and pathological processes. NNMT catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM) to yield S-adeno-syl-L-homocysteine (SAH) and N1-methylnicotinamide (MNAM), directly linking methylation balance with nicotinamide adenosine dinucleotide (NAD+) contents. NNMT acts on either the SAM-methylation balance or both NAD+ metabolism, depending on the tissue involved or pathological settings where metabolic demand is increased. Under physiological conditions, the liver act as an essential metabolic organ with abundant NNMT expression, while NNMT hepatic function is not mediated by its methyltransferase activity due to other major methyltransferases such as glycine N-methyltransferase (GNMT) in the liver. However, hepatic NNMT, as well as its metabolite is improperly regulated and linked to the worse pathological states in liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, and hepatocellular carcinoma (HCC), suggesting a potential role in the process of liver diseases. In this review, we summarize how NNMT regulates cell methylation balance and NAD metabolism, and extensively outline the current knowledge concerning the functions of NNMT in hepatic metabolism including glucose, lipid and energy, with a specific focus on the contribution of NNMT to the pathophysiology of liver-related diseases. NNMT is involved in the development and progression of liver diseases. Understanding the complex NNMT regulatory network and its effects on pathogenesis could provide new therapeutic strategies in the context of liver diseases.

Overview of Innate Immune Cell Landscape in Liver Aging.

Aging is a biological process with a gradual decline in functional capacity, and this process often enhances the risk of chronic disease morbidity and mortality. With advanced age, the immune system undergoes a process of remodeling that can lead to a chronic inflammatory state, termed immunosenescence and inflammaging, respectively. Immunosenescence is accompanied by changes in the number, proportion, and functional capacity of the innate immune cells. The accumulation of dysfunctional immune cells and the presence of low-grade inflammation can lead to organ damage and expedite the aging process. The liver, crucial in regulating the body's metabolism and immune function, is not exempt from these effects. Age-related modifications affect its immune function and regenerative abilities, potentially increasing the prevalence of age-related liver diseases. While aging's impact on the liver is relatively less severe compared to other organ systems, it still experiences an infiltration of innate immune cells and heightened inflammation levels. This review will elaborate on how aging affects the liver's innate immune cells, such as neutrophils, macrophages, dendritic cells, mast cells, and innate lymphoid cells. It will also explore potential strategies for delaying immunosenescence to alleviate these age-related changes.

lncRNA Mirt2 upregulates miR-1246 through methylation to suppress LPS-induced lung cell apoptosis.

INTRODUCTION: Long noncoding RNA Mirt2 has been proven to be a suppressor of lipopolysaccharide (LPS) (a key player in sepsis)-induced inflammation responses. Therefore, Mirt2 may also participate in sepsis. This study was carried out to analyze the interactions between Mirt2 and microRNA-1246 (miR-1246) in sepsis, with a specific focus on sepsis-induced acute lung injury (sepsis-ALI). METHODS: Forty sepsis patients (sepsis group; 23 males and 17 females; 40-65 years, 48.6 ± 6.3 years), 40 sepsis patients with acute lung injury (sepsis-ALI group, 23 males and 17 females; 40-65 years, 48.7 ± 6.4 years), and 40 healthy controls (control group, 23 males and 17 females; 40-65 years, 48.6 ± 6.1 years) were included. Mirt2 and miR-1246 expression in plasma samples from these patients were determined by a reverse transcription-quantitative polymerase chain reaction (PCR). Overexpression of Mirt2 and miR-1246 was achieved in human bronchial epithelial cells (HBEpCs) to explore the interaction between them. The effects of Mirt2 overexpression on miR-1246 methylation were analyzed by methylation-specific PCR. Cell apoptosis analysis was performed to analyze the role of Mirt2 and miR-1246 in the apoptosis of HBEpCs. RESULTS: Mirt2 expression was downregulated in sepsis and was further downregulated in patients with sepsis-ALI. Mirt2 and miR-1246 found to be positively correlated. Downregulation of Mirt2 and miR-1246 was observed in HBEpCs with LPS treatment. In HBEpCs, Mirt2 overexpression increased miR-1246 expression but decreased its gene methylation. Cell apoptosis analysis showed that Mirt2 and miR-1246 negatively regulated the apoptosis of HBEpCs induced by LPS. In addition, miR-1246 inhibition reduced the inhibitory effects of Mirt2 overexpression on cell apoptosis. CONCLUSIONS: Mirt2 may upregulate miR-1246 through methylation to suppress lung cell apoptosis.

The dynamic of platelet count as a novel and valuable predictor for 90-day survival of hepatitis B virus-related acute-on-chronic liver failure patients.

BACKGROUND: The prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is extremely poor due to multiple organ dysfunction. OBJECTIVES: To investigate the prognostic risk factors and create a 90-day prognostic predictive model for the patients with HBV-ACLF. METHODS: Demographic information, clinical examination, and laboratory test results of the enrolled patients were collected to study the prognostic risk factors. Univariate and multivariate analysis and stepwise Logistic regression were performed to develop the predictive model. External validation was performed to verify the model. RESULTS: A total of 333 HBV-ACLF patients and 86 HBV-non-ACLF patients were included in this study. Age, alpha-fetoprotein (AFP), total bilirubin (TBIL), platelet (PLT), and international normalized ratio (INR) were found to be independent risk factors for poor outcomes of HBV-ACLF patients. The formula identified for the linear predictor (LP) of the prognosis of HBV-ACLF patients is thus: LPACLF=-5.04-0.056×age-0.002×AFP-0.010×PLT+0.002×TBIL+0.877×INR. The area under curve (AUC) of the receiver operating characteristic curve (ROC) was 0.7835 (95% CI 0.7248-0.8423). CONCLUSIONS: A predictive model with good calibration and discrimination for 90-day survival of HBV-ACLF patients, including 5 variables, namely age, AFP, PLT, TBIL, and INR was established. Platelet count was a sensitive and dynamic variable for the prognosis of HBV-ACLF.

Platelet microparticles-derived miR-25-3p promotes the hepatocyte proliferation and cell autophagy via reducing B-cell translocation gene 2.

Platelets are critical regulators of liver regeneration, but the mechanisms are still not fully understood. Platelets have been shown to contain a wide variety of microRNAs (miRNAs) and play an important role in many diseases. However, the mechanism that how the platelet microparticles (PMPs)-derived miRNA regulate the hepatocyte proliferation is not very clear. In this study, we have successfully isolated and identified PMPs. We also found that PMPs, which could be well integrated into the HHL-5 cells, could upregulate the level of miR-25-3p in HHL-5 cells. Meanwhile, we found that PMPs-derived miR-25-3p promoted HHL-5 cells proliferation by accelerating cells into the S phase, and enhanced the autophagy by increasing the LC3II expression and reducing the P62 expression. Then, we proved that the miR-25-3p could target the B-cell translocation gene 2 (BTG2) and downregulate the expression levels of the BTG2 gene in HHL-5 cells. In addition, the overexpression of BTG2 significantly inhibited the proliferation and autophagy abilities of HHL-5 cells, while cotransfected miR-25-3p mimics or PMPs could partially rescue HHL-5 cells proliferation and autophagy. Furthermore, we proved that PMPs accelerated hepatocyte proliferation by regulating autophagy pathways. Therefore, PMPs-derived miR-25-3p promoted HHL-5 cell proliferation and autophagy by targeting BTG2, which may be a new therapeutic method for liver regeneration.

Tuberculosis-associated hemophagocytic lymphohistiocytosis with initial presentation of fever of unknown origin in a general hospital: An analysis of 8 clinical cases.

The study aimed to investigate the clinical features and prognoses of patients with tuberculosis (TB) who had secondary hemophagocytic lymphohistiocytosis (HLH).Patients first presenting with fever of unknown origin, who were ultimately diagnosed with TB-associated secondary HLH, were assessed retrospectively. We summarized and analyzed clinical manifestations, laboratory examinations, diagnoses, treatments, and prognoses of patients using clinical data, outpatient follow-up, and telephone follow-up in combination with literature review.Among patients admitted to the hospital with fever of unknown origin in the past 10 years, 371 patients were diagnosed with TB. Among them, 8 cases were diagnosed as tuberculosis-associated HLH (TB-HLH). The proportion of females among TB-HLH patients was higher than the proportion of females among TB patients. Within the same time period, 227 cases met the diagnostic criteria for HLH, among which TB-HLH patients accounted for 3.52% of the cases. None of the 8 TB-HLH patients had underlying diseases, and a majority of them had short symptom durations, rapid progression, along with multisystem and multiorgan dysfunctions. Their clinical manifestations were inconsistent with the typical clinical manifestations and imaging results characteristic of TB. Compared with patients with TB in our hospital during the same period, the 8 TB-HLH patients had a higher proportion of blood-disseminated TB and tuberculous meningitis. Apart from this, the hematological damage in these patients was higher than the common clinical manifestations of TB, and they also had a high proportion of respiratory failure. All 8 TB-HLH patients received antitubercular therapy, and 6 of them were also treated for HLH. However, their morbidity and mortality were significantly higher than that for reported cases of TB-HLH cases, both domestically and abroad, which may be attributed to the fever of unknown origin.Patients with TB-HLH had poor prognoses and no specific clinical manifestations. Therefore, cases of atypical TB and severe TB should be carefully monitored to achieve early diagnosis and early intervention.

Acute myeloid leukemia presenting as erythema nodosum: A case report.

RATIONALE: Erythema nodosum (EN), a type of septal panniculitis, could be a rare nonspecific cutaneous presentation of acute myeloid leukemia (AML). PATIENT CONCERNS: A 58-year-old Chinese female was admitted for a 4-week history of painful cutaneous lesions, accompanied by a sternal pain and fever. The lesions once resolved spontaneously but then recurred. Physical examination revealed warm, tender, indurated, rounded, erythematous to violaceous nodules in bilateral lower extremities, ranging in diameter from 1 to 6 cm. Blood marrow examination was compatible with AML-M2. DIAGNOSES: AML-M2 presenting as EN. INTERVENTIONS: Daunorubicin and cytarabine were used in induction chemotherapy. The patient achieved complete remission and her skin lesions disappeared simultaneously. Six courses of consolidation chemotherapy were conducted in the following 6 months. OUTCOMES: The patient died due to AML relapse. LESSONS: The case strengthens the awareness of cutaneous involvement of AML and raises oncological vigilance in patients with EN.

Przewalskin A: A new C23 terpenoid with a 6/6/7 carbon ring skeleton from Salvia przewalskii maxim.

Przewalskin A (1), a novel C23 terpenoid with a 6/6/7 carbon ring skeleton, was isolated from Salvia przewalskii. Its structure was determined by comprehensive 1D NMR, 2D NMR, and MS spectroscopic analysis and subsequently confirmed by a single-crystal X-ray diffraction study of its PDC oxidation derivative (2). Compounds 1 and 2 showed modest anti-HIV-1 activity with EC50 = 41 and 89 microg/mL, respectively.