Association of social health with all-cause mortality and cause-specific mortality: A population-based cohort study.

BACKGROUND: Previous studies only focused on the individual social factors, without considering the overall social health patterns. The present study aimed to develop an integrated social health score (SHS) and investigate its associations with all-cause, cardiovascular disease (CVD), cancer mortality. METHODS: A total of 330,716 participants (mean age 56.3 years; 52.4 % female) from UK Biobank was included between 2006 and 2010, and thereafter followed up to 2021. SHS was calculated by using information on social connections, social engagement and social support. Cox proportional hazards models was used to estimate the hazard ratios and 95 % confidence intervals (CIs) of the association between SHS and all-cause and cause-specific mortality and the 4-way decomposition was used to quantify the mediating effect of lifestyle factors. RESULTS: During a median follow-up period of 12.4 years, 37,897 death cases were recorded, including 4347 CVD and 10,380 cancer cases. The SHS was inversely associated with the risks of all-cause, CVD and cancer mortality in a dose-dependent manner (P for trend <0.001). The association between SHS with all-cause mortality was mediated by lifestyle factors including diet score, smoking status and alcohol consumption. CONCLUSION: Integrated SHS was inversely associated with risks of all-cause, CVD and cancer mortality, and the associations were partially mediated by lifestyle factors. Our study highlights the importance of maintaining high levels of social health by jointly enhancing social involvement, expanding social networks, and cultivating enduring intimate relationships across the life course.

Trajectories of depressive symptoms and risk of cardiovascular disease, cancer and mortality: a prospective cohort study.

Background: Depressive symptoms are established risk factors for various health outcomes. However, previous studies assessed depressive symptoms at a single time point, neglecting individual variations over time. Aims: To identify depressive symptoms trajectories through repeated measures and examine their associations with cardiovascular disease (CVD), cancer and mortality. Methods: This study included 20 634 UK Biobank participants free of CVD and cancer at baseline with two or more assessments of depressive symptoms during 2006-2016. Group-based trajectory modelling identified depressive symptoms trajectories. Incident CVD, cancer and mortality were followed up until 2021 through linked registries. Results: Six depressive symptoms trajectories were identified: no symptoms (n=6407), mild-stable (n=11 539), moderate-stable (n=2183), severe-decreasing (n=206), moderate-increasing (n=177) and severe-stable (n=122). During a median follow-up of 5.5 years, 1471 CVD cases, 1275 cancer cases and 503 deaths were documented. Compared with the no symptoms trajectory, the mild-stable, moderate-stable and severe-stable trajectories exhibited higher CVD risk, with hazard ratios (HRs) (95% CIs) of 1.19 (1.06 to 1.34), 1.32 (1.08 to 1.34) and 2.99 (1.85 to 4.84), respectively. Moderate-increasing and severe-stable trajectories were associated with higher mortality risks, with HRs (95% CIs) of 2.27 (1.04 to 4.93) and 3.26 (1.55 to 6.88), respectively. However, the severe-decreasing trajectory was not associated with higher risks of adverse outcomes. We did not find significant associations between any trajectory and cancer. Conclusions: Trajectories related to stable and increasing depressive symptoms, but not the trajectory associated with severe depressive symptoms at the initial assessment but decreasing at the follow-up, were associated with higher risks of CVD and mortality. Alleviating severe depressive symptoms at the initial onset may mitigate CVD and mortality risks.

Healthy lifestyle and the risk of depression recurrence requiring hospitalisation and mortality among adults with pre-existing depression: a prospective cohort study.

BACKGROUND: Although lifestyle-based treatment approaches are recommended as important aspects of depression care, the quantitative influence of aggregated healthy lifestyles on depression recurrence and mortality remains unknown. OBJECTIVE: To investigate the association between healthy lifestyle and the risks of first-time hospitalisation for recurrent depression and mortality. METHODS: 26 164 adults with depression (mean (SD) age, 56.0 (7.9) years) were included from UK Biobank between 2006 and 2010 and followed up until 2022. Depression was defined as a physician's diagnosis in hospital admissions or the use of prescribed antidepressant medication. A weighted healthy lifestyle score (HLS) was calculated based on smoking, alcohol consumption, diet, sleep pattern, physical activity, social health, employment status and greenspace interaction. FINDINGS: Over a 13.3-year follow-up, 9740 cases of first-time hospitalisation due to depression recurrence and 1527 deaths were documented. Compared with the lowest HLS tertile, the highest tertile was associated with a 27% lower risk (HR=0.73, 95% CI 0.69 to 0.77) of first-time hospitalisation for depression recurrence and a 22% (HR=0.78, 95% CI 0.68 to 0.91) lower risk of mortality among adults with depression. Lower risks of first-time hospitalisation for depression recurrence were observed among those who smoked less, drank more alcohol, followed healthier diets and sleep patterns, spent more time employed in current job or had greater exposure to greenspace. CONCLUSION AND IMPLICATIONS: Greater adherence to healthy lifestyle was associated with a lower risk of hospitalisation and mortality among adults with pre-existing depression. Incorporating behaviour modification as an essential part of clinical practice for depressed patients could complement medication-based therapies.

Apoptotic body-inspired nanotherapeutics efficiently attenuate osteoarthritis by targeting BRD4-regulated synovial macrophage polarization.

Bromodomain-containing protein 4 (BRD4) is the most well-studied BET protein that is important for the innate immune response. We recently revealed that targeting BRD4 triggers apoptosis in tumor-associated macrophages, but its role in synovial macrophages and joint inflammation is largely unknown. Herein, we demonstrated that BRD4 was highly expressed in the iNOS-positive M1 macrophages in the human and mouse osteoarthritis (OA) synovium, and conditional knockout of BRD4 in the myeloid lineage using Lyz2-cre; BRD4flox/flox mice significantly abolished anterior cruciate ligament transection (ACLT)-induced M1 macrophage accumulation and synovial inflammation. Accordingly, we successfully constructed apoptotic body-inspired phosphatidylserine-containing nanoliposomes (PSLs) loaded with the BRD4 inhibitor JQ1 to regulate inflammatory macrophages. JQ1-loaded PSLs (JQ1@PSLs) exhibited a higher cellular uptake by macrophages than fibroblast-like synoviocytes (FLSs) in vitro and in vivo, as well as the reduction in proinflammatory M1 macrophage polarization. Intra-articular injections of JQ1@PSLs showed prolonged retention within the joint, and remarkably reduced synovial inflammation and joint pain via suppressing M1 polarization accompanied by reduced TRPA1 expression by targeted inhibition of BRD4 in the macrophages, thus attenuating cartilage degradation during OA development. The results show that BRD4-inhibiting JQ1@PSLs can targeted-modulate macrophage polarization, which opens a new avenue for efficient OA therapy via a "Trojan horse".

Single-cell RNA sequencing reveals S100a9hi macrophages promote the transition from acute inflammation to fibrotic remodeling after myocardial ischemia‒reperfusion.

Rationale: The transition from acute inflammation to fibrosis following myocardial ischemia‒reperfusion (MIR) significantly affects prognosis. Macrophages play a pivotal role in inflammatory damage and repair after MIR. However, the heterogeneity and transformation mechanisms of macrophages during this transition are not well understood. Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) and mass cytometry to examine murine monocyte-derived macrophages after MIR to investigate macrophage subtypes and their roles in the MIR process. S100a9-/- mice were used to establish MIR model to clarify the mechanism of alleviating inflammation and fibrosis after MIR. Reinfusion of bone marrow-derived macrophages (BMDMs) after macrophage depletion (MD) in mice subjected to MIR were performed to further examine the role of S100a9hi macrophages in MIR. Results: We identified a unique subtype of S100a9hi macrophages that originate from monocytes and are involved in acute inflammation and fibrosis. These S100a9hi macrophages infiltrate the heart as early as 2 h post-reperfusion and activate the Myd88/NFκB/NLRP3 signaling pathway, amplifying inflammatory responses. As the tissue environment shifts from proinflammatory to reparative, S100a9 activates transforming growth factor-ß (Tgf-ß)/p-smad3 signaling. This activation not only induces the transformation of myocardial fibroblasts to myofibroblasts but also promotes fibrosis via the macrophage-to-myofibroblast transition (MMT). Targeting S100a9 with a specific inhibitor could effectively mitigate acute inflammatory damage and halt the progression of fibrosis, including MMT. Conclusion: S100a9hi macrophages are a promising therapeutic target for managing the transition from inflammation to fibrosis after MIR.

Autophagy induced by hypoxia in pulpitis is mediated by HIF-1α/BNIP3.

OBJECTIVE: Hypoxia-inducible factor-1α (HIF-1α) and its downstream factor, 19 kDa BCL-2 interacting protein 3 (BNIP3), promote cellular autophagy under hypoxic conditions. However, their roles in pulpitis are unclear. Therefore, the changes in inflammatory response and autophagy levels caused by hypoxia during pulpitis were evaluated. Additionally, the regulatory mechanism of HIF-1α/BNIP3 in cellular autophagy in pulpitis was explored. DESIGN: Pulp from dental pulp tissues of healthy individuals and patients with pulpitis (n = 10) were exposed and combined with a low oxygen simulation chamber to construct pulpitis (n = 6), hypoxia (n = 6), and hypoxia+pulpitis (n = 6) rat models. Hematoxylin and eosin and immunohistochemical staining were used to detect the localization and expression levels of HIF-1α, BNIP3, and autophagy marker protein, LC3B. Transmission electron microscopy was used to confirm autophagosome formation. An in vitro hypoxic model of human dental pulp cells was established, and HIF-1α chemical inhibitor 3-(5'-hydroxymethyl-2'-furyl)- 1-benzylindazole (YC-1) was administered. Immunofluorescence and western blotting were used to detect the localization and protein levels of HIF-1α, BNIP3, and LC3B. RESULTS: Autophagy is significantly increased and HIF-1α and BNIP3 are elevated in inflamed dental pulp tissue. Both pulp exposure and hypoxia intervention cause inflammatory reactions in rat dental pulp tissue, accompanied by the autophagy activation. Hypoxia significantly enhances HIF-1α/BNIP3 and autophagy activation. BNIP3 downregulates and autophagy reduces after treatment with YC-1. CONCLUSIONS: In pulpitis, activation of the HIF-1α/BNIP3 signaling pathway driven by hypoxia leads to increased autophagy. This provides a new molecular explanation for autophagy activation in apical periodontitis and new insights into the pathogenesis of the disease.

Cancer pain intensity and perceived social support in palliative care: 1-week prospective study.

OBJECTIVES: Pain is a complex and multidimensional experience affected by psychosocial factors. Perceived social support (PSS) has been considered as a positive psychosocial resource for effective regulation of cancer patients' well-being. Our study examined the relationship between PSS and pain intensity under 1-week palliative care. METHODS: A prospective study was conducted of terminal cancer inpatients (N=84) recruited from the hospice ward. Pain intensity was assessed on admission and 1 week later, and patients completed self-report questionnaires assessing PSS at admission. The repeated designed analysis of variance was used to explore the correlate of PSS with cancer pain. RESULTS: Pain intensity decreased after 1 week (t=2.303, p=0.024), and 47.62% gained pain relief. For pain intensity, there was a significant PSS group×time interaction effect detected (F=4.544, p=0.036). Pain intensity in the high PSS group was significantly reduced 1 week later (p=0.008), while the change of pain intensity was not significant in the low PSS group (p=0.609). CONCLUSIONS: PSS at admission predicted the 1-week development of pain intensity. Identifying PSS of terminal cancer patients leads to early interventions that are more effective in improving pain management of palliative care.

Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/ß-catenin signaling.

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21-/-) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21-/- and Ctsk-cre; Trim21f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/ß-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

Association of pain management and positive expectations with psychological distress and spiritual well­being among terminally ill cancer patients admitted to a palliative care unit.

BACKGROUND: Although palliation of psycho-spiritual distress is of great importance in terminally ill cancer patients, there is a little information about screening patients who benefit from palliative care and identifying the cancer care targets. This study explored the relationship of pain management and positive expectations with depression, anxiety and spiritual well-being (SWB) in terminal cancer patients admitted to a palliative care unit. METHODS: Eighty-four terminal cancer inpatients were recruited from the Hospice Ward, Shengjing Hospital of China Medical University. Optimism and general self-efficacy (GSE) were evaluated at admission. Patients completed self-report questionnaires on SWB, depression, anxiety and pain both on admission and one week later. The repeated designed analysis of variance was used to explore the correlates of depression, anxiety and SWB (meaning, peace, faith). RESULTS: In our sample, only cancer pain diminished significantly one week later. For depression (p = 0.041) and faith (p = 0.013), there was a significant pain group (relieved vs. not relieved) × time interaction effect, such that those with satisfied pain control experienced the improved psycho-spiritual outcomes at 1 week. The relationship between positive expectations, peace and faith was also statistically significant, indicating that the improvement of peace or faith was significant in the low group of optimism and GSE. CONCLUSIONS: Our findings indicated that pain management lied at the center of depression and SWB, meaning that effective pain management may reduce depression, and improve SWB among terminal cancer patients. Moreover, positive expectations, especially for optimism, may be the new target for SWB-related intervention research. Palliative care nurse should require the identification of terminal cancer patients who may more benefit from short-term palliative care, and target them with effective cancer care.

Associations of healthy lifestyle with depression and post-depression dementia: A prospective cohort study.

BACKGROUND: Depressive symptoms may be a risk factor or prodrome of dementia, but the modifiable risk factors for dementia after onset of depression has not been fully elucidated. The current study aimed to investigate the associations of lifestyle factors with depression and post-depression dementia. METHODS: Our analysis was based on data from the ongoing UK Biobank study, which included 497,533 participants (age 37-73 years) between 2006 and 2010, and thereafter followed up to 2020. High-risk lifestyle factors included current smoking, heavy alcohol intaking, poor diet pattern, physically inactive. Multistate models were used to estimate the transition-specific hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: During a 14.8-year follow-up, 23,164 participants developed depression, and 989 developed post-depression dementia. The incidence rate of dementia in people with depression was far more than those who were free of depression. In multistate model, high-risk lifestyle factors were substantially associated with higher risks of incident depression (HR = 2.14, 95 % CI: 1.95-2.35), dementia (HR = 1.87, 95 % CI: 1.51-2.31), and post-depression dementia (HR = 1.72, 95 % CI: 1.13-2.62). When the analyses were divided by individual lifestyle factors, we found that only physically inactive contributed significantly to the development of dementia after the onset of depression (HR = 1.15, 95 % CI: 1.01-1.30). CONCLUSION: Our study found that high-risk lifestyle factors were associated with higher risk of transition from depression to dementia, highlighting the great significance of integrating comprehensive behavioral interventions, particularly for regular physical activity, for prevention of both depression and post-depression dementia.

Anti-Tumor Effects of Engineered VNP20009-Abvec-Igκ-mPD-1 Strain in Melanoma Mice via Combining the Oncolytic Therapy and Immunotherapy.

Programmed cell death protein 1/Programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors are the most promising treatments for malignant tumors currently, but the low response rate limits their further clinical utilization. To address this problem, our group constructed an engineered strain of VNP20009-Abvec-Igκ-mPD-1 [V-A-mPD-1 (mPD-1, murine PD-1)] to combine oncolytic bacterial therapy with immunotherapy. Further, we evaluated its growth performance and mPD-1 expression ability in vitro while establishing the melanoma mice model to explore its potential anti-cancer effects in tumor therapy. Our results indicated that the V-A-mPD-1 strain has superior growth performance and can invade B16F10 melanoma cells and express PD-1. In addition, in the melanoma mice model, we observed a marked reduction in tumor volume and the formation of a larger necrotic area. V-A-mPD-1 administration resulted in a high expression of mPD-1 at the tumor site, inhibiting tumor cell proliferation via the down-regulation of the expression of rat sarcoma (Ras), phosphorylated mitogen-activated protein kinase (p-MEK)/MEK, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK expression significantly inhibited tumor cell proliferation. Tumor cell apoptosis was promoted by down-regulating phosphoinositide 3 kinase (PI3K) and protein kinase B (AKT) signaling pathways, as evidenced by an increased Bcl-2-associated X protein/B cell lymphoma-2 (Bax/Bcl-2) expression ratio. Meanwhile, the expression levels of systemic inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α), were substantially reduced. In conclusion, our research demonstrated that V-A-mPD-1 has an excellent anti-tumor effect, prompting that the combined application of microbial therapy and immunotherapy is a feasible cancer treatment strategy.

Modified no-touch technique for radio-cephalic arteriovenous fistula increases primary patency and decreases juxta-anastomotic stenosis.

OBJECTIVE: Low primary patency rate is a major problem of radio-cephalic arteriovenous fistula (RC-AVF) creation. Radial artery deviation and reimplantation (RADAR) is associated with low juxta-anastomotic stenosis rate. However, inflow artery stenosis is prominent with RADAR. To further reduce injury to veins and arteries during operation, a modified no-touch technique (MNTT) was used to create RC-AVF. METHODS: We retrospectively reviewed our prospectively maintained database of patients with end-stage renal disease (ESRD)s undergoing RC-AVF creation for hemodialysis using either the MNTT between January 2021 and January 2022 (MNTT group) or conventional surgical procedure ( end-to-side vein-to-artery anastomosis) between October 2016 and October 2017 (Control group). Patients who chose to undergo RC-AVF surgery underwent standardized preoperative mapping and postoperative fistula evaluations using duplex ultrasound. Additionally, 4D flow MRI data were used to visualize and quantify the hemodynamics of one RC-AVF by MNTT. Outcomes included primary patency, juxta-anastomotic stenosis, and maturation rates. RESULTS: Forty patients underwent RC-AVFs by MNTT, compared to 60 patients in the control group. The MNTT group had a higher primary unassisted patency rate than the control group (p = 0.038). Juxta-anastomotic stenosis (all on the cephalic vein) occurred in 4 (10%) patients who underwent MNTT. RC-AVF maturation rates after 3 months were not different between both groups (maturation rate: 90% and 81.7% in the MNTT and control groups, respectively, p = 0.253). COX regression showed that both conventional AVF surgery (p = 0.031) and smaller cephalic vein diameter (p = 0.034) were associated with higher odds of RC-AVF failure. The AVF flow within the proximal vein remained helical during cardiac cycle. The distribution of wall shear stress (WSS) and oscillatory shear index (OSI) differed from that of conventional surgical AVF. CONCLUSION: RC-AVF by MNTT increases primary patency rate and decreases juxta-anastomotic stenosis rate. The improvement in hemodynamics may be one of the important reasons for the better patency rate of in the RC-AVF by MNTT group.

Versatile Nano-PROTAC-Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy.

Recent evidence has indicated that overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4) contributes to a poor prognosis of lung cancers, and the suppression of its expression promotes cell apoptosis and leads to tumor shrinkage. Proteolysis targeting chimera (PROTAC) has recently emerged as a promising therapeutic strategy with the capability to precisely degrade targeted proteins. Herein, a novel style of versatile nano-PROTAC (CREATE (CRV-LLC membrane/DS-PLGA/dBET6)) is developed, which is constructed by using a pH/GSH (glutathione)-responsive polymer (disulfide bond-linked poly(lactic-co-glycolic acid), DS-PLGA) to load BRD4-targeted PROTAC (dBET6), followed by the camouflage with engineered lung cancer cell membranes with dual targeting capability. Notably, CREATE remarkably confers simultaneous targeting ability to lung cancer cells and tumor-associated macrophages (TAMs). The pH/GSH-responsive design improves the release of dBET6 payload from nanoparticles to induce pronounced apoptosis of both cells, which synergistically inhibits tumor growth in both subcutaneous and orthotopic tumor-bearing mouse model. Furthermore, the efficient tumor inhibition is due to the direct elimination of lung cancer cells and TAMs, which remodels the tumor microenvironment. Taken together, the results elucidate the construction of a versatile nano-PROTAC enables to eliminate both lung cancer cells and TAMs, which opens a new avenue for efficient lung cancer therapy via PROTAC.

Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein.

AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 µM, CC50 > 25 µM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 µM to 1.92 µM). AB-506 demonstrated activity across HBV genotypes A-H and maintains antiviral activity against nucleos(t)ide analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.

Therapeutic effect of neohesperidin on TNF-α-stimulated human rheumatoid arthritis fibroblast-like synoviocytes.

During the pathogensis of rheumatoid arthritis (RA), activated RA fibroblast-like synoviocytes (RA-FLSs) combines similar proliferative features as tumor and inflammatory features as osteoarthritis, which eventually leads to joint erosion. Therefore, it is imperative to research and develop new compounds, which can effectively inhibit abnormal activation of RA-FLSs and retard RA progression. Neohesperidin (Neo) is a major active component of flavonoid compounds with anti-inflammation and anti-oxidant properties. In this study, the anti-inflammation, anti-migration, anti-invasion, anti-oxidant and apoptosis-induced effects of Neo on RA-FLSs were explored to investigate the underlying mechanism. The results suggested that Neo decreased the levels of interleukin IL-1ß, IL-6, IL-8, TNF-α, MMP-3, MMP-9 and MMP-13 in FLSs. Moreover, Neo blocked the activation of the MAPK signaling pathway. Furthermore, treatment with Neo induced the apoptosis of FLSs, and inhibited the migration of FLSs. It was also found that Neo reduced the accumulation of reactive oxygen species (ROS) induced by TNF-α. Taken together, our results highlighted that Neo may act as a potential and promising therapeutic drug for the management of RA.

Host Poly(A) Polymerases PAPD5 and PAPD7 Provide Two Layers of Protection That Ensure the Integrity and Stability of Hepatitis B Virus RNA.

Noncanonical poly(A) polymerases PAPD5 and PAPD7 (PAPD5/7) stabilize hepatitis B virus (HBV) RNA via the interaction with the viral posttranscriptional regulatory element (PRE), representing new antiviral targets to control HBV RNA metabolism, hepatitis B surface antigen (HBsAg) production, and viral replication. Inhibitors targeting these proteins are being developed as antiviral therapies; therefore, it is important to understand how PAPD5/7 coordinate to stabilize HBV RNA. Here, we utilized a potent small-molecule AB-452 as a chemical probe, along with genetic analyses to dissect the individual roles of PAPD5/7 in HBV RNA stability. AB-452 inhibits PAPD5/7 enzymatic activities and reduces HBsAg both in vitro (50% effective concentration [EC50] ranged from 1.4 to 6.8 nM) and in vivo by 0.94 log10. Our genetic studies demonstrate that the stem-loop alpha sequence within PRE is essential for both maintaining HBV poly(A) tail integrity and determining sensitivity toward the inhibitory effect of AB-452. Although neither single knockout (KO) of PAPD5 nor PAPD7 reduces HBsAg RNA and protein production, PAPD5 KO does impair poly(A) tail integrity and confers partial resistance to AB-452. In contrast, PAPD7 KO did not result in any measurable changes within the HBV poly(A) tails, but cells with both PAPD5 and PAPD7 KO show reduced HBsAg production and conferred complete resistance to AB-452 treatment. Our results indicate that PAPD5 plays a dominant role in stabilizing viral RNA by protecting the integrity of its poly(A) tail, while PAPD7 serves as a second line of protection. These findings inform PAPD5-targeted therapeutic strategies and open avenues for further investigating PAPD5/7 in HBV replication. IMPORTANCE Chronic hepatitis B affects more than 250 million patients and is a major public health concern worldwide. HBsAg plays a central role in maintaining HBV persistence, and as such, therapies that aim at reducing HBsAg through destabilizing or degrading HBV RNA have been extensively investigated. Besides directly degrading HBV transcripts through antisense oligonucleotides or RNA silencing technologies, small-molecule compounds targeting host factors such as the noncanonical poly(A) polymerase PAPD5 and PAPD7 have been reported to interfere with HBV RNA metabolism. Herein, our antiviral and genetic studies using relevant HBV infection and replication models further characterize the interplays between the cis element within the viral sequence and the trans elements from the host factors. PAPD5/7-targeting inhibitors, with oral bioavailability, thus represent an opportunity to reduce HBsAg through destabilizing HBV RNA.

Long non-coding RNA small nucleolar RNA host gene 1 knockdown suppresses the proliferation, migration and invasion of osteosarcoma cells by regulating microRNA-424-5p/FGF2 in vitro.

The aim of the present study was to clarify the effect of long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) on the proliferation, migration and invasion of osteosarcoma (OS) cells and to explore the potential underlying mechanisms. The expression levels of SNHG1, microRNA (miR)-424-5p and fibroblast growth factor 2 (FGF2) in OS tissues and cells were detected using reverse transcription-quantitative polymerase chain reaction. OS cell proliferation, migration and invasion were analysed by MTT, wound healing and Transwell invasion assays, respectively. The targeting relationships between SNHG1 and miR-424-5p, as well as between miR-424-5p and FGF2, were confirmed using RNA-binding protein immunoprecipitation and/or dual-luciferase reporter gene assays. The results demonstrated that the expression levels of SNHG1 and FGF2 were upregulated, whereas the expression of miR-424-5p was downregulated in OS tissues and cells. The silencing of SNHG1 significantly inhibited the proliferation, migration and invasion of OS cells. Additionally, FGF2 was shown to be a target of miR-424-5p, which in turn, was a target of SNHG1. miR-424-5p silencing and FGF2 overexpression both reversed the suppressive effects of SNHG1 knockdown on the proliferation, migration and invasion of OS cells. Thus, the silencing of SNHG1 may inhibit the proliferation, migration and invasion of OS cells by regulating the miR-424-5p/FGF2 axis.

Differences in aluminum tolerance and immobilization between two indigenous ectomycorrhizal fungi Lactarius deliciosus and Pisolithus tinctorius from Southwest China's forest stands.

Aluminum (Al) toxicity severely decreases plant growth and productivity in acidic soil globally. Ectomycorrhizal (ECM) fungi can promote host plant's Al-tolerance by acting as a physical barrier or bio-filter. However, little information is available on the role of ECM fungus on Al immobilization with respect to Al-tolerance. This present study aimed to screen a promising indigenous ECM fungus with high Al-tolerance and to understand its role in Al immobilization related to Al-tolerance. Two ECM fungal strains (Lactarius deliciosus 2 and Pisolithus tinctorius 715) isolated from forest stands in Southwest China were cultured in vitro with 0.0, 1.0 or 2.0 mM Al addition for 21 days to compare their Al accumulation and Al-tolerance. Meanwhile, fungal mycelia were incubated in 0.037 mM Al3+ solutions, and then Al3+ concentrations in the solution were determined at time 2, 5, 10, 20, 40, 60, 120, 180, and 240 min, and the Al3+ immobilization characteristics were evaluated using the pseudo-first order, pseudo-second order and intraparticle diffusion models. Results showed that 1.0 or 2.0 mM Al3+ addition significantly increased fungal biomass production by 23% or 41% in L. deliciosus 2, not in P. tinctorius 715. Fungal Al3+ concentrations in L. deliciosus 2 and P. tinctorius 715 were significantly increased by 293% and 103% under 2.0 mM than under 1.0 mM Al3+ addition. The pH values in the culture solution were significantly decreased by 0.43 after 21 d fungus growth but no changes between these two fungi under the same Al3+ addition. Fungal Al3+ immobilization showed a three-stage trend with initially a rapid rate followed a relatively slower rate until reaching equilibrium. The pseudo-second order model was the best (R2 = 0.98 and 0.99 for L. deliciosus 2 and P. tinctorius 715) to fit the experimentally observed data among the three models. Compared to P. tinctorius 715, L. deliciosus 2 also had greater intercept value, cation exchange capacity (CEC), and extracellular Al3+ proportion in fungal mycelia. Additionally, bio-concentration on Al3+, active site numbers for Al3+, boundary layer thickness, CEC, and immobilization on the cell wall in fungal mycelia were involved in ECM fungal Al-tolerance. These results show that both ECM fungi are Al-tolerant while L. deliciosus 2 is a promising indigenous ECM isolate with higher Al-tolerance in Southwest China, and they can be hence applied to the afforestation and ecological restoration in acidic soil.

The visceral fat area to leg muscle mass ratio is significantly associated with the risk of hyperuricemia among women: a cross-sectional study.

BACKGROUND: A significant positive association was found in previous studies among obesity, visceral fat accumulation, and hyperuricemia. The purpose of this study was to explore the association between the ratio of visceral fat area to leg muscle mass (VFA-to-LMM) and hyperuricemia, and verify the role of gender differences in the association. METHODS: A total of 3393 (43.3% are men) participants from Tianjin Union Medical Center-Health Management Center were recruited for this cross-sectional study. The VFA-to-LMM ratio was used as the independent variable. Hyperuricemia, a serum uric acid level ≥ 416 µmol/L in men and in menopausal women and ≥ 357 µmol/L in premenopausal women, was used as the dependent variable. Multiple logistic regression analysis was used to estimate the odds ratio and the 95% confidence interval between the VFA-to-LMM ratio and hyperuricemia. RESULTS: The overall prevalence of hyperuricemia was 14.8% (8.9% in women, and 22.5% in men). After adjustment by age, smoking status (for males), menopause status (for females), drinking status, exercise frequency, blood pressure, alanine aminotransferase, fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, creatinine, and history of diseases, a strong positive association was found between the VFA-to-LMM ratio and hyperuricemia in both men (4th vs. 1st quartile 1.60, 95%CI: 1.03-2.49) and women (4th vs. 1st quartile 5.22, 95%CI: 2.44-12.56). After additional adjustment by BMI, there was still a significant positive association in women (4th vs. 1st quartile 2.57, 95%CI: 1.06-6.77). The results of subgroup analysis showed that pre-menopausal women (4th vs. 1st quartile OR: 3.61) have a higher risk of hyperuricemia than postmenopausal women (4th vs. 1st quartile OR: 1.94) with the increase of the VFA-to-LMM ratio. Besides, the interaction analysis results showed the highest risk of hyperuricemia when VFA and LMM were both in the highest quantile (OR: 11.50; 95% CI: 4.86-31.98). CONCLUSION: The VFA-to-LMM ratio was positively associated with the risk of hyperuricemia in women after adjustment by confounders. Pre-menopausal women have a higher risk of hyperuricemia than postmenopausal women with the increase of the VFA-to-LMM ratio. In addition, the highest risk of hyperuricemia was demonstrated when both VFA and LMM were at the highest quartile.

Association Between the EAT-Lancet Diet Pattern and Risk of Type 2 Diabetes: A Prospective Cohort Study.

BACKGROUND: The EAT-Lancet Commission has promulgated a sustainable dietary guideline and recommended that it was designed to improve the human health and support environmental sustainability. OBJECTIVE: This research was designed to explore the association between this healthy diet pattern (EAT-Lancet diet pattern, EAT-LDP) and risk of type 2 diabetes (T2D). METHODS: Between 2006 and 2010, a total of 59,849 participants from the UK Biobank without diabetes, cardiovascular disease, or cancers were included at baseline. The EAT-LDP score was constructed on the sum of 14 food components and then categorized into three tertiles. Multivariable Cox proportional hazards regression models were conducted to explore the association between EAT-LDP score and the risk of incident T2D. A mediation analysis was also implemented to disentangle the role of body mass index (BMI) and waist circumference in the relationship between EAT-LDP score and T2D. RESULTS: During a median follow-up of 10 years, 2,461 incident T2D cases were recorded. In analyses that compared tertile 3 of the EAT-LDP score (highest) with tertile 1 (lowest), the hazard ratio (HR) for T2D was 0.81 (95% CI: 0.72-0.90) after adjusting for sociodemographic status and health-related factors. Participants who reported a one-point increase in the diet score were associated with a 6% decrease in risk of T2D (HR: 0.94, 95% CI: 0.91-0.97). A significant indirect association was observed between the EAT-LDP score and T2D (ß: 0.66, 95% CI: 0.65-0.67), indicating that 44% of the association of EAT-LDP score with T2D was mediated by BMI. Additionally, 40% of the association of EAT-LDP score with T2D was mediated by waist circumference was also observed. CONCLUSIONS: Our findings indicate that a higher adherence to EAT-LDP contributes to lower risk of T2D. Further independent validation is needed to be conducted before applying the EAT-LDP to inform dietary guidelines.