Association between human herpesvirus 8 and lipid profile in northwest China: A cross-sectional study.

Human herpesvirus 8 (HHV-8) infection shows obvious regional and ethnic differences. Although studies have shown that these differences may be associated with lipid metabolism, to date, no large-scale studies have explored this. This study explored the seropositivity rate of HHV-8 among 2516 residents from 10 regions of northwest China and then the correlates of HHV-8 infection with lipid profile. The HHV-8 serological positivity rate was 15.6% among all residents. The HHV-8 seroprevalence ranged 11.2-27.6% among different ethnicities. Across different BMI levels, the positive rates of HHV-8 were 27.6%, 16.9%, and 13.6% for a BMI < 18.5, 18.5-24.9, and ≥25, respectively. HHV-8 seropositivity rate was lower for hypertensive people (12.6%) than for non-hypertensive people (16.7%). Univariate logistic regression analyses revealed that age, hypertension, systolic blood pressure, BMI, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) significantly correlated with HHV-8 seropositivity (p < 0.05). Multivariate logistic regression analysis after adjusting for confounding factors showed that HDL-C (odds ratio [OR]: 0.132, 95% confidence interval [CI], 0.082-0.212; p < 0.001) and BMI (OR: 0.959, 95% CI 0.933-0.986; p = 0.003) were associated with HHV-8 seropositivity. Subgroup analyses concerning ethnicity, sex, or age demonstrated a consistent relationship with HDL-C. The results of HHV-8 seropositivity and BMI were inconsistent in the subgroups. However, Spearman's correlation analysis between HHV-8 serum antibody titer and HDL-C levels showed no linear relationship among HHV-8 seropositive individuals (ρ = -0.080, p = 0.058). HHV-8 serum antibody titers were also not significantly correlated with BMI (ρ = -0.015, p = 0.381). Low HDL-C levels may be an independent risk factor for HHV-8 infection, but there is no significant correlation between HDL-C levels and HHV-8 antibody titers.

Multisystem health comorbidity networks of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing, but its subsequent health consequences have not been thoroughly examined. METHODS: A phenome-wide association study was conducted to map the associations of MASLD with 948 unique clinical outcomes among 361,021 Europeans in the UK Biobank. Disease trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of MASLD. The associations jointly verified by observational and polygenic phenome-wide analyses were further replicated by two-sample Mendelian randomization analysis using data from the FinnGen study and international consortia. FINDINGS: The observational and polygenic phenome-wide association study revealed the associations of MASLD with 96 intrahepatic and extrahepatic diseases, including circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic diseases. Sequential patterns of MASLD-related extrahepatic comorbidities were primarily found in circulatory, metabolic, and inflammatory diseases. Mendelian randomization analyses supported the causal associations between MASLD and the risk of several intrahepatic disorders, metabolic diseases, cardio-cerebrovascular disease, and ascites but found no associations with neurological diseases. CONCLUSIONS: This study elucidated multisystem comorbidities and health consequences of MASLD, contributing to the development of combination interventions targeting distinct pathways for health promotion among patients with MASLD. FUNDING: X.L. was funded by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019) and Y.D. was funded by the Key Project of Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (GZY-ZJ-KJ-24077) and the National Natural Science Foundation of China (82001673 and 82272860).

Sleep, physical activity, and sedentary behaviors in relation to overall cancer and site-specific cancer risk: A prospective cohort study.

Large prospective studies are required to better elucidate the associations of physical activity, sedentary behaviors (SBs), and sleep with overall cancer and site-specific cancer risk, accounting for the interactions with genetic predisposition. The study included 360,271 individuals in UK Biobank. After a median follow-up of 12.52 years, we found higher total physical activity (TPA) level and higher sleep scores were related to reduced risk of cancer while higher SB level showed a positive association with cancer. Compared with high TPA-healthy sleep group and low SB-healthy sleep group, low TPA-poor sleep group and high SB-poor sleep group had the highest risk for overall cancer, breast cancer, and lung cancer. Adherence to a more active exercise pattern was associated with a lower risk of cancer irrespective of genetic risk. Our study suggests that improving the quality of sleep and developing physical activity habits might yield benefits in mitigating the cancer risk.

The application of B1 inhomogeneity-corrected variable flip angle T1 mapping for assessing liver fibrosis.

PURPOSE: The aim of this study was to evaluate the diagnostic accuracy of the B1 inhomogeneity-corrected variable flip angle (VFA) method using native T1 values in the staging of liver fibrosis. METHODS: Eighty-three patients who presented for liver biopsy due to varying degrees of liver damage, underwent MR examinations and had T1-mapping images of the liver acquired using the B1 inhomogeneity-corrected VFA VIBE method. Among them, 65 patients underwent Fibroscan, and their results were used to evaluate the elasticity of liver tissue. Additionally, T1-mapping images were collected from 19 normal control patients. Independent sample t-tests were used to analyze the correlation between T1 mapping and Fibroscan. The diagnostic efficacy of T1 mapping in patients with different stages of liver fibrosis was evaluated using receiver operating characteristic (ROC) curves. RESULTS: The consistency between different observer groups was intraclass correlation coefficient (ICC) =0.802. T1 mapping demonstrated significant differences between mid-stage liver fibrosis (S = 2) and late-stage liver fibrosis (S = 3), as well as moderate inflammation (G = 2) and severe inflammation (G = 3), P < 0.05. The Area Under Curve(AUC) values of T1 mapping for early liver fibrosis (S ≥ 1), significant liver fibrosis (S ≥ 2), advanced liver fibrosis (S ≥ 3), and end-stage liver fibrosis (S = 4) were 0.760, 0.709, 0.790, and 0.768, respectively. T1 mapping combined with Fibroscan had an AUC value of 0.860. CONCLUSIONS: The B1 inhomogeneity-corrected VFA T1 mapping may be useful for the staging of liver fibrosis. It has a superior diagnostic efficiency for diagnosing advanced fibrosis (≥S3), while native T1 values combined with Fibroscan have potential value for the staging of liver fibrosis.

Dietary patterns in the progression of metabolic dysfunction-associated fatty liver disease to advanced liver disease: a prospective cohort study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health problem. Dietary intervention plays an important role in patients with MAFLD. OBJECTIVES: We aimed to provide a reference for dietary patterns in patients with MAFLD. METHODS: The presence of MAFLD was determined in the United Kingdom Biobank cohort. Nine dietary pattern scores were derived from the dietary records. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). The contrast test was employed to calculate the heterogeneity across MAFLD statuses. RESULTS: We identified 175,300 patients with MAFLD at baseline. Compared with non-MAFLD, MAFLD was significantly associated with chronic liver disease (CLD) (HR: 3.48; 95% CI: 3.15, 3.84), severe liver disease (SLD) (HR: 2.87; 95% CI: 2.63, 3.14), liver cancer (HR: 1.93; 95% CI: 1.67, 2.23), and liver-related death (LRD) (HR: 1.93; 95% CI: 1.67, 2.23). In the overall cohort, the alternate Mediterranean diet (aMED) (HRCLD: 0.53; 95% CI: 0.37, 0.76; HRSLD: 0.52; 95% CI: 0.37, 0.72), planetary health diet (PHD) (HRCLD: 0.62; 95% CI: 0.47, 0.81; HRSLD: 0.65; 95% CI: 0.51, 0.83), plant-based low-carbohydrate diet (pLCD) (HRCLD: 0.65; 95% CI: 0.49, 0.86; HRSLD: 0.66; 95% CI: 0.51, 0.85), and healthful plant-based diet index (hPDI) (HRCLD: 0.63; 95% CI: 0.47, 0.84; HRSLD: 0.61; 95% CI: 0.47, 0.78) were associated with a lower risk of CLD and SLD. Additionally, unhealthful plant-based diet index (uPDI) was associated with increased risk of CLD (HR: 1.42; 95% CI: 1.09,1.85), SLD (HR: 1.50; 95% CI: 1.19, 1.90), and LRD (HR: 1.88; 95% CI: 1.28-2.78). The aforementioned associations remained consistently strong within the MAFLD subgroup while exhibiting less pronounced in the non-MAFLD group. However, no significant heterogeneity was observed across different MAFLD statuses. CONCLUSIONS: These findings highlight the detrimental effects of MAFLD on the development of subsequent liver diseases and the importance of dietary patterns in managing MAFLD.

Delivery of Synthetic Interleukin-22 mRNA to Hepatocytes via Lipid Nanoparticles Alleviates Liver Injury.

Hepatocellular injury, a pivotal contributor to liver diseases, particularly hepatitis, lacks effective pharmacological treatments. Interleukin-22 (IL-22), crucial for liver cell survival, shows potential in treating liver diseases by regulating repair and regeneration through signal transducer and activator of transcription 3 (STAT3) activation. However, the short half-life and off-target effects limit its clinical applications. To address these issues, lipid nanoparticles are employed to deliver synthetic IL-22 mRNA (IL-22/NP) for in situ IL-22 expression in hepatocytes. The study reveals that IL-22/NP exhibits liver-targeted IL-22 expression, with increased IL-22 levels detected in the liver as early as 3 h postintravenous injection, lasting up to 96 h. Furthermore, IL-22/NP activates STAT3 signaling in an autocrine or paracrine manner to upregulate downstream factors Bcl-xL and CyclinD1, inhibiting hepatocyte apoptosis and promoting cell proliferation. The therapeutic efficacy of IL-22/NP is demonstrated in both chronic and acute liver injury models, suggesting IL-22 mRNA delivery as a promising treatment strategy for hepatitis and liver diseases involving hepatocellular injury.

Internal iliac artery ligation as a damage control method in hemodynamically unstable pelvic fractures: A systematic review of the literature.

PURPOSE: Internal iliac artery ligation (IIAL) has been used as a damage control procedure to treat hemodynamically unstable pelvic fracture for many years. However, there is ongoing debate regarding the effectiveness and safety of this hemostatic method. Therefore, we performed a systematic literature review to assess the efficacy and safety of IIAL for pelvic fracture hemostasis. METHODS: Three major databases, PubMed, Embase, and Google Scholar, were searched to screen eligible original studies published in English journals. Two reviewers independently read the titles, abstracts, and full texts of all literature. Articles were included if they reported the use and effects of IIAL. RESULTS: A total of 171 articles were initially identified, with 22 fully meeting the inclusion criteria. Among the analyzed cases, up to 66.7% of patients had associated abdominal and pelvic organ injuries, with the urethra being the most frequently injured organ, followed by the bowel. The outcomes of IIAL for achieving hemostasis in pelvic fractures were found to be satisfactory, with an effective rate of 80%. Hemorrhagic shock was the leading cause of death, followed by craniocerebral injury. Notably, no reports of ischemic complications involving the pelvic organs due to IIAL were found. CONCLUSION: IIAL has a good effect in treating hemodynamically unstable pelvic fracture without the risk of pelvic organ ischemia. This procedure should be considered a priority for hemodynamically unstable pelvic fracture patients with abdominal organ injuries.

Life's Essential 8, genetic susceptibility, and the risk of psoriatic disease: a prospective cohort study.

BACKGROUND: Psoriatic disease (PsD) is closely associated with cardiovascular diseases. The Life's Essential 8 (LE8) score is a new metric for assessing cardiovascular health (CVH), where a higher score indicates better CVH. However, the longitudinal association between LE8 score and the risk of PsD remains uncertain. The main aim of the present study was to explore the association between LE8 scores and the risk of PsD. OBJECTIVE: To investigate the associations between LE8 score, genetic susceptibility, and the risk of PsD within a cohort design. METHODS: This cohort study included 261,642 participants from the UK Biobank without PsD at baseline. LE8 comprises eight indicators: diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Cox proportional hazard models were employed to examine the association between the participants' LE8 scores, PsD genetic risk, and the risk of PsD. Hazard ratios (HRs) and 95% confidential intervals (CIs) were calculated. RESULTS: During an average follow-up of 12.32 years, 1,501 participants developed PsD. Compared to participants with low LE8 scores, the HRs (95% CIs) of developing PsD for those with moderate and high LE8 scores were 0.51 (0.43, 0.59) and 0.34 (0.27, 0.42) after adjustments, respectively. Dose-response analysis revealed a linear negative association between continuous LE8 score and the risk of developing PsD (P < 0.001), with no evidence of non-linear association detected. The genetic susceptibility to PsD did not modify this association (P for interaction = 0.63). Subgroup analyses revealed that women demonstrated a more pronounced beneficial association between LE8 scores and PsD risk (P for interaction = 0.02). CONCLUSIONS: Our study suggests that a higher LE8 score, regardless of genetic risk, was associated with a lower risk of PsD, particularly among women. Consequently, maintaining a high CVH status is recommended to prevent PsD and assess associated risks.

Comprehensive analysis of cuproptosis-related genes involved in immune infiltration and their use in the diagnosis of hepatic ischemia‒reperfusion injury: an experimental Study.

BACKGROUND: Hepatic ischemia reperfusion injury (HIRI) is a common injury not only during liver transplantation but also during major hepatic surgery. HIRI causes severe complications and affects the prognosis and survival of patients. Cuproptosis, a newly identified form of cell death, plays an important role in a variety of illnesses. However, its role in HIRI remains unknown. MATERIALS AND METHODS: The GSE151648 dataset was mined from the Gene Expression Omnibus (GEO) database, and differences were analyzed for intersections. Based on the differentially expressed genes (DEGs), functional annotation, differentially expressed cuproptosis-related genes (DE-CRGs) identification and lasso logistic regression were conducted. Correlation analysis of DE-CRGs and immune infiltration was further conducted, and DE-CRGs were applied to construct an HIRI diagnostic model. The hierarchical clustering method was used to classify the specimens of HIRI, and functional annotation was conducted to verify the accuracy of these DE-CRGs in predicting HIRI progression. The GSE14951 microarray dataset and GSE171539 single-cell sequencing dataset were chosen as validation datasets. At the same time, the significance of DE-CRGs was verified using a mouse model of HIRI with cuproptosis inhibitors and inducers. Finally, a network of transcription-factor-DE-CRGs and miRNA-DE-CRGs was constructed to reveal the regulation mechanisms. And potential drugs for DE-CRGs were predicted using Drug Gene Interaction Database (DGIdb). RESULTS: Overall, 2390 DEGs and 19 DE-CRGs were identified. Through machine learning algorithms, 8 featured DE-CRGs (GNL3, ALAS1, TSC22D2, KLF5, GTF2B, DNTTIP2, SLFN11 and HNRNPU) were screened, and 2 cuproptosis-related subclusters were defined. Based on the 8 DE-CRGs obtained from the HIRI model (AUC=0.97), the nomogram model demonstrated accuracy in predicting HIRI. Eight DE-CRGs were highly expressed in HIRI samples and were negatively related to immune cell infiltration. A higher level of immune infiltration and expression of CRG group B was found in the HIRI population. Differences in cell death and immune regulation were found between the 2 groups. The diagnostic value of the 8 DE-CRGs was confirmed in the validation of two datasets. The identification of 7 DE-CRGs (SLFN11 excluded) by HIRI animal model experiments was also confirmed. Using hTFtarget, miRWalk and DGIDB database, we predicted that 17 transcription factors, 192 miRNAs and 10 drugs might interact with the DE-CRGs. CONCLUSION: This study shows that cuproptosis may occur in HIRI and is correlated with immune infiltration. Additionally, a cuproptosis-related predictive model was constructed for studying the causes of HIRI and developing targeted treatment options for HIRI.

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Ni2P active site ensembles tune electrocatalytic nitrate reduction selectivity.

We demonstrate that active site ensembles on transition metal phosphides tune the selectivity of the nitrate reduction reaction. Using Ni2P nanocrystals as a case study, we report a mechanism involving competitive co-adsorption of H* and NOx* intermediates. A near 100% faradaic efficiency for nitrate reduction over hydrogen evolution is observed at -0.4 V, while NH3 selectivity is maximized at -0.2 V vs. RHE.

A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy.

Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSCCPT/SNAP that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy.

Insufficiency of quality of life as the treatment endpoint for balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension.

Background and Objectives: The ability of a quality of life (QoL) to guide balloon pulmonary angioplasty (BPA) among patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) has not been fully investigated. This study explored the relationship between QoL scores and hemodynamics in CTEPH patients after BPA and examined whether QoL could be applied as a treatment endpoint. Materials and Methods: This cohort study included patients with inoperable CTEPH who had undergone at least four sessions of BPA. The patients' demographic and clinical data as well as hemodynamic parameters and scores from the RAND 36-item short-form QoL questionnaire were recorded and compared before and after BPA. Results: After BPA treatments, clinical characteristics, hemodynamic parameters, as well as QoL score improved significantly. A physical component summary (PCS) score of 35 or 46 can be used as the cutoff value for predicting better World Health Organization functional classification (WHO FC). Patients who had a higher PCS would have longer 6-min walk distance (6MWD), lower pulmonary vascular resistance (PVR), and better cardiac output (CO) both before and after BPA. However, 19 patients (55.9%) with a higher PCS score after BPA did not achieve the goal of mean pulmonary arterial pressure (mPAP) ≤30 mmHg. During the follow-up period, a significant reduction of PVR was observed, but the PCS score improved a little. Conclusions: QoL is a useful tool for assessing the exercise endurance of patients with inoperable CTEPH treated with BPA, but is insufficient to serve as a treatment endpoint for BPA.

Photoacoustic Imaging-Guided Self-Adaptive Hyperthermia Supramolecular Cascade Nano-Reactor for Diabetic Periodontal Bone Regeneration.

Commencing with the breakdown of the diabetic osteoimmune microenvironment, multiple pathogenic factors, including hyperglycemia, inflammation, hypoxia, and deleterious cytokines, are conjointly involved in the progression of diabetic periodontal bone regeneration. Based on the challenge of periodontal bone regeneration treatment and the absence of real-time feedback of blood oxygen fluctuation in diabetes mellitus, a novel self-adaptive hyperthermia supramolecular cascade nano-reactor ACFDG is constructed via one-step supramolecular self-assembly strategy to address multiple factors in diabetic periodontal bone regeneration. Hyperthermia supramolecular ACFDG possesses high photothermal conversion efficiency (32.1%), and it can effectively inhibit the vicious cycle of ROS-inflammatory cascade through catalytic cascade reactions, up-regulate the expression of heat shock proteins (HSPs) under near-infrared (NIR) irradiation, which promotes periodontal bone regeneration. Remarkably, ACFDG can provide real-time non-invasive diagnosis of blood oxygen changes during periodontal bone regeneration through photoacoustic (PA) imaging, thus can timely monitor periodontal hypoxia status. In conclusion, this multifunctional supramolecular nano-reactor combined with PA imaging for real-time efficacy monitoring provides important insights into the biological mechanisms of diabetic periodontal bone regeneration and potential clinical theranostics.

A conjoint analysis of renal structure and omics characteristics reveal new insight to yak high-altitude hypoxia adaptation.

BACKGROUND: Yaks have unique adaptive mechanisms to the hypoxic environment, in which the kidney plays an important role. The aim of this study was to explore the histological changes of yak kidney at different altitudes and the metabolites and genes associated with adaptation to the hypoxic environment. METHODS: We analyzed the tissue structure and transcriptomic metabolomic data of yak kidney tissue at two altitudes, 2600 and 4400 m. We compared and identified the morphological adaptations of the kidney and the metabolites and genes associated with hypoxia adaptation in yaks. Changes in renal morphological adaptations, differential metabolites and genes were compared and identified, combining the two in a joint analysis. RESULTS: High-altitude yak kidneys showed significant adaptive changes: increased mitochondria, increased glomerular thylakoid area, and decreased localized ribosomes. Transcriptomics and metabolomics identified 69 DAMs (Differential metabolites) and 594 DEGs (differential genes). Functional enrichment analysis showed that the DAMs were associated with protein digestion and absorption, ABC transporter, and MTOR signaling pathway; the DEGs were significantly enriched in Cholesterol metabolism and P53 signaling pathway. The joint analysis indicated that metabolites such as lysine and arginine, as well as key genes such as ABCB5 and COL1A2, were particularly affected under hypoxic conditions, whereas changes in mitochondria in the tissue structure may be related to the expression of MFN1 and OPA1, and changes in glomerular thylakoid membranes are related to VEGFA and TGFB3. CONCLUSION: The kidney regulates metabolites and gene expression related to hormone synthesis, protein metabolism, and angiogenesis by adjusting the mitochondrial and glomerular thylakoid membrane structure to support the survival of yaks in high-altitude environments.

LncRNA SNHG14 silencing attenuates the progression of diabetic nephropathy via the miR-30e-5p/SOX4 axis.

BACKGROUND: Diabetic nephropathy (DN) is a diabetic complication. LncRNAs are reported to participate in the pathophysiology of DN. Here, the function and mechanism of lncRNA small nucleolar RNA host gene 14 (SNHG14) in DN were explored. METHODS: Streptozotocin (STZ)-induced DN mouse models and high glucose (HG)-treated human mesangial cells (MCs) were used to detect SNHG14 expression. SNHG14 silencing plasmids were applied to examine the function of SNHG14 on proliferation and fibrosis in HG-treated MCs. Potential targets of SNHG14 were predicted using bioinformatics tools and verified by luciferase reporter, RNA pulldown, and northern blotting assays. The functional role of SNHG14 in DN in vivo was detected by injection with adenoviral vector carrying sh-SNHG14 into DN mice. Serum creatinine, blood urea nitrogen, blood glucose, 24-h proteinuria, relative kidney weight, and renal pathological changes were examined in DN mice. RESULTS: SNHG14 expression was elevated in the kidneys of DN mice and HG-treated MCs. SNHG14 silencing inhibited proliferation and fibrosis of HG-stimulated MCs. SNHG14 bound to miR-30e-5p to upregulate SOX4 expression. In rescue assays, SOX4 elevation diminished the effects of SNHG14 silencing in HG-treated MCs, and SOX4 silencing reversed the effects of SNHG14 overexpression. In in vivo studies, SNHG14 downregulation significantly ameliorated renal injuries and renal interstitial fibrosis in DN mice. CONCLUSIONS: SNHG14 silencing attenuates kidney injury in DN mice and reduces proliferation and fibrotic phenotype of HG-stimulated MCs via the miR-30e-5p/SOX4 axis.

Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods.

BACKGROUND: Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported. RESULTS: Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR. CONCLUSIONS: Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

All-stage targeted red blood cell membrane-coated docetaxel nanocrystals for glioma treatment.

Challenges for glioma treatment with nanomedicines include physio-anatomical barriers (the blood-brain barrier and blood-brain tumor barrier), low drug loading capacity, and limited circulation time. Here, a red blood cell membrane-coated docetaxel drug nanocrystal (pV-RBCm-NC(DTX)), modified with pHA-VAP (pV) for all-stage targeting of glioma, was designed. The NC(DTX) core exhibited a high drug loading capacity but low in vivo stability, and the RBCm coating significantly enhanced the stability and prolonged in vivo circulation. Moreover, the Y-shaped targeting ligand pV was modified by a mild avidin-biotin interaction, which endowed RBCm-NC(DTX) with superior barrier-crossing ability and therapeutic efficacy. The integration of nanocrystal technology, cell membrane coating, and the avidin-biotin insertion method into this active targeting biomimetic formulation represents a promising drug delivery strategy for glioma.

A novel peptide-drug conjugate for glioma-targeted drug delivery.

The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel "Y"-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery.

Expression Localization of the KRT32 Gene and Its Association of Genetic Variation with Wool Traits.

Changes in keratin gene expression and spatiotemporal regulation determine the compositional content and cellular localization of wool keratin, thereby affecting wool traits. Therefore, keratin gene family member 32 (KRT32) was selected for a study using RT-qPCR, immunofluorescence, and penta-primer amplification refractory mutation system (PARMS) techniques. The results showed that KRT32 mRNA was highly expressed in the skin and localized to the inner root sheath (IRS), outer root sheath (ORS) and dermal papilla (DP). Sequencing results identified eight SNPs in KRT32, and association analyses revealed that the variations were significantly associated with multiple traits in wool (p < 0.05), including MFD, CF and MFC. The constructed haplotype combination H2H3 has higher CF and smaller MFD than other haplotype combination (p < 0.05). In conclusion, KRT32 can be used as a candidate gene for molecular genetic improvement of wool in Gansu Alpine Fine-wool sheep.