The role of lysosomal membrane proteins in glucose and lipid metabolism.

Lysosomes have long been regarded as the "garbage dump" of the cell. More recently, however, researchers have revealed novel roles for lysosomal membranes in autophagy, ion transport, nutrition sensing, and membrane fusion and repair. With active research into lysosomal membrane proteins (LMP), increasing evidence has become available showing that LMPs are inextricably linked to glucose and lipid metabolism, and this relationship represents mutual influence and regulation. In this review, we summarize the roles of LMPs in relation to glucose and lipid metabolism, and describe their roles in glucose transport, glycolysis, cholesterol transport, and lipophagy. The role of transport proteins can be traced back to the original discoveries of GLUT8, NPC1, and NPC2, which were all found to have significant roles in the pathways involved in glucose and lipid metabolism. CLC-5 and SIDT2-knockout animals show serious phenotypic disorders of metabolism, and V-ATPase and LAMP-2 have been found to interact with proteins related to glucose and lipid metabolism. These findings all emphasize the critical role of LMPs in glycolipid metabolism and help to strengthen our understanding of the independent and close relationship between LMPs and glycolipid metabolism.

The lysosomal membrane protein Sidt2 is a vital regulator of mitochondrial quality control in skeletal muscle.

The role of Sidt2 in the process of glucose and lipid metabolism has been recently reported. However, whether Sidt2 is involved in the metabolic regulation in skeletal muscle remains unknown. In this study, for the first time, using skeletal muscle-selective Sidt2 knockout mice, we found that Sidt2 was vital for the quality control of mitochondria in mouse skeletal muscle. These mice showed significantly reduced muscle tolerance and structurally abnormal mitochondria. Deletion of the Sidt2 gene resulted in decreased expression of mitochondrial fusion protein 2 (Mfn2) and Dynamin-related protein 1 (Drp1), as well as peroxisome proliferator-activated receptor γ coactivator-1 (PGC1-α). In addition, the clearance of damaged mitochondria in skeletal muscle was inhibited upon Sidt2 deletion, which was caused by blockade of autophagy flow. Mechanistically, the fusion of autophagosomes and lysosomes was compromised in Sidt2 knockout skeletal muscle cells. In summary, the deletion of the Sidt2 gene not only interfered with the quality control of mitochondria, but also inhibited the clearance of mitochondria and caused the accumulation of a large number of damaged mitochondria, ultimately leading to the abnormal structure and function of skeletal muscle.

Lower urinary tract symptoms in an elderly women caused by degeneration of the pubic symphysis.

BACKGROUND: Lower urinary tract symptoms are very common in elderly women, and transvaginal delivery and multiple deliveries have been confirmed to be risk factors. Transvaginal delivery and multiple deliveries may lead to an increase in pubic symphysis degeneration. CASE PRESENTATION: A 79-year-old woman consulted a urologist because of worsening lower urinary tract symptoms such as frequent urination and urodynia. Color ultrasound and cystoscopy suggested the possibility of a bladder mass. A lump on the anterior wall of the bladder was observed although the surface mucosa was normal. Physical examination showed obvious tenderness in the posterior area of the pubic symphysis. Further urological computed tomography (CT) and pelvic magnetic resonance imaging (MRI) showed a nodular bony protuberance in the posterior part of the pubic symphysis, which was more obvious than before, with compression changes near the anterior wall of bladder. Open pelvic surgery showed that nodular bone tissue originating from the pubic symphysis significantly oppressed the anterior wall of the bladder behind the pubic symphysis. After resection of the nodule, the lower urinary tract symptoms were relieved significantly. CONCLUSIONS: Pubic symphysis degeneration caused by transvaginal delivery may be an important cause of lower urinary tract symptoms in women. Pelvic CT or MRI is necessary to diagnosis this condition.

A Study on Railway Surface Defects Detection Based on Machine Vision.

The detection of rail surface defects is an important tool to ensure the safe operation of rail transit. Due to the complex diversity of track surface defect features and the small size of the defect area, it is difficult to obtain satisfying detection results by traditional machine vision methods. The existing deep learning-based methods have the problems of large model sizes, excessive parameters, low accuracy and slow speed. Therefore, this paper proposes a new method based on an improved YOLOv4 (You Only Look Once, YOLO) for railway surface defect detection. In this method, MobileNetv3 is used as the backbone network of YOLOv4 to extract image features, and at the same time, deep separable convolution is applied on the PANet layer in YOLOv4, which realizes the lightweight network and real-time detection of the railway surface. The test results show that, compared with YOLOv4, the study can reduce the amount of the parameters by 78.04%, speed up the detection by 10.36 frames per second and decrease the model volume by 78%. Compared with other methods, the proposed method can achieve a higher detection accuracy, making it suitable for the fast and accurate detection of railway surface defects.

The Effects of Sidt2 on the Inflammatory Pathway in Mouse Mesangial Cells.

In patients with chronic kidney disease, the abnormal activation of inflammatory pathways is usually an important factor leading to renal fibrosis and further deterioration of renal function. Finding effective intervention targets of the inflammatory signaling pathway is an important way to treat chronic kidney disease. As a newly discovered lysosomal membrane protein, the correlation between SID1 transmembrane family member 2 (Sidt2) and the inflammatory signaling pathway has not been reported. The aim of this study was to investigate the effect of Sidt2 on inflammation by inhibiting the expression of the Sidt2 gene in a mouse mesangial cell line mediated by a lentiviral CRISPR/Cas9 vector. Hematoxylin and eosin staining and microscopy found that the mesangial cells lost their normal morphology after inhibiting the expression of Sidt2, showing that the cell body became smaller, the edge between the cells was unclear, and part of the nucleus was pyknotic and fragmented, appearing blue-black. The expressions of IKK ß, p-IKK α/ß, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the NF-κB pathway of the Sidt2 -/- group were higher than those of the Sidt2 +/+ group. p-Jak2 and IL6 increased in the Jak/Stat pathway, and p-ERK and p-P38 increased in the MAPK pathway. The expressions of IKK ß, p-IKK α/ß, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the NF-κB pathway of the Sidt2 +/++LPS group were significantly higher than those in the Sidt2 +/+ group. The expressions of IKK ß, p-IKK α/ß, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the Sidt2 -/-+LPS group were higher than those in the Sidt2 -/- group. The expressions of p-IKK α/ß, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the Sidt2 -/-+LPS group were higher than those in the Sidt2 +/++LPS group. In the Jak/Stat pathway, the protein expressions of p-Jak2 and IL6 in the Sidt2 +/++LPS group were higher than those in the Sidt2 +/+ group. The expressions of p-Jak2 and IL6 in the Sidt2 -/-+LPS group were higher than those in the Sidt2 -/- group. The expressions of p-Jak2 and IL6 in the Sidt2 -/-+LPS group were higher than those in the Sidt2 +/++LPS group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the MAPK pathway in the Sidt2 +/++LPS group were higher than those in the Sidt2 +/+ group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the Sidt2 -/-+LPS group were higher than those in the Sidt2 -/- group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the Sidt2 -/-+LPS group were higher than those in the Sidt2 +/++LPS group. These data suggested that deletion of the Sidt2 gene changed the three inflammatory signal pathways, eventually leading to the damage of glomerular mesangial cells in mice.

A meta-analysis and The Cancer Genome Atlas data of prostate cancer risk and prognosis using epithelial cell adhesion molecule (EpCAM) expression.

BACKGROUND: Epithelial cell adhesion molecule (EpCAM) expression has been reported in many types of cancer, including prostate cancer (PCa). However, the role of EpCAM expression remains inconsistent. We conducted a meta-analysis to assess the clinicopathological and prognostic significance of EpCAM expression in PCa. METHODS: Publications were searched online using electronic databases. The available data were obtained from The Cancer Genome Atlas (TCGA). The odds ratios (ORs) or hazard ratios (HRs) with their 95% confidence intervals (CIs) were calculated. RESULTS: We identified seven studies in which immunohistochemistry was used and that included 871 prostatic tissue samples. EpCAM expression was significantly higher in PCa samples than in benign and normal tissue samples (OR = 77.93, P = 0.002; OR = 161.61, P <  0.001; respectively). No correlation of EpCAM overexpression with pT stage and lymph node metastasis was observed; however, EpCAM overexpression showed a significant correlation with Gleason score (OR = 0.48, P = 0.012) and bone metastasis (OR = 145.80, P <  0.001). Furthermore, TCGA data showed that EpCAM overexpression was not closely correlated with age, pT stage, lymph node metastasis, number of lymph node, prostate-specific antigen level, Gleason score, biochemical recurrence, and overall survival. Based on multivariate Cox proportional-hazards regression analysis, a significant correlation was observed between EpCAM overexpression and 5-year worse biochemical recurrence free-survival. CONCLUSIONS: EpCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of PCa. Further studies are needed to verify these findings.

Autophagy dysregulation caused by ApoM deficiency plays an important role in liver lipid metabolic disorder.

Autophagy is thought to be a key mechanism in maintaining the balance of liver lipid metabolism. However, the relationship between apolipoprotein M (ApoM) and autophagy has not been reported, and the role of ApoM in triglyceride metabolism is still unclear. In this study, we investigated the correlation between ApoM and autophagy and liver triglyceride metabolism in ApoM-knockout animal and cellular models. First, we observed that spontaneous hepatic steatosis developed in the liver of adult ApoM-/- mice, which was presented as the accumulation of large quantities of lipid droplets in hepatocytes under electron microscopy; Oil Red O staining showed significant accumulation of triglycerides. At the molecular level, the expression of lipid synthesis-associated proteins (primarily triglyceride synthesis) as well as acetyl-CoA carboxylase alpha (ACACA), fatty acid synthase (FASN) and sterol regulatory element-binding protein 1 (SREBP1) was upregulated. Moreover, lipid metabolic disorder and accumulation were accompanied by dysfunction in autophagy, which displayed predominantly as inhibition of the degradation pathway; for example, P62 protein accumulated and key proteins involved in the initiation of autophagy including ATG7, ATG5-12, Beclin1 and the LC3BII/LC3BI ratio were upregulated as a feedback response. When the autophagy dysfunction was ameliorated by the activation of autophagy pathways induced by starvation, the lipid metabolic disorder was corrected to a certain extent. This suggests that the autophagy dysfunction caused by the deficiency of ApoM is an important factor in hepatic steatosis (triglyceride accumulation). ApoM plays a key role in normal autophagy activity in the liver and thereby further regulates the metabolism of liver lipids, particularly triglycerides.

Deletion of ApoM gene induces apoptosis in mouse kidney via mitochondrial and endoplasmic reticulum stress pathways.

Apolipoprotein M (ApoM) is involved in lipid metabolism, and especially is involved in reverse cholesterol transport. However, the relationship between ApoM and apoptosis has been rarely reported. This study aimed to investigate the effect of ApoM on apoptosis using an ApoM gene-deficient mice (ApoM-/-) model and a mouse mesangial cell model with suppressed ApoM gene expression. First, we observed by transmission electron microscopy that mitochondrial damage and endoplasmic reticulum stress were abnormally altered in the kidneys of ApoM-/- mice compared with wild-type mice, showing mitochondrial swelling, vacuolization, myeloid changes, and expansion of the rough endoplasmic reticulum. At the molecular level, the expression of pro-apoptotic related proteins such as AIF, Bax, chop, clever-caspase 3, clever-caspase 7, clever-caspase 9, and clever-caspase 12 increased, and the expression of anti-apoptotic protein Bcl-2 decreased. Secondly, by interfering with the expression of the ApoM gene in mouse mesangial cells, we found that, compared with the control group (NC-si), the cells of the experimental group (siApoM) showed decreased cell viability, nuclear chromatin condensation, nuclear lysis, and an increased proportion of early apoptotic cells. The results in cells at the molecular level were consistent with those at the tissue level. These data indicated that the deletion of the ApoM gene led to upregulation of apoptosis in mouse kidney tissues and mesangial cells through the mitochondrial and endoplasmic reticulum pathways.

Lower pole approach in retroperitoneal laparoscopic radical nephrectomy: a new approach for the management of renal vascular pedicle.

BACKGROUND: The objective of this study was to examine the effectiveness and safety of lower pole (LP) approach in retroperitoneal laparoscopic radical nephrectomy (LRN). METHODS: One hundred thirty-two renal cancer patients were scheduled for selective retroperitoneal LRN. The surgery parameters and outcomes were compared. Out of 132 patients, 78 (59.1%) patients underwent LRN via LP approach, while 54 (40.9%) patients underwent LRN via lateroposterior space (LPS) approach. RESULTS: Compared to LPS group, the LP group had a higher body mass index (27.0 ± 1.7 kg/m2 vs. 24.5 ± 1.8 kg/m2, P <  0.0001) and a larger tumor size (6.9 ± 3.5 cm vs. 4.1 ± 3.3 cm, P <  0.0001). The LP approach reduced the volumes of blood loss and transfusion significantly (135.3 ± 17.2 mL vs. 219.6 ± 30.9 mL, P <  0.0001; 55.6 ± 28.3 vs. 141.1 ± 50.4 mL, P <  0.0001) as compared to the LPS approach. The LP approach also decreased the risk of conversion to open procedure (1.3 vs. 7.4%, P <  0.05). CONCLUSIONS: The LP approach is an effective and safe alternative to the LPS approach for retroperitoneal LRN and might be more suitable for patients with obesity, large tumors, tumors located at the medial part of the kidney, or renal pedicular adhesion.

Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice.

Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2(-/-) mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2(-/-) mice, there were obvious fat degeneration and inflammatory changes. Almost all of the liver cells demonstrated different levels of lipid droplet accumulation and cell swelling, and some of the cells demonstrated balloon-like changes. Infiltration of inflammatory cells was observed in the portal area and hepatic lobule. Electron microscopy showed that macrophages tended to be attached to the endothelial cells, and a large number of lipid droplets were present in the liver cells. Oil red O staining showed that there were significantly increased number of deep straining particles in the liver cells of Sidt2(-/-) mice, and the TG content in liver tissue was also significantly increased. Detection of key genes and proteins related to fat synthesis showed that mRNA and protein levels of the SREBP1c in the liver of Sidt2(-/-) mice were significantly elevated, and the downstream genes acetyl-CoA carboxylase, fatty acid synthase, and mitochondrial glycerol 3-phosphate acyltransferase were significantly upregulated. In addition, there was severe endoplasmic reticulum stress (ERS) in the liver of Sidt2(-/-) mice, which had significantly increased levels of markers specific for unfolded protein response activation, Grp78 and CHOP, as well as significant elevation of downstream p-PERK, p-eIF2a, p-IRE1a, along with ER damage. These results suggest that Sidt2(-/-) mice had spontaneous nonalcoholic fatty liver disease (NAFLD) accompanied by ERS. In summary, as a lysosomal membrane protein, Sidt2 plays an important role in the pathogenesis of NAFLD, and ERS may mediate the occurrence and development of this disease in Sdit2 deficiency mice.

Endoplasmic reticulum stress of Kupffer cells involved in the conversion of natural regulatory T cells to Th17 cells in liver ischemia-reperfusion injury.

BACKGROUND AND AIM: Our previous studies have shown that regulatory T cells (Tregs) are reduced and Th17 cells are elevated in liver insults. Recent studies have indicated the critical role of endoplasmic reticulum (ER) stress of Kupffer cells (KCs) in evoking liver inflammation following reperfusion. The objective of this study was to investigate the role of ER stress of KCs in the conversion of Tregs to Th17 cells and the effect on liver ischemia-reperfusion injury. METHODS: The partial warm liver ischemia-reperfusion injury mouse model was adopted. ER stress of KCs and the frequency of Tregs and Th17 cells following reperfusion were analyzed. Apart from depletion and adoptive transfer of KCs, KCs were isolated from ischemic lobes and co-cultured with Tregs to study the effect of KCs on Tregs and Th17 cells. RESULTS: It was found that KCs induced ER stress, decreased natural Tregs (nTregs), and increased Th17 cells after reperfusion. Depletion of KCs modulated the reduction of nTregs and elevation of Th17 cells. Co-culture with stressed KCs led to the reduction in nTregs and elevation of Th17 cells. This effect was suppressed by anti-interleukin-6. Adoptive transfer of these stressed KCs resulted in the reduction in nTregs and elevation of Th17 cells and caused liver injury. CONCLUSION: Endoplasmic reticulum stress of KCs contributed to the conversion of nTregs to Th17 cells due to interleukin-6, resulting in the worsening of liver insult.

Effects of hyperlipidaemia on plasma apolipoprotein M levels in patients with type 2 diabetes mellitus: an independent case-control study.

BACKGROUND: Apolipoprotein M (apoM) is mainly enriched in high-density lipoprotein (HDL) cholesterol and is slightly present in low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein cholesterol. apoM is involved in HDL formation and HDL-mediated reverse cholesterol transport. apoM is also associated with hyperlipidaemia and type 2 diabetes mellitus (T2DM). Significantly high plasma apoM levels are detected in hyperlipidaemia mice with a defective LDL receptor. By contrast, low plasma apoM levels are observed in patients with T2DM, which is often accompanied with hyperlipidaemia. However, the underlying mechanism of this condition is poorly understood. This research aims to examine the changes in apoM levels in patients with hyperlipidaemia and to determine the effects of hyperlipidaemia on plasma apoM levels in patients with T2DM. METHODS: This study included patients with hyperlipidaemia (n = 79), patients with T2DM but without hyperlipidaemia (n = 125), patients with T2DM and hyperlipidaemia (n = 98), and healthy controls (n = 105). Their plasma apoM concentrations were measured with enzyme-linked immunosorbent assay. RESULTS: The average plasma apoM concentrations were 18 % higher in the hyperlipidaemia group (26.63 ± 10.35 ng/µL) than in the healthy controls (22.61 ± 10.81 ng/µL, P <0.01). The plasma apoM concentrations were lower in the T2DM without hyperlipidaemia group (18.54 ± 10.33 ng/µL, P <0.01) and the T2DM with hyperlipidaemia group (19.83 ± 7.41 ng/µL, P <0.05) than in the healthy controls. Similar to apoA-I (1.29 ± 0.33 g/L vs. 1.28 ± 0.31 g/L, P >0.05), the plasma apoM concentrations in the T2DM with hyperlipidaemia group did not significantly differ from those in the T2DM without hyperlipidaemia group (P >0.05). Multivariate linear regression analysis showed that hyperlipidaemia (ß = 5.18, P = 0.007) is an independent promoting factor of plasma apoM levels and diabetes (ß = -3.09, P = 0.005) is an inhibiting factor of plasma apoM levels. CONCLUSION: Plasma apoM concentrations are higher in patients with hyperlipidaemia than in healthy controls. Low plasma apoM levels in patients with T2DM are likely caused by diabetes but are not induced by hyperlipidaemia.

A single-nucleotide polymorphism C-724 /del in the proter region of the apolipoprotein M gene is associated with type 2 diabetes mellitus.

BACKGROUND: Apolipoprotein M (apoM) was the carrier of the biologically active lipid mediator sphingosine-1-phospate in high density lipoprotein cholesterol (HDL-C) and played a critical role in formation and maturation of prebeta-HDL-C particles. The plasma apoM levels were decreased obviously in patients with type 2 diabetes mellitus (T2DM). A new single-nucleotide polymorphism (SNP) C-724del in apoM promoter was associated with a higher risk for coronary artery diseases (CAD) and myocardial infarction, could reduce promoter activities and apoM expression in vitro. The primary aim of the present case-controls study was to investigate the effect of apoM SNP C-724del on apoM expression in vivo and its association with T2DM susceptibility in an eastern Han Chinese cohort. METHODS: Two hundred and fifty-nine T2DM patients and seventy-six healthy controls were included in this study. Amplifying DNA of apoM proximal promoter region including SNP C-724del by Real-Time Polymerase Chain Reaction (RT-PCR) and amplicons sequencing. The plasma apoM concentrations were assayed by enzyme linked immunosorbentassay (ELISA). RESULTS: Four polymorphic sites, rs805297 (C-1065A), rs9404941 (T-855C), rs805296 (T-778C), C-724del were confirmed. rs805297 (C-1065A) and rs9404941 (T-855C) showed no statistical difference in allele frequencies and genotype distributions between T2DM patients and healthy controls just as previous studies. It's worth noting that the difference of rs805296 (T-778C) between these two groups was not found in this study. In SNP C-724del, the frequency of del allele and mutant genotypes (del/del, C/del) were higher in T2DM patients compared with healthy controls (p = 0.035; P = 0.040, respectively), while the plasma apoM levels of C-724del mutant allele carriers compared with the wide-type homozygotes carriers were not statistically different in T2DM patients (18.20 ± 8.53 ng/uL vs 20.44 ± 10.21 ng/uL, P = 0.245). CONCLUSION: The polymorphism C-724del in the promoter region of the apoM gene could confer the risk of T2DM among eastern Han Chinese. Unfortunately, the lowing of plasma apoM levels of C-724del mutant allele carriers compared with the wide-type homozygotes carriers in T2DM patients was not statistically different in present study, so further researchs were needed by enlarging the sample.

EBER-negative inflammatory pseudotumor-like follicular dendritic cell sarcoma of liver: A case report.

RATIONALE: Inflammatory pseudotumor-like follicular dendritic cell sarcoma (IPT-like FDCS) of the liver is rare. It was previously believed that Epstein-Barr virus (EBV) positivity was a necessary criterion for pathological diagnosis. However, we found that there were also cases of EBV negativity. Therefore, clinicians and pathologists are reminded that EBV positivity is not a necessary condition for diagnosis. PATIENT CONCERNS: A 70-year-old female underwent computed tomography (CT) examination for upper abdominal discomfort, which revealed the presence of a liver tumor. Follow-up revealed that the tumor had progressively increased in size. DIAGNOSIS: The final diagnosis was an IPT-like follicular cell sarcoma, based on CT, MRI, HE staining, and immunohistochemical staining. INTERVENTIONS: The patient underwent a laparoscopic left hemihepatectomy. OUTCOMES: The patient has not undergone any special treatment, such as radiotherapy and chemotherapy, and has been followed up for over 3 years without experiencing any recurrence. LESSONS: IPT-like FDCS is a rare tumor that lacks definitive criteria, and its diagnosis mainly relies on pathological findings. Previously, it was believed that being EBV-positive was an important condition for diagnosis. Primary IPT-like FDCS in the liver is even rarer, and the patient in this case tested negative for EBV. It may be necessary for pathologists to consider the role of EBV in the diagnosis of IPT-like FDCS.

Causal effects of plasma metabolites on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study.

Background: Despite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD. Methods: A genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction. Results: Our thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy. Conclusion: This study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.

A Flexible Long-Wave Infrared Radiation Modulator Integrated with Electrochromic Behavior for Dual-Band Camouflage.

Electrochromic devices (ECDs), which are capable of modulating optical properties in the visible and long-wave infrared (LWIR) spectra under applied voltage, are of great significance for military camouflage. However, there are a few materials that can modulate dual frequency bands. In addition, the complex and specialized structural design of dual-band ECDs poses significant challenges. Here, we propose a novel approach for a bendable ECD capable of modulating LWIR radiation and displaying multiple colors. Notably, it eliminates the need for a porous electrode or a grid electrode, thereby improving both the response speed and fabrication feasibility. The device employs multiwalled carbon nanotubes (MWCNTs) as both the transparent electrode and the LWIR modulator, polyaniline (PANI) as the electrochromic layer, and ionic liquids (HMIM[TFSI]) as the electrolyte. The ECD is able to reduce its infrared emissivity (Δε = 0.23) in a short time (resulting in a drop in infrared temperature from 50 to 44 °C) within a mere duration of 0.78 ± 0.07 s while changing its color from green to yellow within 3 s when a positive voltage of 4 V is applied. In addition, it exhibits excellent flexibility, even under bending conditions. This simplified structure provides opportunities for applications such as wearable adaptive camouflage and multispectral displays.

GABA Analogue HSK16149 in Chinese Patients With Diabetic Peripheral Neuropathic Pain: A Phase 3 Randomized Clinical Trial.

Importance: Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China. Objective: To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP. Design, Setting, and Participants: This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose. Intervention: In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment. Main Outcomes and Measures: The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences. Results: Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common. Conclusions and Relevance: Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04647773.

NOX, the main regulator in oxidative stress in experimental models of phenylketonuria?

AIM: To reveal the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in the integration of the redox signal in the oxidative molecular regulation mechanism in phenylketonuria (PKU). METHODS: The blood samples were obtained from Pahenu2-BTBR PKU and wild-type mice, respectively. Phe concentration, total antioxidant capacity (T-AOC), glutathione (GSH) and maleic dialdehyde (MDA) were analyzed. After collection of the mononuclear cells, reverse transcription polymerase chain reaction (RT-PCR) for NOX was performed. In addition, NOX activity and superoxide in mononuclear cells were determined. RESULTS: Compared to the control group, Phe concentration, T-AOC and MDA were markedly increased in PKU mice (p<0.01, p<0.05, p<0.01, respectively). However, the GSH level in PKU mice was less than that in control group (p<0.05). The mRNA level of subunits of NOX included p47phox and p67phox, were increased in PKU mice (p<0.05), however, the gp91phox had no obvious change in the two groups (p>0.05). NOX activity and superoxide were also remarkably elevated in PKU mice (p<0.05). CONCLUSION: NOX may play an important role in the integration of the redox signal in the oxidative molecular regulation mechanism in PKU.

The role of lysosomal membrane proteins in autophagy and related diseases.

As a self-degrading and highly conserved survival mechanism, autophagy plays an important role in maintaining cell survival and recycling. The discovery of autophagy-related (ATG) genes has revolutionized our understanding of autophagy. Lysosomal membrane proteins (LMPs) are important executors of lysosomal function, and increasing evidence has demonstrated their role in the induction and regulation of autophagy. In addition, the functional dysregulation of the process mediated by LMPs at all stages of autophagy is closely related to neurodegenerative diseases and cancer. Here, we review the role of LMPs in autophagy, focusing on their roles in vesicle nucleation, vesicle elongation and completion, the fusion of autophagosomes and lysosomes, and degradation, as well as their broad association with related diseases.

The functions of SID1 transmembrane family, member 2 (Sidt2).

The SID1 transmembrane family, member 2, namely, Sidt2, is a highly glycosylated multichannel lysosomal transmembrane protein, but its specific physiological function remains unknown. Lysosomal membrane proteins are very important for the executive functioning of lysosomes. As an important part of the lysosomal membrane, Sidt2 can maintain the normal morphology of lysosomes and help stabilize them from the acidic pH environment within. As a receptor/transporter, it binds and transports nucleic acids and mediates the uptake and degradation of RNA and DNA by the lysosome. During glucose metabolism, deletion of Sidt2 can cause an increase in fasting blood glucose and the impairment of grape tolerance, which is closely related to the secretion of insulin. During lipid metabolism, the loss of Sidt2 can cause hepatic steatosis and lipid metabolism disorders and can also play a role in signal regulation and transport. Here, we review the function of the lysosomal membrane protein Sidt2, and focus on its role in glucose and lipid metabolism, autophagy and nucleotide (DNA/RNA) transport.