Modulating JAK2/STAT3 signaling by quercetin in Qiling Baitouweng Tang: a potential therapeutic approach for diffuse large B-cell lymphoma.

Qiling Baitouweng Tang (QLBTWT) is a traditional clinical formula for treating diffuse large B-cell lymphoma (DLBCL), but its molecular action is not fully understood. This research is utilized in silico analysis and liquid chromatography tandem mass spectrometry (LC‒MS/MS) to identify the active constituents of QLBTWT with anti-DLBCL properties and their targets. The study identified 14 compounds, including quercetin, naringenin, and astilbin, as potentially effective against DLBCL. Molecular modeling highlighted the favorable interaction of quercetin with the JAK2 protein. In vitro studies confirmed the ability of quercetin to inhibit DLBCL cell growth and migration while inducing apoptosis and causing G2/M phase cell cycle arrest. Molecular dynamics simulations revealed that quercetin binds to JAK2 as a type II inhibitor. In vivo studies in U2932 xenograft models demonstrated that QLBTWT inhibited tumor growth in a dose-dependent manner, which was associated with the JAK2/STAT3 signaling pathway. Overall, this study elucidates the therapeutic effect of QLBTWT on DLBCL through quercetin-mediated suppression of the JAK2/STAT3 pathway, offering novel therapeutic insights for DLBCL.

Prophylactic Dose of Rivaroxaban Versus Warfarin for the Treatment of Isolated Calf Muscle Vein Thrombosis: A Retrospective Propensity Score-Matched Analysis.

BACKGROUND: Prophylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT); nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy. METHODS: A retrospective analysis of 472 ICMVT patients who received 2 different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching. RESULTS: 242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); no major bleeding events occurred in each group, and clinically relevant nonmajor bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619-3.347, P = 0.397) and clinically relevant nonmajor bleeding events (odds ratio 0.483, 95% confidence interval 0.161-1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the 2 groups (odds ratio 0.589, 95% confidence interval 0.375-0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm), and risk factors for VTE (nonsurgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05). CONCLUSIONS: In this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR >2.0 for >50% of the time); but it was not conducive to complete clot resolution.

Phlorizin from Lithocarpus litseifolius [Hance] Chun ameliorates FFA-induced insulin resistance by regulating AMPK/PI3K/AKT signaling pathway.

BACKGROUND: Insulin resistance (IR) is the central pathophysiological feature in the pathogenesis of metabolic syndrome, obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia. As the main active ingredient in Lithocarpus litseifolius [Hance] Chun, previous studies have shown that phlorizin (PHZ) can reduce insulin resistance in the liver. However, the effect of phlorizin on attenuating hepatic insulin resistance has not been fully investigated, and whether this effect is related to AMPK remains unclear. PURPOSE: The present study aimed to further investigate the effect of phlorizin on attenuating insulin resistance and the potential action mechanism. METHODS: Free fatty acids (FFA) were used to induce insulin resistance in HepG2 cells. The effects of phlorizin and FFA on cell viability were detected by MTT analysis. Glucose consumption, glycogen synthesis, intracellular malondialdehyde (MDA), superoxide dismutase (SOD), total cholesterol (TC), and triglyceride (TG) contents were quantified after phlorizin treatment. Glucose uptake and reactive oxygen species (ROS) levels in HepG2 cells were assayed by flow cytometry. Potential targets and signaling pathways for attenuating insulin resistance by phlorizin were predicted by network pharmacological analysis. Moreover, the expression levels of proteins related to the AMPK/PI3K/AKT signaling pathway were detected by western blot. RESULTS: Insulin resistance was successfully induced in HepG2 cells by co-treatment of 1 mM sodium oleate (OA) and 0.5 mM sodium palmitate (PA) for 24 h. Treatment with phlorizin promoted glucose consumption, glucose uptake, and glycogen synthesis and inhibited gluconeogenesis in IR-HepG2 cells. In addition, phlorizin inhibited oxidative stress and lipid accumulation in IR-HepG2 cells. Network pharmacological analysis showed that AKT1 was the active target of phlorizin, and the PI3K/AKT signaling pathway may be the potential action mechanism of phlorizin. Furthermore, western blot results showed that phlorizin ameliorated FFA-induced insulin resistance by activating the AMPK/PI3K/AKT signaling pathway. CONCLUSION: Phlorizin inhibited oxidative stress and lipid accumulation in IR-HepG2 cells and ameliorated hepatic insulin resistance by activating the AMPK/PI3K/AKT signaling pathway. Our study proved that phlorizin played a role in alleviating hepatic insulin resistance by activating AMPK, which provided experimental evidence for the use of phlorizin as a potential drug to improve insulin resistance.

Renal cell carcinoma in an adult-onset ESRD patient with nephronophthisis harboring NPHP3 deletion: A case report.

Background: Nephronophthisis (NPHP) is a rare autosomal recessive inherited tubulointerstitial nephropathy, the most prevalent genetic cause of end-stage renal disease (ESRD) in children. Convincing evidence indicated that the overall prevalence of NPHP in adult-onset ESRD is very likely to be an underestimation. Therefore, understanding the genetic background and clinicopathologic features of adult-onset NPHP is warranted. Case presentation: we reported one intriguing case with concurrent NPHP3 c.2694-2_2694-1delAG (splicing) variant and c.1082C > G (p.S361C) variant. A 48-year-old male was admitted to our hospital, complained about renal dysfunction for 10 years, and found right renal space-occupying lesion for 1 week. One of the most interesting clinical features is adult-onset ESRD, which differs from previous cases. Another discovery of this study is that the NPHP harboring NPHP3 deletion may be associated with clear cell renal cell carcinoma. Conclusion: In conclusion, we report two mutations in the NPHP3 gene that cause NPHP with adult-onset ESRD and renal clear cell carcinoma in a Chinese family, enriching the clinical features of NPHP.

Enhancing nasopharyngeal carcinoma cell radiosensitivity by suppressing AKT/mTOR via CENP-N knockdown.

OBJECTIVE: Investigating the impact of centromere protein N (CENP-N) on radiosensitivity of nasopharyngeal carcinoma (NPC) cells. METHODS: Using immunohistochemistry and immunofluorescence to detect CENP-N expression in tissues from 35 patients with radiosensitive or radioresistant NPC. Assessing the effect of combined CENP-N knockdown and radiotherapy on various cellular processes by CCK-8, colony formation, flow cytometry, and Western blotting. Establishing a NPC xenograft model. When the tumor volume reached 100 mm3, a irradiation dose of 6 Gy was given, and the effects of the combined treatment were evaluated in vivo using immunofluorescence and Western blotting techniques. RESULTS: The level of CENP-N was significantly reduced in radiosensitive tissues of NPC (p < 0.05). Knockdown of CENP-N enhanced NPC radiosensitivity, resulting in sensitizing enhancement ratios (SER) of 1.44 (5-8 F) and 1.16 (CNE-2Z). The combined treatment showed significantly higher levels of proliferation suppression, apoptosis, and G2/M phase arrest (p < 0.01) compared to either CENP-N knockdown alone or radiotherapy alone. The combined treatment group showed the highest increase in Bax and γH2AX protein levels, whereas the protein Cyclin D1 exhibited the greatest decrease (p < 0.01). However, the above changes were reversed after treatment with AKT activator SC79. In vivo, the mean volume and weight of tumors in the radiotherapy group were 182 ± 54 mm3 and 0.16 ± 0.03 g. The mean tumor volume and weight in the combined treatment group were 84 ± 42 mm3 and 0.04 ± 0.01 g. CONCLUSION: Knockdown of CENP-N can enhance NPC radiosensitivity by inhibiting AKT/mTOR.

Nickel-Catalyzed Reductive Cross-Coupling of Aziridines and Allylic Chlorides.

A nickel-catalyzed reductive cross-coupling of aziridines and allylic chlorides was realized by using manganese metal as the reducing agent. This protocol afforded a convenient approach to obtain ß-allyl-substituted arylethylamines bearing various functional groups. The utility of this reaction was also demonstrated by scale-up preparation and diverse transformations, including the synthesis of Baclofen and several bioactive molecular motifs.

Development and validation a model for predicting overall survival of bladder cancer with lung metastasis: a population-based study.

BACKGROUND: Although the number of patients with bladder cancer and lung metastasis is increasing there is no accurate model for predicting survival in these patients. METHODS: Patients enrolled in the Surveillance, Epidemiology, and End Results database between 2010 and 2015 were selected for the study. Univariate and multivariate Cox regression were used to determine independent prognostic factors, followed by development of a nomogram based on the multivariate Cox regression models. The consistency index, receiver operating characteristic curve, and calibration curve were used to validate the prognostic nomogram. RESULTS: 506 eligible bladder cancer patients with lung metastasis were enrolled in the study and then divided randomly into training and validation sets (n = 356 vs. n = 150). Multivariate Cox regression analysis indicated that age at diagnosis, primary site, histological type, surgery of the primary site, chemotherapy, bone metastasis, and liver metastasis were prognostic factors for overall survival (OS) in patients with lung metastasis in the training set. The C-index of the nomogram OS was 0.699 and 0.747 in the training and validation sets, respectively. ROC curve estimation of the nomogram in the training and validation sets showed acceptable accuracy for classifying 1-year survival, with an area under the curve (AUC) of 0.766 and 0.717, respectively. More importantly, the calibration plot showed the nomogram had favorable predictive accuracy in both the training and validation sets. CONCLUSIONS: The prognostic nomogram created in our study provides an individualized diagnosis, remedy, and risk evaluation for survival in patients with bladder cancer and lung metastasis. The nomogram would therefore enable clinicians to make more precise treatment decisions for patients with bladder cancer and lung metastasis.

Specific knockout of Notch2 in Treg cells significantly inhibits the growth and proliferation of head and neck squamous cell carcinoma in mice.

OBJECTIVE: To investigate the effect of Notch2 gene knockout in Treg cells on head and neck squamous cell carcinoma (HNSCC) in mice. METHODS: A mouse model of HNSCC was constructed. Flow cytometry and immunofluorescence were used to examine the numbers of related immune cells and programmed cell death in tumor cells in the spleen and tumor microenvironment of mice. Western blotting was used to measure the expression of related proteins in tumor tissues. RESULTS: The tumor volume of regulatory T (Treg) cell-specific Notch2-knockout mice (experimental group) was significantly smaller than that of control mice (control group) (P < 0.05). Compared with those in the control group, the number of Treg cells and the expression of Ki67 in Treg cells in the spleen and tumor tissue were significantly decreased in the experimental group, while the numbers of CD45+ hematopoietic cells, CD4+ T cells, CD8+ T cells, T helper 1 (Th1) cells, CD11b+ cells (macrophages), and CD11b+CD11c+ cells (dendritic cells) and the expression of Ki67 in CD4+ T cells and CD8+ T cells were significantly increased (P < 0.05). There was no significant difference in the number of Th2 cells between the two groups (P > 0.05). Immunofluorescence analysis showed that the numbers of CD4+ T cells and CD8+ T cells in the tumor tissue in the experimental group were significantly higher than those in the control group (P < 0.05). Compared with that in the control group, programmed cell death in the experimental group was significantly increased (P < 0.05). Moreover, the expression levels of NLRP3, Caspase-1 and GSDMD in the tumor tissues of the experimental group were higher than those in the control group (P < 0.01), while the expression levels of BCL2, Bax, ATG5, LC3 and p62 were not significantly different (P > 0.05). CONCLUSIONS: Specific knockout of the Notch2 gene in Treg cells significantly decreases the function of Treg cells, inhibits the growth of HNSCC and improves the immune microenvironment in mice, thus effectively treating HNSCC.

In Vivo and In Vitro Assay to Address Dendritic Cell Antigen Cross-Presenting Capacity.

Antigen cross-presentation by dendritic cells is an important pathway to prime CD8+ T cells in infections, cancer, and other immune-mediated pathologies. Particularly in cancer, cross-presentation of tumor-associated antigens is crucial for an effective antitumor CTL response. The mostly accepted cross-presentation assay is to use chicken ovalbumin (OVA) as a model antigen and then utilize OVA-specific TCR transgenic CD8+ T (OT-I) cells to measure the cross-presenting capacity. Here we describe in vivo and in vitro assays to measure the function of antigen cross-presentation using cell-associated OVA.

Methyl eugenol protects the kidney from oxidative damage in mice by blocking the Nrf2 nuclear export signal through activation of the AMPK/GSK3ß axis.

Disrupted redox homeostasis contributes to renal ischemia-reperfusion (IR) injury. Abundant natural products can activate nuclear factor erythroid-2-related factor 2 (Nrf2), thereby providing therapeutic benefits. Methyl eugenol (ME), an analog of the phenolic compound eugenol, has the ability to induce Nrf2 activity. In this study, we investigated the protective effects of ME against renal oxidative damage in vivo and in vitro. An IR-induced acute kidney injury (AKI) model was established in mice. ME (20 mg·kg-1·d-1, i.p.) was administered to mice on 5 consecutive days before IR surgery. We showed that ME administration significantly attenuated renal destruction, improved the survival rate, reduced excessive oxidative stress and inhibited mitochondrial lesions in AKI mice. We further demonstrated that ME administration significantly enhanced Nrf2 activity and increased the expression of downstream antioxidative molecules. Similar results were observed in vitro in hypoxia/reoxygenation (HR)-exposed proximal tubule epithelial cells following pretreatment with ME (40 µmol·L-1). In both renal oxidative damage models, ME induced Nrf2 nuclear retention in tubular cells. Using specific inhibitors (CC and DIF-3) and molecular docking, we demonstrated that ME bound to the binding pocket of AMPK with high affinity and activated the AMPK/GSK3ß axis, which in turn blocked the Nrf2 nuclear export signal. In addition, ME alleviated the development of renal fibrosis induced by nonfatal IR, which is frequently encountered in the clinic. In conclusion, we demonstrate that ME modulates the AMPK/GSK3ß axis to regulate the cytoplasmic-nuclear translocation of Nrf2, resulting in Nrf2 nuclear retention and thereby enhancing antioxidant target gene transcription that protects the kidney from oxidative damage.

Primary intestinal lymphangiectasia presenting as limb convulsions: A case report.

BACKGROUND: Primary intestinal lymphangiectasia (PIL) is a rare protein-losing enteropathy characterized by abnormally dilated lymphatic structures, resulting in leakage of lymph (rich in protein, lymphocytes, and fat) from the intestinal mucosal and submucosal layers and thus hypoproteinemia, lymphopenia, hypolipidemia, and pleural effusion. CASE SUMMARY: A 19-year-old Chinese male patient complained of recurrent limb convulsions for the last 1 year. Laboratory investigations revealed low levels of calcium and magnesium along with hypoproteinemia and high parathyroid hormone levels, whereas gastroscopy exhibited chronic non-atrophic gastritis and duodenal lymphatic dilatation. Subsequent gastric biopsy showed moderate chronic inflammatory cell infiltration distributed around a small mucosal patch in the descending duodenum followed by lymphatic dilatation in the mucosal lamina propria, which was later diagnosed as PIL. The following appropriate medium-chain triglycerides nutritional support significantly improved the patient's symptoms. CONCLUSION: Since several diseases mimic the clinical symptoms displayed by PIL, like limb convulsions, low calcium and magnesium, and loss of plasma proteins, it is imperative to conduct a detailed analysis to avoid any misdiagnosis while pinpointing the correct clinical diagnosis and simultaneously ruling out other clinical aspects in the reported cases without any past disease history. A careful assessment should always be made to ensure an accurate diagnosis in a timely manner so that the patient can be delivered quality health services for a positive health outcome.

Nickel-Catalyzed Three-Component Cross-Electrophile Coupling of 1,3-Dienes with Aldehydes and Aryl Bromides.

We herein report a Ni-catalyzed three-component cross-electrophile coupling of 1,3-dienes with aldehydes and aryl bromides using manganese metal as the reducing agent. This efficient protocol accomplishes dicarbofunctionalization of 1,3-dienes to synthesize diverse structural 1,4-disubstituted homoallylic alcohols by forming two new C-C bonds in one time. Mechanistic study suggests that an allyl-nickel(I) species is involved in the catalytic cycle.

Seed oil of Rosa roxburghii Tratt against non-alcoholic fatty liver disease in vivo and in vitro through PPARα/PGC-1α-mediated mitochondrial oxidative metabolism.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis and hepatocyte injury, is an obesity-induced metabolic dysregulation with few available therapeutic options. Enhancement of the mitochondrial function was considered as an effective treatment for NALFD. Unsaturated fatty acids (UFAs) have been shown to have beneficial effects on metabolic syndrome disease such as hyperlipidemia, coronary artery disease and cardiovascular diseases. The seed oil of Rosa roxburghii Tratt (ORRT) was of high quality in terms of its high amount of unsaturated fatty acids. However, the effects of ORRT on NALFD have not been reported so far. PURPOSE: The study aimed to evaluate the protective effects and molecular mechanism of ORRT for the treatment of NAFLD in vivo and in vitro. METHODS: The beneficial effects, especially improving the mitochondrial function, and the potential mechanism of ORRT on NAFLD were studied both in vivo and in vitro. Lipid levels were determined by triglyceride (TG), total cholesterol (TC), and Oil Red O staining. Oxidative stress and inflammation were assessed by detecting antioxidant enzyme activity, MDA content, and ELISA assay. Blood TG, TC, HDL-c and LDL-c levels were measured in HFD mice. Western blot analyses were used to determine the levels of the protein involved in fatty acid oxidation, oxidative metabolism, and mitochondria biogenesis and function. The mitochondrial membrane potential level was measured by JC-1 staining to teste the effect of ORRT on mitochondrial function in vitro. GW6471 (inhibitor of PPARα) was used to confirm the relationship between PPARα and PGC-1α. RESULTS: ORRT significantly restrained NAFLD progression by attenuating lipid accumulation, oxidative stress and inflammatory response. Furthermore, ORRT upregulated thermogenesis-related gene expressions, such as uncoupling protein 1 (UCP1) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that the expression of key genes involved in fatty acid oxidation (e.g., CPT-1α, ACADL, PPARα) and in mitochondrial biogenesis and function (e.g., TFAM, NRF1, PGC-1α, and COX IV) was significantly increased. Together with the observed MMP improvement, these findings suggested that ORRT activated the mitochondrial oxidative pathway. Additionally, GW6471 inhibited the ORRT on promoting the expression of PGC-1α, CPT-1α, and ACADL. In conclusion, ORRT possessed the potential to prevent lipid accumulation via the PPARα/PGC-1α signaling pathway, which could be developed as a natural health-promoting oil against NAFLD.

[Effect of Celastrol Based on IRAK4/ERK/p38 Signaling Pathway on Proliferation and Apoptosis of Multiple Myeloma Cells].

OBJECTIVE: To investigate the effect of celastrol on the proliferation and apoptosis of human multiple myeloma (MM) cell lines, reveal the relationship between IRAK4/ERK/p38 signaling pathway and celastrol regulating the proliferation and apoptosis of H929 and ARP-1 cells, and explore whether celastrol combined with bortezomib has synergistic effect. METHODS: CCK-8 method was used to detect the viability of MM cell lines H929 and ARP-1 treated by different concentrations of celastrol, bortezomib, and their combination, and the synergistic effect was determined by Kim's formula. The apoptosis rate of H929 cells and necrosis rate of ARP-1 were detected by Annexin V/PI method. The expression of key proteins and apoptosis proteins in IRAK4/ERK/p38 signaling pathway were detected by Western blot. RESULTS: Celastrol could significantly inhibit the proliferation of H929 and ARP-1 cells (r=0.9018, r=0.9244) and induce apoptosis in a time-dependent manner. Compared with the control group, celastrol could significantly up-regulate the expression of PARP and cleaved caspase-3 while down-regulate the expression of p-IRAK4, p-ERK, and p-p38 in H929 and ARP-1 cells. Celastrol and bortezomib alone inhibited the proliferation of H929 and ARP-1 cells. Compared with celastrol and bortezomib alone, their combination had lower cell survival rate and higher apoptosis rate (P<0.05). CONCLUSION: Celastrol can inhibit the proliferation and promote the apoptosis of H929 and ARP-1 cells, which may be related to inhibiting the phosphorylation of IRAK4 and blocking the activation of IRAK4/ERK/p38 signaling pathway. Celastrol combined with bortezomib has synergistic effect, which can more effectively inhibit the proliferation and induce apoptosis of H929 and ARP-1 cells.

Clinicopathological features of neuronal intranuclear inclusion disease diagnosed by skin biopsy.

STUDY OBJECTIVES: Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder, with complex and diverse of clinical manifestations characterized by eosinophilic hyaline inclusions in neurons and somatic cells. Due to the improvement in diagnostic methods, NIID is being increasingly diagnosed. METHODS: Herein, we reported three NIID cases, which were diagnosed by skin biopsy and FMR1 gene, after DWI showed the characteristic corticomedullary junction hyperintensity. Then we reviewed all the published cases of NIID in PubMed, which were diagnosed by the same method. RESULTS: We discussed 15 NIID cases, including three cases diagnosed by us. The average age was 63.4 ± 14.0 years. The average time from onset of symptom to diagnosis was 5.4 ± 7.9 years. Nine cases had dementia or cognitive impairment. Three cases presented with encephalitis. Three cases showed bladder dysfunction and two cases only presented with dizziness and headache. Two cases showed acute neurological deficit mimicking stroke. All cases were diagnosed by skin biopsy, after DWI showed abnormal corticomedullary junction hyperintensity. Ten cases showed inclusions in sweat gland cells, and seven cases in adipocytes, sweat gland cells, and fibroblasts. EMG was performed in five cases, four of whom had abnormal results, showing simultaneous involvement of motor and sensory nerves. CONCLUSIONS: The results indicated that inclusions were more easily detected in sweat gland cells in skin biopsy. The early stage of NIID could only characterized by autonomic nerve function involvement. Combined autonomic nerve dysfunction might be another relatively common manifestation in NIID.

SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury.

Tubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein 130 (SAP130) from the damaged tubular cells mediated necroinflammation by triggering macrophage activation via miRNA-219c(miR-219c)/Mincle-dependent mechanism in unilateral ureteral obstruction (UUO) and cisplatin-induced AKI mouse models, and in patients with acute tubule necrosis (ATN). In the AKI kidneys, we found that Mincle expression was tightly correlated to the necrotic tubular epithelial cells (TECs) with higher expression of SAP130, a damaged associated molecule pattern (DAMP), suggesting that SAP130 released from damaged tubular cells may trigger macrophage activation and necroinflammation. This was confirmed in vivo in which administration of SAP130-rich supernatant from dead TECs or recombinant SAP130 promoted Mincle expression and macrophage accumulation which became worsen with profound tubulointerstitial inflammation in LPS-primed Mincle WT mice but not in Mincle deficient mice. Further studies identified that Mincle was negatively regulated via miR-219c-3p in macrophages as miR-219c-3p bound Mincle 3'-UTR to inhibit Mincle translation. Besides, lentivirus-mediated renal miR-219c-3p overexpression blunted Mincle and proinflammatory cytokine expression as well as macrophage infiltration in the inflamed kidney of UUO mice. In conclusion, SAP130 is released by damaged tubules which elicit Mincle activation on macrophages and renal necroinflammation via the miR-219c-3p-dependent mechanism. Results from this study suggest that targeting miR-219c-3p/Mincle signaling may represent a novel therapy for AKI.

Original Designed Uniportal-Bichannel Spinal Endoscopic System (UBiSES) for Foraminoplasty in Percutaneous Endoscopic Transforaminal Discectomy.

OBJECTIVE: The study introduced uniportal-bichannel spinal endoscopic system (UBiSES) and explored the feasibility of applying UBiSES to conduct lumbar foraminoplasty in percutaneous endoscopic transforaminal discectomy (PETD). METHODS: This is a cohort study. 36 patients confirmed as L5/S1 lumbar disc herniation (LDH) in our hospital from March, 2019 to November, 2019 were enrolled. 36 patients were divided into two groups named the UBiSES group (n = 18, male: female = 8:10) and the TESSYS group (n = 18, male: female = 10:8). The average age of the UBiSES group and the TESSYS group were 40.94 ± 12.39 years old and 39.78 ± 13.02 years old respectively. PETD via uniportal-bichannel foraminoplasty assisted by UBiSES was adopted on the UBiSES group while PETD via conventional foraminoplasty was performed on the TESSYS group. One experienced surgeon with more than 4000 cases of lumbar surgery performed PETD on all patients. The demographic data, the duration of working cannula placement (minutes), decompression time (minutes), radiation exposure time (seconds), complications, Visual Analogue Scale (VAS), Oswestry Disability Index (ODI) scores and modified MacNab criteria were recorded and analyzed. The magnetic resonance imaging (MRI) and computed tomography (CT) were conducted to evaluate the radiographic improvement. RESULTS: PETD via lumbar foraminoplasty was successfully performed in all cases. The follow-up points were 3 months, 6 months, and 12 months. The average follow-up period of all patients was 15.78 ± 2.29 months. There was no statistic difference in age (P = 0.81), sex (P = 0.51) and follow-up (P = 0.14) between two groups. The duration of working cannula placement was 19.08 ± 2.30 min in the UBiSES group and 24.90 ± 4.71 min in the TESSYS group and there was significant difference between two groups (P < 0.05). There was no statistic difference in decompression time between the UBiSES group (44.18 ± 5.70 min) and the TESSYS group (47.46 ± 5.96 min) (P = 1.70). The radiation exposure time was 28.00 ± 4.70 s in the UBiSES group and 40.50 ± 5.73 s in the TESSYS group respectively, and has significant difference between two groups (P < 0.05). Furthermore, there was significant different in the duration of working cannula placement and radiation exposure time in male or female between the UBiSES group and the TESSYS group (P < 0.05). For male or female, no difference observed in decompression time and follow-up period between two groups. Postoperative VAS of low back and leg at every follow-up point (1 day, 3 months, 6 months, 12 months) was improved significantly in both groups compared with their preoperative VAS (P < 0.05). The postoperative ODI (3 months, 6 months, 12 months) has decreased significantly in both the UBiSES group and the TESSYS group compared with their preoperative ODI (P < 0.05). 94.44% patients received an excellent or good recovery in the UBiSES group and 88.89% for the TESSYS group. There was no poor result reported in both groups. The radiographic images showed satisfactory foraminoplasty and sufficient decompression of nerve in both groups. No postoperative complications were observed during follow-ups in the UBiSES group. Two patients in the TESSYS group experienced postoperative dysesthesia and the symptom was disappeared in 5 days and 7 days respectively with dexamethasone and neurotrophic drugs treatment. CONCLUSIONS: The original designed UBiSES could effectively and safely enlarge the foramen with an extensive surgical view and space under full-time and real-time visualization and get satisfactory efficacy.

Urinary small extracellular vesicles derived CCL21 mRNA as biomarker linked with pathogenesis for diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of renal failure, whereas the effective and early diagnostic biomarkers are still lacking. METHODS: Fourteen cytokines and chemokines mRNA were detected in urinary extracellular vesicles (EVs) from the screening cohort including 4 healthy controls (HC), 4 diabetes mellitus (DM) and 4 biopsy-proven DN patients, and was validated in another 16 HC and 15 DM and 28 DN patients. Correlation analysis was performed between the candidate biomarkers and clinic parameters as well as kidney histological changes. The findings were also confirmed in DN rat model with single injection of STZ. RESULTS: The number of small EVs secreted in urine was increased in DN patients compared to DM patients and healthy controls, with expression of AQP1 (a marker of proximal tubules) and AQP2 (a marker of distal/collecting tubules). Small EVs derived CCL21 mRNA increased significantly in DN patients and correlated with level of proteinuria and eGFR. Interestingly, elevated CCL21 mRNA from urine small EVs was observed in DN patients with normal renal function and could discriminate early DN patients from DM more efficiently compared to eGFR and proteinuria. CCL21 also showed an accurate diagnostic ability in distinguishing incipient from overt DN. Histologically, CCL21 mRNA expression increased progressively with the deterioration of tubulointerstitial inflammation and showed the highest level in nodular sclerosis group (class III) in DN patients. Remarkable infiltration of CD3 positive T cells including both CD4 and CD8 positive T cell population were observed in DN patients with high-CCL21 expression. Besides, accumulation of CD3 positive T cells correlated with level of urinary small EVs derived CCL21 and co-localized with CCL21 in the tubulointerstitium in DN patients. Finally, the correlation of CCL21 expression in renal cortex and urinary small EVs was confirmed in STZ-induced DN rat model. CONCLUSIONS: Urinary small EVs derived CCL21 mRNA may serve as early biomarker for identifying DN linked with pathogenesis. CCL21 mRNA mediated T cell infiltration may constitute the key mechanism of chronic inflammation in DN.

Diagnostic value of autofluorescence laryngoscope in early laryngeal carcinoma and precancerous lesions: A systematic review and meta-analysis.

OBJECTIVE: We aim to evaluate the diagnostic value of autofluorescence laryngoscope (AFL) in early laryngeal carcinoma and precancerous lesions. aWe also assess the value of AFL in diagnosis of early laryngeal carcinoma and precancerous lesions in comparison with that of white light laryngoscope (WL). METHODS: The databases consisting of PubMed, Cochrane Library, Web of science and CNKI were systematically searched to find pertinent literatures of AFL in diagnosing early laryngeal carcinoma and precancerous lesions. We made a quality evaluation of every study we included using the modified Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The pooled sensitivities, specificities were calculated using Meta-Disc 1.4. And we estimated the summary receiver operating characteristic curves (SROC) and area under the curves (AUC). RESULTS: We finally included 23 studies. The results of AFL in diagnosing early laryngeal carcinoma and precancerous lesions showed higher sensitivity of 0.91 (95%CI: 0.89-0.93; χ²=43.78, p = 0.0025) and specificity of 0.80 (95%CI: 0.77-0.82; χ²=130.64, p = 0.000), and the weighted AUC of AFL was 0.948 ± 0.013 (95%CI: 0.921-0.974) and the diagnostic accuracy (Q*) was 0.887 ± 0.018. The sensitivity and specificity of WL were 0.74 (95%CI: 0.70-0.77; χ²=52.40, p = 0.000) and 0.89 (95%CI: 0.87-0.90; χ²=299.22, p = 0.000), and the weighted AUC of WL was 0.835 ± 0.029 (95%CI: 0.777-0.892) and the diagnostic accuracy (Q*) was 0.767 ± 0.027. CONCLUSION: The meta-analysis and systematic review suggested that AFL had high diagnostic value in early laryngeal carcinoma and precancerous lesions, and its diagnostic value was higher than that of WL. These results indicated that AFL can provide good guidance for the early detection of laryngeal carcinoma and precancerous lesions.