Diabetic nephropathy (DN) as a global health concern is closely related to inflammation and oxidation. Isoliquiritigenin (ISL), a natural flavonoid compound, has been demonstrated to inhibit ...inflammation in macrophages. Herein, we investigated the effect of ISL in protecting against the injury in STZ-induced type 1 DN and in high glucose-induced NRK-52E cells. In this study, it was revealed that the administration of ISL not only ameliorated renal fibrosis and apoptosis, but also induced the deterioration of renal function in diabetic mice. Mediated by MAPKs and Nrf-2 signaling pathways, respectively, upstream inflammatory response and oxidative stress were neutralized by ISL in vitro and in vivo. Moreover, as further revealed by the results of molecular docking, sirtuin 1 (SIRT1) binds to ISL directly, and the involvement of SIRT1 in ISL-mediated renoprotective effects was confirmed by studies using in vitro models of SIRT1 overexpression and knockdown. In summary, by reducing inflammation and oxidative stress, ISL has a significant pharmacological effect on the deterioration of DN. The benefits of ISL are associated with the direct binding to SIRT1, the inhibition of MAPK activation, and the induction of Nrf-2 signaling, suggesting the potential of ISL for DN treatment.
Cataracts, named for pathological light scattering in the lens, are known to be associated with increased large protein aggregates, disrupted protein phase separation, and/or osmotic imbalances in ...lens cells. We have applied synchrotron phase contrast X-ray micro-computed tomography to directly examine an age-related nuclear cataract model in Cx46 knockout (Cx46KO) mice. High-resolution 3D X-ray tomographic images reveal amorphous spots and strip-like dense matter precipitates in lens cores of all examined Cx46KO mice at different ages. The precipitates are predominantly accumulated in the anterior suture regions of lens cores, and they become longer and dense as mice age. Alizarin red staining data confirms the presence of calcium precipitates in lens cores of all Cx46KO mice. This study indicates that the spatial and temporal calcium precipitation is an age-related event associated with age-related nuclear cataract formation in Cx46KO mice, and further suggests that the loss of Cx46 promotes calcium precipitates in the lens core, which is a new mechanism that likely contributes to the pathological light scattering in this age-related cataract model.
The aim of this study was to define the effectiveness and safety of ultrasound(US)-guided percutaneous microwave ablation(MWA) for benign thyroid nodules with one session treatment. A total 121 ...benign thyroid nodules in 100 euthyroid patients underwent MWA in one medical center between August 2014 and December 2015. MWA was performed with an internally cooled antenna under local anesthesia. The volume of the nodule, cosmetic score and symptom score were compared before and after the procedure. The volume reduction rate(VRR) was also evaluated. The side effects and complications were observed. As a result, microwave ablation was associated with a significant decrease in nodule volume{1.05±1.05mL (0.08~4.33mL)vs 8.56±4.21mL(4.05~22.66mL), p<0.001} at 12-month follow-up. The largest diameter was also decreased {1.36±0.53cm(0.60~3.73cm) vs 2.94±0.55cm(2.00~4.40cm) , p<0.001}. The symptom score and cosmetic score were decreased significantly after the procedure(1.71±0.68 vs 3.31±1.13, p<0.001; 1.16±0.37 vs 2.37±0.94, p<0.001). The VRR was 57.66±22.95%, .70.23±20.07%, 85.97±14.04% at 3-, 6- and 12-month follow-up after ablation , respectively. Two patients(2.0%) experienced hoarseness and recovered within 2 months. Two patients(2.0%) developed slight burn on cervical skin. One case(1%) developed Horner Syndrome, recovered within 2 months. Ultrasound-guided percutaneous microwave ablation developed significant volume reduction on benign thyroid nodules, with achieving improvement in symptom score and cosmetic grading. The treatment was well tolerated.
Abstract Aim Surgery had a significant impact on 25-hydroxyvitamin D (25-(OH)D) levels. Uncertainty still existed regarding the effects of peri-operative 25(OH)D deficiency on colorectal cancer (CRC) ...patients’ prognosis. The purpose of the present study was to explore the potential association between the peri-operative 25(OH)D deficiency and the survival outcome of CRC. Methods Seven electronic databases including PubMed, EMBASE, Web of Science, The Cochrane Library, OvidMEDLINE(R), China National Knowledge Infrastructure (CNKI) and Wangfang data were searched without language limitations. The primary outcomes were overall survival and all-cause mortality. Secondary outcomes were the incidence of 25(OH)D deficiency and risk variables for low 25(OH)D level in the peri-operative period. Results 14 eligible studies were obtained with 9324 patients for meta-analysis. In the peri-operative period, the pooled incidence of blood 25(OH)D deficiency was 59.61% (95% CI: 45.74–73.48). The incidence of blood 25(OH)D deficiency post-operatively (66.60%) was higher than that pre-operatively (52.65%, 95% CI: 32.94–72.36). Male (RR = 1.09, 95% CI: 1.03–1.16), rectum tumor (RR = 1.23, 95% CI: 1.03–1.47), spring and winter sampling (RR = 1.24, 95% CI: 1.02–1.49) were the risk factors for the 25(OH)D deficiency. The association between the low 25(OH)D post-operatively and short-term overall survival (HR = 0.43, 95% CI: 0.24–0.77) was most prominent, while a low 25(OH)D pre-operatively (HR = 0.47, 95% CI: 0.31–0.70) was more significantly associated with long-term all-cause mortality than that after surgery. Conclusion Peri-operative 25(OH)D impacted the CRC patients’ prognosis. Due to possible confounding effects of systemic inflammatory response (SIR), simultaneous measurement of vitamin D and SIR is essential for colorectal survival.
Recent genetic studies show that the Eph/ephrin bidirectional signaling pathway is associated with both congenital and age-related cataracts in mice and humans. We have investigated the molecular ...mechanisms of cataractogenesis and the roles of ephrin-A5 and EphA2 in the lens. Ephrin-A5 knockout ⁻/⁻ mice often display anterior polar cataracts while EphA2⁻/⁻ lenses show very mild cortical or nuclear cataracts at weaning age. The anterior polar cataract of ephrin-A5⁻/⁻ lenses is correlated with multilayers of aberrant cells that express alpha smooth muscle actin, a marker for mesenchymal cells. Only select fiber cells are altered in ephrin-A5⁻/⁻ lenses. Moreover, the disruption of membrane-associated β-catenin and E-cadherin junctions is observed in ephrin-A5⁻/⁻ lens central epithelial cells. In contrast, EphA2⁻/⁻ lenses display normal monolayer epithelium while disorganization is apparent in all lens fiber cells. Immunostaining of ephrin-A5 proteins, highly expressed in lens epithelial cells, were not colocalized with EphA2 proteins, mainly expressed in lens fiber cells. Besides the previously reported function of ephrin-A5 in lens fiber cells, this work suggests that ephrin-A5 regulates β-catenin signaling and E-cadherin to prevent lens anterior epithelial cells from undergoing the epithelial-to-mesenchymal transition while EphA2 is essential for controlling the organization of lens fiber cells through an unknown mechanism. Ephrin-A5 and EphA2 likely interacting with other members of Eph/ephrin family to play diverse functions in lens epithelial cells and/or fiber cells.
Department of Physiology and Biophysics, SUNY at Stony Brook, Stony Brook, New York; and School of Optometry, University of California at Berkeley, Berkeley, California
The cells of most mammalian ...organs are connected by groups of cell-to-cell channels called gap junctions. Gap junction channels are made from the connexin (Cx) family of proteins. There are at least 20 isoforms of connexins, and most tissues express more than 1 isoform. The lens is no exception, as it expresses three isoforms: Cx43, Cx46, and Cx50. A common role for all gap junctions, regardless of their Cx composition, is to provide a conduit for ion flow between cells, thus creating a syncytial tissue with regard to intracellular voltage and ion concentrations. Given this rather simple role of gap junctions, a persistent question has been: Why are there so many Cx isoforms and why do tissues express more than one isoform? Recent studies of lens Cx knockout (KO) and knock in (KI) lenses have begun to answer these questions. To understand these roles, one must first understand the physiological requirements of the lens. We therefore first review the development and structure of the lens, its numerous transport systems, how these systems are integrated to generate the lens circulation, the roles of the circulation in lens homeostasis, and finally the roles of lens connexins in growth, development, and the lens circulation.
Purpose
Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. Non-alcoholic Fatty Liver Disease (NAFLD) was possibly among the risk factors for thyroid carcinoma. It is uncertain ...whether NAFLD is associated with the aggressiveness of PTC.
Methods
We obtained data on patients with PTC who had undergone surgery at the First Affiliated Hospital of Wenzhou Medical University between January 2020 and February 2022. Pre-and post-operative data were obtained from electronic medical records and analyzed. Patients were split into two groups based on the NAFLD diagnostic criteria and compared using univariate and multivariate analysis through a logistic regression model.
Results
In all, 3468 patients with PTC were included in this study, of which 594 (17.1%) were diagnosed with NAFLD. NAFLD was found to be an independent risk factor for lymph node metastasis (
OR
= 1.285 95%
CI:
1.052–1.570), incidence of
BRAF
V600E
mutation (
OR
= 1.504, 95%
CI:
1.148–1.972) and later tumor stage at diagnosis (
OR
= 2.310, 95%
CI:
1.700–3.139) in PTC. The association mentioned above remained significant in subgroups of patients with Hashimoto’s thyroiditis (HT), hypertension, diabetes (DM), high triglyceride (TG) levels, low levels of high-density lipoprotein-cholesterol (HDL-C), and high body mass index (BMI). In subgroup of female rather than male, NAFLD was an independent risk factor for lymph node metastasis (
OR
= 1.638 95%
CI:
1.264–2.123), incidence of
BRAF
V600E
mutation (
OR
= 1.973, 95%
CI:
1.368–2.846) as well as later tumor stage (
OR
= 2.825, 95%
CI:
1.964–4.063) in PTC. However, NAFLD was not a risk factor for the larger tumor size (>1 cm), extra-thyroidal extension (ETE), or multifocality in PTC.
Conclusion
Our cross-sectional study indicated that there is a strong association of NAFLD with higher incidence of lymph node metastasis, higher incidence of
BRAF
V600E
mutation and later TNM stage than non-NAFLD in females with PTC.
Congenital cataract is the most frequent inherited ocular disorder and the most leading cause of lifelong visual loss. The screening of pathogenic mutations can be very challenging in some cases, for ...congenital cataracts are clinically and genetically heterogeneous diseases. The aim of this study is to investigate the mutation spectrum and frequency of 54 cartaract-associated genes in 27 Chinese families with congenital cataracts. Variants in 54 cataract-associated genes were screened by targeted next-generation sequencing (NGS) and then validated by Sanger sequencing. We identified pathogenic variants in 62.96% (17/27) of families, and over 52.94% (9/17) of these variants were novel. Among them, three are splicing site mutations, four are nonsense mutations, seven are missense mutations, two are frame shift mutations and one is intronic mutation. This included identification of: complex ocular phenotypes due to two novel PAX6 mutations; progressive cortical cataract and lamellar cataract with lens subluxation due to two novel CRYGS mutations. Mutations were also found in rarely reported genes including CRYBA4, CRYBA2, BFSP1, VIM, HSF4, and EZR. Our study expands the mutation spectrum and frequency of genes responsible for congenital cataracts. Targeted next-generation sequencing in inherited congenital cataract patients provided significant diagnostic information.
To examine the mechanism by which a novel connexin 50 (Cx50) mutation, Cx50 V44A, in a Chinese family causes suture-sparing autosomal dominant congenital nuclear cataracts.
Family history and ...clinical data were recorded and direct gene sequencing was used to identify the disease-causing mutation. The Cx50 gene was cloned from a human lens cDNA library. Connexin protein distributions were assessed by fluorescence microscopy. Hemichannel functions were analyzed by dye uptake assay. Formation of functional channels was assessed by dye transfer experiments.
Direct sequencing of the candidate GJA8 gene revealed a novel c.131T>C transition in exon 2, which cosegregated with the disease in the family and resulted in the substitution of a valine residue with alanine at codon 44 (p. V44A) in the extracellular loop 1 of the Cx50 protein. Both Cx50 and Cx50V44A formed functional gap junctions, as shown by the neurobiotin transfer assay. However, unlike wild-type Cx50, Cx50V44A was unable to form open hemichannels in dye uptake experiments.
This work identified a unique congenital cataract in the Chinese population, caused by the novel mutation Cx50V44A, and it showed that the V44A mutation specifically impairs the gating of the hemichannels but not the gap junction channels. The dysfunctional hemichannels resulted in the development of human congenital cataracts.
Purpose
To investigate the changes of the serum parathyroid hormone (PTH) and calcium level, as well as bone mineral density (BMD), after percutaneous ultrasound-guided microwave ablation (MWA) for ...primary hyperparathyroidism (pHPT) caused by single hyperfunctional nodule.
Methods
The study enrolled 20 patients with a total of 20 nodules of MWA treatment to pHPT in one session. The normalization rate of the serum PTH and calcium was evaluated at every 6 months during 2-year follow-up after MWA. The bone mineral density (BMD) at lumbar spine and femoral neck were also compared before and after the procedure.
Results
The normalization rate of both PTH and serum calcium at 6-, 12-, 24-month follow-up was 66.6%, 80.0%, and 62.5%, respectively. Though the normalization rate of serum calcium level at 6-, 12-, and 24-month visit after MWA was 100%. The BMD increased 12, 24 months after MWA at lumbar spine (1.022 ± 0.155, 1.057 ± 0.151 vs 0.965 ± 0.145 g/cm
2
,
p
< 0.01) and femoral neck at 2-year assessment (0.819 ± 0.094 vs 0.771 ± 0.102 g/cm
2
,
p
= 0.015). Seven nodules disappeared in 20 nodules (35.0%), average ablation time was 122.29 ± 107.54 s (34–460 s). Six patients encountered voice change during the procedure, one participant was confirmed recurrent laryngeal injuries but recovered within 2 months.
Conclusions
Percutaneous ultrasound-guided microwave ablation results in improvement of biochemical profiles and bone mineral density in subjects with single hyperfunctional parathyroid nodule. However, the long-term efficacy of the MWA remains to be verified.
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