Hyperglycemia-induced oxidative stress exacerbates mitochondrial apoptosis damage to cochlear stria vascularis pericytes via the ROS-mediated Bcl-2/CytC/AIF pathway.

OBJECTIVES: Diabetes is closely linked to hearing loss, yet the exact mechanisms remain unclear. Cochlear stria vascularis and pericytes (PCs) are crucial for hearing. This study investigates whether high glucose induces apoptosis in the cochlear stria vascularis and pericytes via elevated ROS levels due to oxidative stress, impacting hearing loss. METHODS: We established a type II diabetes model in C57BL/6J mice and used auditory brainstem response (ABR), Evans blue staining, HE staining, immunohistochemistry, and immunofluorescence to observe changes in hearing, blood-labyrinth barrier (BLB) permeability, stria vascularis morphology, and apoptosis protein expression. Primary cultured stria vascularis pericytes were subjected to high glucose, and apoptosis levels were assessed using flow cytometry, Annexin V-FITC, Hoechst 33342 staining, Western blot, Mitosox, and JC-1 probes. RESULTS: Diabetic mice showed decreased hearing thresholds, reduced stria vascularis density, increased oxidative stress, cell apoptosis, and decreased antioxidant levels. High glucose exposure increased apoptosis and ROS content in pericytes, while mitochondrial membrane potential decreased, with AIF and cytochrome C (CytC) released from mitochondria to the cytoplasm. Adding oxidative scavengers reduced AIF and CytC release, decreasing pericyte apoptosis. DISCUSSION: Hyperglycemia may induce mitochondrial apoptosis of cochlear stria vascularis pericytes through oxidative stress.

Bionic Artificial Skin Based on Self-Healable Ionogel Composites with Tailored Mechanics and Robust Interfaces.

Bionic artificial skin which imitates the features and functions of human skin, has broad applications in wearable human-machine interfaces. However, equipping artificial materials with skin-like mechanical properties, self-healing ability, and high sensitivity remains challenging. Here, inspired by the structure of human skin, an artificial skin based on ionogel composites with tailored mechanical properties and robust interface is prepared. Combining finite element analysis and direct ink writing (DIW) 3D printing technology, an ionogel composite with a rigid skeleton and an ionogel matrix is precisely designed and fabricated, realizing the mechanical anisotropy and nonlinear mechanical response that accurately mimic human skin. Robust interface is created through co-curing of the skeleton and matrix resins, significantly enhancing the stability of the composite. The realization of self-healing ability and resistance to crack growth further ensure the remarkable durability of the artificial skin for sensing application. In summary, the bionic artificial skin mimics the characteristics of human skin, including mechanical anisotropy, nonlinear mechanical response, self-healing capability, durability and high sensitivity when applied as flexible sensors. These strategies provide strong support for the fabrication of tissue-like materials with adaptive mechanical behaviors.

Effect of amino acid supplementation on short-term complications after gastrointestinal tumor surgery: the AMIGITS randomized clinical trial.

BACKGROUND: There is a scarcity of large randomized clinical trials on the efficacy and safety of high-dose amino acid supplementation (AAS) in patients with gastrointestinal tumors undergoing surgical treatment. METHODS: This pragmatic, randomized, controlled, single-center, open-label, parallel-group AMIGITS trial was performed in a tertiary care teaching hospital. Patients with gastrointestinal tumors were randomly assigned to receive either AAS or standard care (SC). Amino acid targets were 2.0 g/kg per day in the AAS group and 1.2 g/kg per day in the SC group. The AAS group received additional amino acids intravenously, while the SC group received an iso-energetic 5% glucose intravenously. RESULTS: Overall, 407 patients (AAS group, 204; SC group, 203) were included in this study. During the intervention, the actual mean daily energy intake did not differ significantly between the AAS and SC groups (25.53 vs. 25.16 kcal/kg per day, P=0.493). However, the actual mean daily amino acid intake was significantly higher in the AAS group than that in the SC group (1.81 vs. 0.94 g/kg per day, P<0.001). The infection incidence during hospitalization and that within 30 days of surgery was significantly lower in the AAS group than that in the SC group (P=0.031 and P=0.024, respectively). The 30-day postoperative incidence of amino acid treatment-related adverse events and other complications did not significantly differ between the two groups. The postoperative hospital stay was significantly different between the two groups (P<0.001). CONCLUSIONS: AAS was associated with a reduced infection incidence within 30 days of major surgery in patients with gastrointestinal tumors and can be a promising strategy.

Association between serum Klotho and major depression: Results from the NHANES 2007-2016 and Mendelian randomization studies.

BACKGROUND: Major depression is a public health problem facing the world. This study aimed to identify the risk factors for major depression and clarify their causal effects. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES). Multifactorial logistic regression analysis was used to calculate the effect of each variable on major depression. Subgroup analyses and interaction tests were conducted to observe the stability of the association between them. Nonlinear correlations were explored using restricted cubic spline plots. The causal effects of serum Klotho on major depression were assessed using Mendelian randomization (MR) analysis. RESULTS: A total of 8359 participated in the study. After adjusting for all covariates, the risk of having major depression was 1.47 times higher for each unit rise in serum Klotho (OR = 1.47, 95 % CI = 1.07-2.02; P = 0.0183). MR analysis showed no causal relationship between serum Klotho levels and risk of major depression (OR = 1.09, 95 % CI = 0.91-1.30; P = 0.4120). Sensitivity analysis verified the reliability of the results. CONCLUSIONS: Serum Klotho is positively associated with an increased risk of major depression in the U.S. population, but MR analyses did not show genetic causality between Klotho and major depression in individuals of European ancestry. Based on the results of the current study, no indication maintaining high levels of Klotho may increase the risk of major depression. LIMITATIONS: The main limitation of this study is the inconsistency of the cross-sectional study and the MR population.

Integrating Bioactive Graded Hydrogel with Radially Aligned Nanofibers to Dynamically Manipulate Wound Healing Process.

Skin wound healing is a complex process that requires appropriate treatment and management. Using a single scaffold to dynamically manipulate angiogenesis, cell migration and proliferation, and tissue reconstruction during skin wound healing is a great challenge. We developed a hybrid scaffold platform that integrates the spatiotemporal delivery of bioactive cues with topographical cues to dynamically manipulate the wound-healing process. The scaffold comprised gelatin methacryloyl hydrogels and electrospun poly(ε-caprolactone)/gelatin nanofibers. The hydrogels had graded cross-linking densities and were loaded with two different functional bioactive peptides. The nanofibers comprised a radially aligned nanofiber array layer and a layer of random fibers. During the early stages of wound healing, the KLTWQELYQLKYKGI peptide, which mimics vascular endothelial growth factor, was released from the inner layer of the hydrogel to accelerate angiogenesis. During the later stages of wound healing, the IKVAVS peptide, which promotes cell migration, synergized with the radially aligned nanofiber membrane to promote cell migration, while the nanofiber membrane also supported further cell proliferation. In an in vivo rat skin wound-healing model, the hybrid scaffold significantly accelerated wound healing and collagen deposition, and the ratio of type I to type III collagen at the wound site resembled that of normal skin. The prepared scaffold dynamically regulated the skin tissue regeneration process in stages to achieve rapid wound repair with clinical application potential, providing a strategy for skin wound repair.

Genetic variation in the aquaporin TONOPLAST INTRINSIC PROTEIN 4;3 modulates maize cold tolerance.

Cold stress is a major abiotic stress that threatens maize (Zea mays L.) production worldwide. Understanding the molecular mechanisms underlying cold tolerance is crucial for breeding resilient maize varieties. Tonoplast intrinsic proteins (TIPs) are a subfamily of aquaporins in plants. Here, we report that TIP family proteins are involved in maize cold tolerance. The expression of most TIP genes was responsive to cold stress. Overexpressing TIP2;1, TIP3;2 or TIP4;3 reduced the cold tolerance of maize seedlings, while loss-of-function mutants of TIP4;3 exhibited enhanced cold tolerance. Candidate gene-based association analysis revealed that a 328-bp transposon insertion in the promoter region of TIP4;3 was strongly associated with maize cold tolerance. This transposon insertion conferred cold tolerance by repressing TIP4;3 expression through increased methylation of its promoter region. Moreover, TIP4;3 was found to suppress stomatal closure and facilitate reactive oxygen species (ROS) accumulation under cold stress, thereby inhibiting the expression of cold-responsive genes, including DEHYDRATION-RESPONSIVE ELEMENT BINDING FACTOR 1 (DREB1) genes and a subset of peroxidase genes, ultimately attenuating maize cold tolerance. This study thus elucidates the mechanism underlying TIP-mediated cold tolerance and identifies a favourable TIP4;3 allele as a potential genetic resource for breeding cold-tolerant maize varieties.

Clinicopathological Features of Pediatric Insulinoma: A Single-Centre Study.

Aims/Background: Insulinoma is an extremely rare condition in pediatric patients. This study aims to examine the pathological and clinical characteristics of pediatric insulinoma. Methods: A retrospective, single-center study was conducted involving five pediatric patients diagnosed with insulinoma. The study involved evaluating the postoperative status of the patients during follow-up and analyzing their clinical manifestations, diagnostic work-up, pathological findings, and therapeutic approaches. Results: The study cohort comprised four males and one female, aged between 4 and 9 years. Common symptoms included dizziness and fatigue. The insulinomas were located in various parts of the pancreas: two in the head, one in the neck, one in the body, and one in the tail. After undergoing subtotal pancreatectomy, four patients experienced no side effects during a follow-up period of 41 to 153 months. One patient, who underwent an incomplete pancreatic resection, required ongoing postoperative treatment with 150 mg Creon due to pancreatic enzyme deficiency. Postoperative pathological results indicated that all cases were low-grade neuroendocrine tumours, classified as grade 1 (G1) or grade 2 (G2). Two cases exhibited capsule invasion, and one case showed microvascular invasion. Despite these invasions, no recurrences or metastases have been observed to date. Conclusion: Surgical resection is a viable treatment option for pediatric insulinoma, yielding a favorable prognosis. The presence of capsular and microvascular invasions does not seem to affect the overall prognosis in these cases.

Curcumin Alleviates Osteoarthritis Through the p38MAPK Pathway: Network Pharmacological Prediction and Experimental Confirmation.

Objective: Osteoarthritis (OA) is a common degenerative disease worldwide. While curcumin has shown therapeutic effects on OA, its mechanism remains unknown. This study aimed to investigate the molecular mechanism of curcumin in treating OA through network pharmacology and both in vivo and in vitro experiments. Methods: Curcumin-related targets were obtained using the HERB and DrugBank databases. GeneCards and DisGeNET were used to build a target database for OA. The STRING database was employed to construct protein-protein interaction networks and analyze related protein interactions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology enrichment analyses of core targets were performed using Metascape. In addition, Autodock software was utilized for molecular docking validation of curcumin and disease targets. Further validation of the main findings was conducted through in vitro and in vivo experiments. In the in vitro experiments, an inflammation model was constructed through nitric oxide donor (SNP) stimulation of chondrocytes. Subsequently, the regulatory effects of curcumin on core targets and signaling pathways were validated using Western blotting and immunofluorescence staining techniques. In the in vivo experiments, an OA model was established by performing medial meniscectomy on male Sprague-Dawley rats. The therapeutic effects were evaluated using enzyme-linked immunosorbent assays, histologic staining, and micro-computed tomography (micro-CT) techniques. Results: Core targets of curcumin relevant to OA therapy included tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, matrix metalloproteinase 9 (MMP-9), B-cell lymphoma 2 (BCL-2), and caspase-3. The major biological processes involved oxidative stress and apoptotic processes, among others. The p38 mitogen-activated protein kinase (p38/MAPK) pathway was identified as the most likely pathway involved. In vitro experiments showed that curcumin significantly reduced oxidative stress levels, inhibited the expression of inflammatory factors IL-6 and Cyclooxygenase-2 (COX-2) and downregulated the expression of MMP-9 and MMP-1. In addition, curcumin was found to regulate the expression of BCL-2 and caspase-3 through the p38/MAPK pathway, inhibiting chondrocyte apoptosis. In vivo animal experiments demonstrated that curcumin significantly reduced the expression of OA-related factors (IL-1, IL-6, and TNF-α). Histological analysis and micro-CT results revealed that curcumin treatment significantly increased cartilage thickness, improved cartilage morphology, structure, and function, inhibited cartilage degradation, and enhanced the resorption of subchondral bone in the knee joints of rats with OA. Conclusion: Curcumin regulates oxidative stress and maintains mitochondrial function, thereby protecting chondrocyte guard. In addition, curcumin attenuates the inflammatory response of chondrocytes by inhibiting the phosphorylation of P38MAPK, slowing down the breakdown of the extrachondral matrix while preventing apoptosis of chondrocytes. Additionally curcumin attenuated cartilage degradation and bone damage while helping to boost bone density.

Co contamination of Si: Plating & aging.

Cobalt has emerged as a vital material in 10 nm technology for localized interconnect layers, potentially offering a compelling alternative to Cu-based interconnects. In this study, we subjected the contamination arising from the presence of cobalt atoms in silicon to comprehensive investigation, employing electron transmission electron microscopy (TEM) observations in conjunction with first-principles calculations. The results show that a dense CoSi layer with a thickness of a few nanometers is formed at the interface of cobalt and Si. The CoSi layer blocks the diffusion of Co atoms into Si. This is due to the semiconducting nature of the covalent bond formed between Co and Si, leading to the emergence of a forbidden zone at the Co/CoSi interface. The diffusion of Co into CoSi is governed by the atomic exchange mechanism, however, the local distortion of the periodic atomic potential due to the presence of the forbidden zone at the Co/CoSi interface hinders the diffusion of Co into Si. Therefore, the deposition of a Co metal layer on a Si chip does not require an additional barrier layer.

Comparison of accelerated and standard infliximab induction regimens in acute severe ulcerative colitis using propensity score analysis: a retrospective multicenter study in China.

Background: The optimal regimen of infliximab salvage in acute severe ulcerative colitis (ASUC) patients remains controversial. This study aimed to compare accelerated and standard infliximab induction in Chinese ASUC patients, and to explore risk factors and concrete accelerated regimens for them. Methods: Data were retrospectively collected from steroid-refractory ASUC patients receiving infliximab as rescue therapy at seven tertiary centers across China. Outcomes including colectomy and clinical remission (Mayo score ≤ 2 and every subscore ≤ 1 at Day 14) rates were compared between patients receiving accelerated and standard infliximab induction using propensity score adjustment for potential confounders. The dose-response relationship was explored by plotting restricted cubic splines. Logistic regression and Cox proportional hazards regression analyses were performed to determine risk factors for adverse outcomes. A systematic review and meta-analysis was also performed. Results: A total of 76 patients were analysed: 29 received standard and 47 received accelerated induction. The accelerated group had a higher 90-day colectomy rate (17.8% vs 0%, P = 0.019) and lower clinical remission rate (27.7% vs 65.5%, P = 0.001). After adjusting for propensity score and institution, there was no significant difference in colectomy or clinical remission rates (both P > 0.05). Dose-effect curves showed decreased colectomy hazard with higher cumulative infliximab dosage within 5 days, with no improvement observed for increasing cumulative infliximab dosage within 28 days. Multivariate logistic regression analyses revealed C-reactive protein of >10 mg/L at infliximab initiation (odds ratio = 5.00, 95% confidence interval: 1.27-24.34) as an independent risk factor for no clinical remission. Meta-analysis also revealed no significant difference in colectomy rates at 3 months (P = 0.54). Conclusions: After adjusting for confounders, there were no significant differences in colectomy or clinical remission rates between accelerated and standard infliximab induction among ASUC patients. Early administration of an intensified dosage within 5 days may be beneficial. Elevated C-reactive protein at infliximab initiation indicated need for intensive treatment.

An Image Dehazing Algorithm for Underground Coal Mines Based on gUNet.

Aiming at the problems of incomplete dehazing, color distortion, and loss of detail and edge information encountered by existing algorithms when processing images of underground coal mines, an image dehazing algorithm for underground coal mines, named CAB CA DSConv Fusion gUNet (CCDF-gUNet), is proposed. First, Dynamic Snake Convolution (DSConv) is introduced to replace traditional convolutions, enhancing the feature extraction capability. Second, residual attention convolution blocks are constructed to simultaneously focus on both local and global information in images. Additionally, the Coordinate Attention (CA) module is utilized to learn the coordinate information of features so that the model can better capture the key information in images. Furthermore, to simultaneously focus on the detail and structural consistency of images, a fusion loss function is introduced. Finally, based on the test verification of the public dataset Haze-4K, the Peak Signal-to-Noise Ratio (PSNR), Structural Similarity (SSIM), and Mean Squared Error (MSE) are 30.72 dB, 0.976, and 55.04, respectively, and on a self-made underground coal mine dataset, they are 31.18 dB, 0.971, and 49.66, respectively. The experimental results show that the algorithm performs well in dehazing, effectively avoids color distortion, and retains image details and edge information, providing some theoretical references for image processing in coal mine surveillance videos.

[Effects of Different Modified Materials on Soil Fungal Community Structure in Saline-Alkali Soil].

Studying the effects of different modified materials on the physicochemical properties and fungal community structure of saline-alkali soil can provide theoretical basis for reasonable improvement of saline-alkali soil. High-throughput sequencing technology was used to explore the effects of five treatments, namely, control (CK), desulfurization gypsum (T1), soil ameliorant (T2), organic fertilizer (T3), and desulfurization gypsum compounds soil ameliorant and organic fertilizer (T4), on soil physicochemical properties and fungal community diversity, composition, and structure of saline-alkali soil in Hetao Plain, Inner Mongolia. The results showed that compared with those in CK, the contents of available phosphorus, available potassium, organic matter, and alkali hydrolysis nitrogen were significantly increased in modified material treatments, and the T4 treatment significantly decreased soil pH. Modified treatments increased the Simpson and Shannon indexes of fungi but decreased the Chao1 index. The dominant fungi were Ascomycota, Basidiomycota, and Mortierellomycota, and the dominant genera were Mortierella, Conocybe, Botryotrichum, Fusarium, and Pseudogymnoascus. The application of modified materials increased the relative abundance of Ascomycota, Basidiomycota, Fusarium, and Pseudogymnoascus, while decreasing the relative abundance of Mortierellomycota, Chytridiomycota, and Mortierella. LEfSe analysis showed that modified treatments altered the fungal community biomarkers. Correlation analysis showed that pH and available potassium were the main environmental factors affecting fungal community structure. The results can provide scientific basis for improving saline-alkali soil and increasing soil nutrients in Hetao Plain, Inner Mongolia.

Strain to shine: stretching-induced three-dimensional symmetries in nanoparticle-assembled photonic crystals.

Stretching elastic materials containing nanoparticle lattices is common in research and industrial settings, yet our knowledge of the deformation process remains limited. Understanding how such lattices reconfigure is critically important, as changes in microstructure lead to significant alterations in their performance. This understanding has been extremely difficult to achieve due to a lack of fundamental rules governing the rearrangements. Our study elucidates the physical processes and underlying mechanisms of three-dimensional lattice transformations in a polymeric photonic crystal from 0% to over 200% strain during uniaxial stretching. Corroborated by comprehensive experimental characterizations, we present analytical models that precisely predict both the three-dimensional lattice structures and the macroscale deformations throughout the stretching process. These models reveal how the nanoparticle lattice and matrix polymer jointly determine the resultant structures, which breaks the original structural symmetry and profoundly changes the dispersion of photonic bandgaps. Stretching induces shifting of the main pseudogap structure out from the 1st Brillouin zone and the merging of different symmetry points. Evolutions of multiple photonic bandgaps reveal potential optical singularities shifting with strain. This work sets a new benchmark for the reconfiguration of soft material structures and may lay the groundwork for the study of stretchable three-dimensional topological photonic crystals.

d-band center engineering of single Cu atom and atomic Ni clusters for enhancing electrochemical CO2 reduction to CO.

The rational design of catalysts with atomic dispersion and a deep understanding of the catalytic mechanism is crucial for achieving high performance in CO2 reduction reaction (CO2RR). Herein, we present an atomically dispersed electrocatalyst with single Cu atom and atomic Ni clusters supported on N-doped mesoporous hollow carbon sphere (CuSANiAC/NMHCS) for highly efficient CO2RR. CuSANiAC/NMHCS demonstrates a remarkable CO Faradaic efficiency (FECO) exceeding 90% across a potential range of -0.6 to -1.2 V vs. reversible hydrogen electrode (RHE) and achieves its peak FECO of 98% at -0.9 V vs. RHE. Theoretical studies reveal that the electron redistribution and modulated electronic structure-notably the positive shift in d-band center of Ni 3d orbital-resulting from the combination of single Cu atom and atomic Ni clusters markedly enhance the CO2 adsorption, facilitate the formation of *COOH intermediate, and thus promote the CO production activity. This study offers fresh perspectives on fabricating atomically dispersed catalysts with superior CO2RR performance.

Association between short-term exposure to ambient air pollutants and the risk of hospital visits for acute upper respiratory tract infections among adults: a time-series study in Ningbo, China.

OBJECTIVES: Acute upper respiratory tract infections (AURTIs) are prevalent in the general population. However, studies on the association of short-term exposure to air pollution with the risk of hospital visits for AURTIs in adults are limited. This study aimed to explore the short-term exposure to air pollutants among Chinese adults living in Ningbo. METHODS: Quasi-Poisson time serious regressions with distributed lag non-linear models (DLNM) were applied to explore the association between ambient air pollution and AURTIs cases. Patients ≥ 18 years who visit three hospitals, being representative for urban, urban-rural junction and rural were included in this retrospective study. RESULTS: In total, 104,441 cases with AURTIs were enrolled in hospital during 2015-2019. The main results showed that particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5), nitrogen dioxide (NO2) and nitrogen dioxide (SO2), were positively associated to hospital visits for AURTIs, except for nitrogen dioxide (O3), which was not statistically significant. The largest single-lag effect for PM2.5 at lag 8 days (RR = 1.02, 95%CI: 1.08-1.40), for NO2 at lag 13 days (RR = 1.03, 95%CI: 1.00-1.06) and for SO2 at lag 5 days (RR = 1.27, 95%CI: 1.08-1.48), respectively. In the stratified analysis, females, and young adults (18-60 years) were more vulnerable to PM2.5 and SO2 and the effect was greater in rural areas and urban-rural junction. CONCLUSIONS: Exposure to ambient air pollution was significantly associated with hospital visits for AURTIs. This study provides epidemiological evidence for policymakers to control better air quality and establish an enhanced system of air pollution alerts.

Low Expression of GRIM-19 Correlates with Poor Prognosis in Patients with Upper Urinary Tract Urothelial Carcinoma.

PURPOSE: This study aimed to clarify the expression of a gene associated with Retinoid- Interferon-Induced Mortality-19 (GRIM-19) in Upper Urinary Tract Urothelial Carcinoma (UUTUC) and its prognostic significance for UUTUC patients. MATERIALS AND METHODS: Immunohistochemical (IHC) staining was used to determine the GRIM-19 expression in 70 paired samples. Progression-Free Survival (PFS) and Cancer-Specific Survival (CSS) were assessed using the Kaplan-Meier method. The independent prognostic factors for PFS and CSS were analyzed by multivariable Cox regression models. RESULTS: IHC staining showed that GRIM-19 expression was significantly decreased in UUTUC, and its cellular location changed from being both cytoplasmic and nuclear to only cytoplasmic. Kaplan- Meier analysis revealed that the patients with tumors expressing low GRIM-19 had a significantly higher risk for tumor progression (P = 0.002) and cancer-specific mortality (P < 0.001) compared to those with high GRIM-19 levels. The Cox regression showed that both GRIM-19 expression (P = 0.025) and lymph node metastasis (LN) (P = 0.007) were independent predictors of progression in the muscle-invasive (MIC) subgroup. GRIM-19 expressions (entire cohort: P = 0.011; MIC subgroup: P = 0.025), LN (entire cohort: P = 0.019; MIC subgroup: P = 0.007), and progression (entire cohort: P < 0.001; MIC subgroup: P < 0.001) were independent predictors of cancer-specific survival. CONCLUSION: Low expression of GRIM-19 in patients with UUTUC had significantly shorter PFS or CSS compared to those with high GRIM-19-expressing tumors. High GRIM-19 expression was also strongly associated with longer PFS in MIC patients. It indicates that GRIM-19 might serve as a promising prognostic biomarker for UUTUC patients.

The protective role of phlorizin against lipopolysaccharide-induced acute orchitis in mice associated with changes in gut microbiota composition.

Objective: Orchitis is a common reproductive disease of male animals, which has serious implications to human and animal reproduction. Additionally, phlorizin (PHN), a common polyphenol in apples and strawberries, has a variety of biological activities, including antioxidant, anti-inflammatory, anti-diabetic, and anti-aging activities. We aimed to determine the protective effects and potential mechanisms of PHN in lipopolysaccharide (LPS)-induced acute orchitis in mice. Method: After 21 days of PHN pretreatment, mice were injected with LPS to induce testicular inflammation, and then the changes of testicular tissue structure, expression of inflammatory factors, testosterone level, expression of testosterone-related genes, adhesion gene and protein expression were detected, and the structural changes in the intestinal flora after PHN treatment were further detected by 16SRNA. Result: Our results demonstrated that PHN treatment reduced LPS-induced testicular injury and body and testicular weight losses. The mRNA expression levels of pro-inflammatory cytokines-related genes and antioxidant enzyme activity were also decreased and elevated, respectively, by PHN administration; however, PHN treatment also reduced the LPS-induced decrease in testosterone levels in the testes. Additionally, further studies found that PHN increased the expression of marker proteins zonula occludens-1 (ZO-1) and occludin associated with the blood testosterone barrier compared with that in LPS treatment groups. To further examine the potential mechanisms of the protective effect of PHN on LPS-induced testicular injury, we compared the differences of gut microbiota compositions between the 100 mg/kg PHN treatment group and the control group using 16SRNA. Metagenomic analyses indicated that the abundances of Bacteroidetes, Muribaculaceae, Lactobacillaceae, uncultured bacterium f Muribaculaceae, and Lactobacillus in the PHN treatment group improved, while potential microbes that can induce intestinal diseases, including Verrucomicrobia, Epsilonbacteraeota, Akkermansiaceae, and Akkermansia decreased in the PHN treatment group. Conclusion: Our results indicate that PHN pretreatment might alleviate orchitis by altering the composition of gut microflora, which may provide a reference for reducing the occurrence of acute orchitis in male animals.

Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives.

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.