Fluoride induces immunotoxicity by regulating riboflavin transport and metabolism partly through IL-17A in the spleen.

The impairment of the immune system by fluoride is a public health concern worldwide, yet the underlying mechanism is unclear. Both riboflavin and IL-17A are closely related to immune function and regulate the testicular toxicity of fluoride. However, whether riboflavin or IL-17A is involved in fluoride-induced immunotoxicity is unknown. Here, we first established a male ICR mouse model by treating mice with sodium fluoride (NaF) (100 mg/L) via the drinking water for 91 days. The results showed that fluoride increased the expression of the proinflammatory factors IL-1ß and IL-17A, which led to splenic inflammation and morphological injury. Moreover, the expression levels of the riboflavin transporters SLC52A2 and SLC52A3; the transformation-related enzymes RFK and FLAD1; and the key mitochondrial functional determinants SDH, COX, and ATP in the spleen were measured via real-time PCR, Western blotting, and ELISA. The results revealed that fluoride disrupted riboflavin transport, transformation, metabolism, and mitochondrial function. Furthermore, wild-type (WT) and IL-17A knockout (IL-17A-/-) C57BL/6 J male mice of the same age were treated with NaF (24 mg/kg·bw, equivalent to 100 mg/L) and/or riboflavin sodium phosphate (5 mg/kg·bw) via gavage for 91 days. Similar parameters were evaluated as above. The results confirmed that fluoride increased riboflavin metabolism through RFK but not through FLAD1. Fluoride also affected mitochondrial function and activated neutrophils (marked with Ly6g) and macrophages (marked with CD68) in the spleen. Interestingly, IL-17A partly mediated fluoride-induced riboflavin metabolism disorder and immunotoxicity in the spleen. This work not only reveals a novel toxic mechanism for fluoride but also provides new clues for exploring the physiological function of riboflavin and for diagnosing and treating the toxic effects of fluoride in the environment.

MiRNA-seq and mRNA-seq revealed the mechanism of fluoride-induced cauda epididymal injury.

The widespread presence of fluoride in water, food, and the environment continues to exacerbate the impact of fluoride on the male reproductive health. However, as a critical component of the male reproductive system, the intrinsic mechanism of fluoride-induced cauda epididymis damage and the role of miRNAs in this process are still unclear. This study established a mouse fluorosis model and employed miRNA and mRNA sequencing; Evans blue staining, Oil Red O staining, TEM, immunofluorescence, western blotting, and other technologies to investigate the mechanism of miRNA in fluoride-induced cauda epididymal damage. The results showed that fluoride exposure increased the fluoride concentration in the hard tissue and cauda epididymis, altered the morphology and ultrastructure of the cauda epididymis, and reduced the motility rate, normal morphology rate, and hypo-osmotic swelling index of the sperm in the cauda epididymis. Furthermore, sequencing results revealed that fluoride exposure resulted in differential expression of 17 miRNAs and 4725 mRNAs, which were primarily enriched in the biological processes of tight junctions, inflammatory response, and lipid metabolism, with miR-742-3p, miR-141-5p, miR-878-3p, and miR-143-5p serving as key regulators. Further verification found that fluoride damaged tight junctions, raised oxidative stress, induced an inflammatory response, increased lipid synthesis, and reduced lipid decomposition and transport in the cauda epididymis. This study provided a theoretical basis for developing miRNA as potential diagnostic markers and therapeutic target drugs for this injury.

Bifidobacterium Relieved Fluoride-Induced Hepatic and Ileal Toxicity via Inflammatory Response and Bile Acid Transporters in Mice.

Fluoride is a pervasive environmental contaminant. Prolonged excessive fluoride intake can inflict severe damage on the liver and intestines. Previous 16S rDNA sequencing revealed a decrease in ileal Bifidobacterium abundance during fluoride-induced hepatointestinal injury. Hence, this work aimed to investigate the possible mitigating function of Bifidobacterium on hepatointestinal injury caused by fluoride. Thirty-six 6-week-old C57BL/6J mice (equally divided between males and females) were allotted randomly to three groups: Ctrl group (distilled water), NaF group, and NaF + Ba group (100 mg/L NaF distilled water). After 10 weeks, the mice were given 1 × 109 CFU/mL Bifidobacterium solution (0.2 mL/day) intragastrically in the NaF + Ba group for 8 weeks, and the mice in other groups were given the same amount of distilled water. Dental damage, bone fluoride content, blood routine, liver and intestinal microstructure and function, inflammatory factors, and regulatory cholic acid transporters were examined. Our results showed that fluoride increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) activities, and the levels of lipopolysaccharide (LPS), IL-1ß, IL-6, TNF-α, and IL-10 levels in serum, liver, and ileum. However, Bifidobacterium intervention alleviated fluoride-induced changes in the above indicators. In addition, Bifidobacterium reduced the mRNA expression levels of bile acid transporters ASBT, IBABP, OST-α, and OST-ß in the ileum. In summary, Bifidobacterium supplementation relieved fluoride-induced hepatic and ileal toxicity via an inflammatory response and bile acid transporters in the liver and ileum of mice.

Riboflavin Attenuates Fluoride-Induced Testicular Injury via Interleukin 17A-Mediated Classical Pyroptosis.

Male reproductive toxicity of fluoride is of great concern worldwide, yet the underlying mechanism is unclear. Pyroptosis is a novel mode of inflammatory cell death, and riboflavin with anti-inflammatory properties has the potential to protect against fluoride damage. However, it is unknown whether pyroptosis is involved in fluoride-induced testicular injury and riboflavin intervention. Here, we first found that riboflavin could alleviate fluoride-caused lower sperm quality and damaged testicular morphology by reducing pyroptosis based on a model of ICR mice treated with NaF (100 mg/L) and/or riboflavin supplementation (40 mg/L) via drinking water for 13 weeks. And then, together with the results of in vitro Leydig cell modelsm it was confirmed that the pyroptosis occurs predominantly through classical NLRP3/Caspase-1/GSDMD pathway. Furthermore, our results reveal that interleukin-17A mediates the process of pyroptosis in testes induced by fluoride and riboflavin attenuation according to the results of our established models of riboflavin- and/or fluoride-treated IL-17A knockout mice. The results not only declare a new mechanism by which fluoride induces testicular injury via interleukin 17A-mediated classical pyroptosis but also provide evidence for the potential clinical application of riboflavin as an effective therapy for fluoride toxicity.

Calcium supplementation attenuates fluoride-induced bone injury via PINK1/Parkin-mediated mitophagy and mitochondrial apoptosis in mice.

Excessive consumption of fluoride can cause skeletal fluorosis. Mitophagy has been identified as a novel target for bone disorders. Meanwhile, calcium supplementation has shown great potential for mitigating fluoride-related bone damage. Hence, this study aimed to elucidate the association between mitophagy and skeletal fluorosis and the precise mechanisms through which calcium alleviates these injuries. A 100 mg/L sodium fluoride (NaF) exposure model in Parkin knockout (Parkin-/-) mice and a 100 mg/L NaF exposure mouse model with 1% calcium carbonate (CaCO3) intervention were established in the current study. Fluoride exposure caused the impairment of mitochondria and activation of PTEN-induced putative kinase1 (PINK1)/E3 ubiquitin ligase Park2 (Parkin)-mediated mitophagy and mitochondrial apoptosis in the bones, which were restored after blocking Parkin. Additionally, the intervention model showed fluoride-exposed mice exhibited abnormal bone trabecula and mechanical properties. Still, these bone injuries could be effectively attenuated by adding 1% calcium to their diet, which reversed fluoride-activated mitophagy and apoptosis. To summarize, fluoride can activate bone mitophagy through the PINK1/Parkin pathway and mitochondrial apoptosis. Parkin-/- and 1% calcium provide protection against fluoride-induced bone damage. Notably, this study provides theoretical bases for the prevention and therapy of animal and human health and safety caused by environmental fluoride contamination.

Riboflavin alleviates fluoride-induced ferroptosis by IL-17A-independent system Xc-/GPX4 pathway and iron metabolism in testicular Leydig cells.

Fluoride is widely found in groundwater, soil, animal and plant organisms. Excessive fluoride exposure can cause reproductive dysfunction by activating IL-17A signaling pathway. However, the adverse effects of fluoride on male reproductive system and the mechanisms remain elusive. In this study, the wild type and IL-17A knockout C57BL/6J mouse were treated with 24 mg/kg·bw·d sodium fluoride and/or 5 mg/kg·bw·d riboflavin-5'-phosphate sodium for 91 days. Results showed that fluoride caused dental fluorosis, increased the levels of ROS in testicular Leydig cells and GSSG in testicular tissue, and did not affect the iron and serum hepcidin levels in testicular tissue. Riboflavin alleviated above adverse changes, whereas IL-17A does not participate in the oxidative stress-mediated reproductive toxicity of fluoride. Based on this, TM3 cells were used to verify the injury of fluoride on Leydig cells. Results showed that fluoride increased mRNA levels of ferroptosis marker SLC3A2, VDAC3, TFRC, and SLC40A1 and decreased Nrf2 mRNA levels in TM3 cells. The ferroptosis inhibitor Lip-1 and DFO were used to further investigate the relationship between male reproductive toxicity and ferroptosis induced by fluoride. We found that the fluoride-induced decrease in cell viability, increase in xCT, TFRC, and FTH protein expression, and decrease in GPX4 protein expression, can all be rescued by Lip-1 and DFO. Similar results were also observed in the riboflavin treatment group. Moreover, riboflavin mitigated fluoride-induced increases in ROS levels and SLC3A2 protein levels. In all, our work revealed that riboflavin inhibited ferroptosis in testicular Leydig cells and improved the declined male reproductive function caused by fluoride. This study provides new perspectives for revealing new male reproductive toxicity mechanisms and mitigating fluoride toxicity damage.

Natural products for gastric carcinoma prevention and treatment: Focus on their antioxidant stress actions in the Correa's cascade.

BACKGROUND: Correa's cascade is a pathological process beginning from gastritis to gastric precancerous lesions, and finally to gastric carcinoma (GC). While the pathogenesis of GC remains unclear, oxidative stress plays a prominent role throughout the entire Correa's cascade process. Studies have shown that some natural products (NPs) could halt and even reverse the development of the Correa's cascade by targeting oxidative stress. METHODS: To review the effects and mechanism by which NPs inhibit the Correa's cascade through targeting oxidative stress, data were collected from PubMed, Embase, Web of Science, ScienceDirect, and China National Knowledge Infrastructure databases from initial establishment to April 2023. NPs were classified and summarized by their mechanisms of action. RESULTS: NPs, such as terpenoid, polyphenols and alkaloids, exert multistep antioxidant stress effects on the Correa's cascade. These effects include preventing gastric mucosal inflammation (stage 1), reversing gastric precancerous lesions (stage 2), and inhibiting gastric carcinoma (stage 3). NPs can directly impact the conversion of gastritis to GC by targeting oxidative stress and modulating signaling pathways involving IL-8, Nrf2, TNF-α, NF-κB, and ROS/MAPK. Among which polyphenols have been studied more and are of high research value. CONCLUSIONS: NPs display a beneficial multi-step action on the Correa's cascade, and have potential value for clinical application in the prevention and treatment of gastric cancer by regulating the level of oxidative stress.

Human diet-derived polyphenolic compounds and hepatic diseases: From therapeutic mechanisms to clinical utilization.

This review focuses on the potential ameliorative effects of polyphenolic compounds derived from human diet on hepatic diseases. It discusses the molecular mechanisms and recent advancements in clinical applications. Edible polyphenols have been found to play a therapeutic role, particularly in liver injury, liver fibrosis, NAFLD/NASH, and HCC. In the regulation of liver injury, polyphenols exhibit anti-inflammatory and antioxidant effects, primarily targeting the TGF-ß, NF-κB/TLR4, PI3K/AKT, and Nrf2/HO-1 signaling pathways. In the regulation of liver fibrosis, polyphenolic compounds effectively reverse the fibrotic process by inhibiting the activation of hepatic stellate cells (HSC). Furthermore, polyphenolic compounds show efficacy against NAFLD/NASH by inhibiting lipid oxidation and accumulation, mediated through the AMPK, SIRT, and PPARγ pathways. Moreover, several polyphenolic compounds exhibit anti-HCC activity by suppressing tumor cell proliferation and metastasis. This inhibition primarily involves blocking Akt and Wnt signaling, as well as inhibiting the epithelial-mesenchymal transition (EMT). Additionally, clinical trials and nutritional evidence support the notion that certain polyphenols can improve liver disease and associated metabolic disorders. However, further fundamental research and clinical trials are warranted to validate the efficacy of dietary polyphenols.

Daily Soil Moisture Retrieval by Fusing CYGNSS and Multi-Source Auxiliary Data Using Machine Learning Methods.

The Cyclone Global Navigation Satellite System (CYGNSS), a publicly accessible spaceborne Global Navigation Satellite System Reflectometry (GNSS-R) data, provides a new alternative opportunity for large-scale soil moisture (SM) retrieval, but with interference from complex environmental conditions (i.e., vegetation cover and ground roughness). This study aims to develop a high-accuracy model for CYGNSS SM retrieval. The normalized surface reflectivity calculated by CYGNSS is fused with variables that are highly related to the SM obtained from optical/microwave remote sensing to solve the problem of the influence of complicated environmental conditions. The Gradient Boost Regression Tree (GBRT) model aided by land-type data is then used to construct a multi-variables SM retrieval model with six different land types of multiple models. The methodology is tested in southeastern China, and the results correlate very well with the existing satellite remote sensing products and in situ SM data (R = 0.765, ubRMSE = 0.054 m3m-3 vs. SMAP; R = 0.653, ubRMSE = 0.057 m3 m-3 vs. ERA5 SM; R = 0.691, ubRMSE = 0.057 m3m-3 vs. in situ SM). This study makes contributions from two aspects: (1) improves the accuracy of the CYGNSS retrieval of SM based on fusion with other auxiliary data; (2) constructs the SM retrieval model with multi-layer multiple models, which is suitable for different land properties.

Natural products and mitochondrial allies in colorectal cancer therapy.

Colorectal cancer (CRC) is a globally prevalent malignancy with a high potential for metastasis. Existing cancer treatments have limitations, including drug resistance and adverse effects. Researchers are striving to develop effective therapies to address these challenges. Impressively, contemporary research has discovered that many natural products derived from foods, plants, insects, and marine invertebrates can suppress the progression, metastasis, and invasion of CRC. In this review, we conducted a comprehensive search of the CNKI, PubMed, Embase, and Web of Science databases from inception to April 2023 to evaluate the efficacy of natural products targeting mitochondria to fight against CRC. Mitochondria are intracellular energy factories involved in cell differentiation, signal transduction, cell cycle regulation, apoptosis, and tumorigenesis. The identified natural products have been classified and summarized based on their mechanisms of action. These findings indicate that natural products can induce apoptosis in colorectal cancer cells by inhibiting the mitochondrial respiratory chain, ROS elevation, disruption of mitochondrial membrane potential, the release of pro-apoptotic factors, modulation of the Bcl-2 protein family to facilitate cytochrome c release, induction of apoptotic vesicle activity by activating the caspase protein family, and selective targeting of mitochondrial division. Furthermore, diverse apoptotic signaling pathways targeting mitochondria, such as the MAPK, p53, STAT3, JNK and AKT pathway, have been triggered by natural products. Natural products such as diosgenin, allopurinol, and clausenidin have demonstrated low toxicity, high efficacy, and multi-targeted properties. Mitochondria-targeting natural products have great potential for overcoming the challenges of CRC therapy.

α-Lipoic acid improves mitochondrial biogenesis and dynamics by enhancing antioxidant and inhibiting Wnt/Ca2+ pathway to relieve fluoride-induced hepatotoxic injury.

Fluoride (F), widely present in water and food, poses a serious threat to liver health, and oxidative damage and mitochondrial damage are its main causes. As a natural mitochondrial protector and antioxidant, α-lipoic acid (ALA)'s alleviating effect on fluorosis liver injury and its underlying mechanism are still unclear. Therefore, this study established a fluorosis ALA intervention mice model to explore the mechanism of mitochondrial biogenesis, mitochondrial dynamics, and Wnt/Ca2+ pathway in ALA attenuating fluorosis liver injury. The results showed that ALA mitigated F-induced weight loss, hepatic structural and functional damage, hepatocytes mitochondrial damage, and decreased antioxidant levels. However, ALA did not reduce F accumulation in the femur. Further mRNA and protein detection results showed that F increased the expression levels of key genes in the mitochondrial fission (Drp1, Mff, and Fis1), mitophagy (Parkin, Pink1, and Prdx3), Wnt/Ca2+ pathway (Wnt5a and CaMK2), and rised the number and intensity of fluorescent spots of Drp1, but decreased the expression levels of key genes in the mitochondrial biogenesis (Sirt1, Sirt3, and PGC-1α) and fusion (OPA1, Mfn2, and Mfn1), and reduced the number and intensity of fluorescent spots of PGC-1α in the liver. However, the intervention of ALA relieved the F-induced changes in the expressions of the above genes. In conclusion, ALA mitigated F-induced hepatic injury through enhancing antioxidant capacity and inhibiting Wnt/Ca2+ pathway to improve mitochondrial biogenesis and dynamics disturbance. This study further reveals the hepatotoxic mechanism of F and the protective mechanism of ALA, and provides a theoretical basis for ALA as a potential preventive and palliative agent for F-induced hepatotoxic injury.

Therapeutic Effects of Baicalin on Diseases Related to Gut-Brain Axis Dysfunctions.

The gut-brain axis is an active area of research. Several representative diseases, including central nervous system disorders (Alzheimer's disease, Parkinson's disease, and depression), metabolic disorders (obesity-related diseases), and intestinal disorders (inflammatory bowel disease and dysbiosis), are associated with the dysfunctional gut-brain axis. Baicalin, a bioactive flavonoid extracted from Scutellaria baicalensis, is reported to exert various pharmacological effects. This narrative review summarizes the molecular mechanisms and potential targets of baicalin in disorders of the gut-brain axis. Baicalin protects the central nervous system through anti-neuroinflammatory and anti-neuronal apoptotic effects, suppresses obesity through anti-inflammatory and antioxidant effects, and alleviates intestinal disorders through regulatory effects on intestinal microorganisms and short-chain fatty acid production. The bioactivities of baicalin are mediated through the gut-brain axis. This review comprehensively summarizes the regulatory role of baicalin in gut-brain axis disorders, laying a foundation for future research, although further confirmatory basic research is required.

FOXP1-GINS1 axis promotes DLBCL proliferation and directs doxorubicin resistance.

GINS1 is overexpressed in several types of cancers including leukemia and linked to poor outcomes. However, GINS1 remains poorly investigated in DLBCL (diffuse large B-cell lymphoma). This project aimed to explore the expression, functions and regulation of GINS1 in DLBCL. In this study, through analysis of clinical specimens from DLBCL patients, we uncovered that GINS1 was upregulated in DLBCL. By EMSA, ChIP and luciferase reporter assays, it was found that FOXP1 transcriptionally activated GINS1 expression by directly binding to the promoter region of the GINS1 gene. Western blotting and RT-PCR also revealed that GINS1 expression positively correlated with FOXP1 in human DLBCL specimens and cell lines. In an in vivo xenograft lymphoma mouse model, the FOXP1/GINS1 regulatory axis was also validated. Moreover, with CCK8 cell proliferation assays and colony formation assay, elevated GINS1 expression was found to be associated with doxorubicin resistance in lymphoma cells. Our findings showed that the FOXP1-GINS1 axis played a critical role in DLBCL development and doxorubicin resistance, and targeting the FOXP1-GINS1 axis could be a potential therapeutic approach for DLBCL treatment.

The synthesis and functionalization of metal organic frameworks and their applications for the selective separation of proteins/peptides.

Recently, proteins separation has drawn great interest for the full investigation of a proteome because the proteins separation is the precondition when conducting clinical research or proteomics research. Metal organic frameworks (MOFs) are fabricated via covalent connection between organic ligands and metal ions/clusters units. MOFs have attracted much attention due to the ultra-high specific surface area, tunable structure, more metal site or unsaturated site, and chemical stability. Over the past decade, different functionalization types of MOFs have been reported in combination with amino acids, nucleic acids, proteins, polymers, and nanoparticles for various applications. In this review, the synthesis and functionalization of MOFs have been thoroughly discussed, and we introduced the existing problems and development trends in these fields. Furthermore, MOFs as advanced adsorbents for selective separation of proteins/peptides are summarized. Additionally, we present a comprehensive prospects and challenges in the preparation of robust functional MOFs-based adsorbents and make a final outlook on their future development prospects in selective separation of proteins/peptides.

Melatonin alleviated fluoride-induced impairment of spermatogenesis and sperm maturation process via Interleukin-17A.

Fluoride-induced male reproductive failure is a major environmental and human health concern, but interventions are still lacking. Melatonin (MLT) has potential functions in regulating testicular damage and interleukin-17 (IL-17) production. This study aims to explore whether MLT can mitigate fluoride-induced male reproductive toxicity through IL-17A, and screen the potential targets. So the wild type and IL-17A knockout mice were employed and treated with sodium fluoride (100 mg/L) by drinking water and MLT (10 mg/kg.BW, intraperitoneal injection per two days starting from week 16) for 18 weeks. Bone F- concentrations, grade of dental damage, sperm quality, spermatogenic cells counts, histological morphology of testis and epididymis, and the mRNA expression of spermatogenesis and maturation, classical pyroptosis related and immune factor genes were detected respectively. The results revealed that MLT supplementations alleviated fluoride-induced impairment of spermatogenesis and maturation process, protecting the morphology of testis and epididymis through IL-17A pathway, and Tesk1 and Pten were identified as candidate targets from 29 regulation genes. Taken together, this study demonstrated a new physiological role for MLT in the protection against fluoride-induced reproductive injury and possible regulation mechanisms, which providing a useful therapeutic strategy for male reproductive function failure caused by fluoride or other environmental pollutants.

Effects of Tai Chi Chuan training on the QoL and psychological well-being in female patients with breast cancer: a systematic review of randomized controlled trials.

Background: Tai Chi Chuan (TCC) may have a positive impact on physical and psychological well-being in breast cancer patients, but the evidence remains limited and inconclusive. This systematic review aims to evaluate the effects of TCC on the quality of life (QoL) and psychological symptoms in women patients with breast cancer. Methods: This review has been registered on PROSPERO (ID: CRD42019141977). Randomized controlled trials (RCTs) of TCC for breast cancer were searched from eight major English and Chinese databases. All trials included were analyzed in accordance with the Cochrane Handbook. The primary outcomes were QoL, anxiety, and depression in patients with breast cancer. Fatigue, sleep quality, cognitive function, and inflammatory cytokine were the secondary outcomes. Results: Fifteen RCTs involving a total of 1,156 breast cancer participants were included in this review. The methodological quality of included trials was generally poor. The pooled results suggested that TCC-based exercise could significantly improve QoL [standardized mean difference (SMD)=0.35, 95%CI: 0.15-0.55, I 2 = 0, model: fixed, IV], anxiety [weighted mean difference (WMD)=-4.25, 95%CI: -5.88 to -2.63, I 2 = 0, model: fixed, IV], and fatigue (SMD=-0.87, 95%CI: -1.50 to -0.24, I 2 = 80.9%, model: random, DL) compared other controls, with moderate to low certainty of evidence. The improvement of QoL and fatigue by TCC was also clinically meaningful. However, TCC-based exercise failed to show any between-group differences in depression, sleep quality, cognitive function, and inflammatory cytokine. Post-hoc analysis revealed that TCC-based exercise outperformed the other exercise in improving shoulder function with very low certainty of evidence. Conclusion: Our findings manifested that TCC-based exercise is helpful for improving the QoL, anxiety, and fatigue in patients with breast cancer within the range of comparisons covered in this study. However, the results must be treated with great caution because of the methodological flaws of included trials. Larger, well-designed, and conducted randomized controlled trials with longer follow-up is warranted in the future to evaluate the important outcomes of TCC for breast cancer. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019141977, identifier, CRD42019141977.

PAX5 and circ1857 affected DLBCL progression and B-cell proliferation through regulating GINS1.

PAX5, a member of the paired box gene family of transcription factors, is a B-cell-specific activator protein that plays important roles during B lymphopoiesis. Two putative PAX5 binding sites in the human GINS1 promoter region were identified. EMSA, ChIP and luciferase assay showed that PAX5 functions as a positive transcription factor for GINS1 expression. Furthermore, coordinated expression of PAX5 and GINS1 was observed in mice B cells under physiological conditions and LPS stimulation situations. A similar pattern was also observed in human DLBCL cell lines under differentiation-inducing conditions. In addition, both PAX5 and GINS1 were highly expressed and significantly correlated in DLBCL specimens and cell lines. These findings suggested that dysregulation of PAX5 played an extremely important role in controlling the universal phenomenon of tumor progression through increased expression of GINS1 in DLBCL. In addition, circ1857 that was generated using back splicing of PAX5 pre-mRNA could further stabilize GINS1 mRNA, modulate GINS1 expression and promote lymphoma progression. To the best of our knowledge, this report is the first to demonstrate the role of GINS1 in DLBCL progression, and the mechanism of GINS1 upregulation using both circ1857 and PAX5 in DLBCL was revealed. Our results suggested that GINS1 may be a possible therapeutic target for DLBCL.

Interleukin-17A knockout or self-recovery alleviated autoimmune reaction induced by fluoride in mouse testis.

Fluoride (F) is usually treated as a hazardous material, and F-caused public health problem has attracted global attention. Previous studies demonstrate that interleukin-17A (IL-17A) plays a crucial role in F-elicited autoimmune orchitis and self-recovery reverses F-induced testicular toxicity to some extent, but these basic mechanisms remain unclear. Thus, we established a 180 d F exposure model of wild type (WT) mice and IL-17A knockout mice (C57BL/6 J background), and 60 d & 120 d self-recovery model based on F exposure model of WT mice, and used various techniques like qRT-PCR, western blot, immunohistochemistry and ELISA to further explore the mechanism of F-induced autoimmune reaction, the role of IL-17A in it and the reversibility of F-caused toxicity in testis. The results indicated that F exposure for 180 d caused the decreased sperm quality, the damaged testis histopathology, the enhanced mRNA and protein expression levels of inflammatory cytokines, the changes of autoantibody such as the appearance and increased content of anti-testicular autoantibodies in sera and the autoantibody deposition in testis, the alterations of autoimmune related genes containing the decreased mRNA and protein expressions of AIRE and FOXP3 with an increase of MHCII, and the reduced protein expressions of CTLA4, and the activation of IL-17A signaling cascade like the elevated mRNA and protein expressions of IL-17A, Act1, NF-κB, AP-1 and CEBPß, and the increased protein expressions of IL-17RC, with a decrease of IκBα. After IL-17A knockout, 29 of 35 F-induced changes were alleviated. In two self-recovery models, all F-caused differences except fluorine concentration in femur were gradually restored in a time-dependent manner. This study concluded that IL-17A knockout or self-recovery attenuated F-induced testicular injury and decrease of sperm quality through alleviating autoimmune reaction which was involved with the activation of IL-17A pathway, the damage of self-tolerance and the enhancement of antigen presentation.

Retinal vein changes after treatment with aflibercept and PRP in high-risk proliferative diabetic retinopathy.

Objective: The objective of the study was to investigate the effectiveness of aflibercept and panretinal photocoagulation (PRP) in the treatment of proliferative diabetic retinopathy (PDR). Methods: A retrospective analysis was performed on 59 patients (59 eyes) with high-risk PDR who were treated with aflibercept and PRP between January 2018 and December 2019. The best corrected visual acuity (BCVA), central foveal thickness (CFT), and retinal vein diameter post-treatment were compared to those before the treatment. Results: The best corrected visual acuity (BCVA) at 6 months (0.49 ± 0.14 logMAR), 12 months (0.54 ± 0.15 logMAR), 18 months (0.48 ± 0.15 logMAR), and 24 months (0.51 ± 0.15 logMAR) post-treatment were superior to the pre-treatment measurement (0.65 ± 0.18 logMAR). The central foveal thickness (CFT) at 6 months (310.67 ± 52.53 µm), 12 months (295.98 ± 45.65 µm), 18 months (282.56 ± 43.57 µm), and 24 months (281.53 ± 51.16 µm) post-treatment were lower than the pre-treatment measurement (456.53 ± 51.49 µm); the retinal vein diameter at 12 months (310.13 ± 24.60 µm), 18 months (309.50 ± 31.58 µm), and 24 months (317.00 ± 27.54 µm) post-treatment were lower than the pre-treatment measurement (361.81 ± 30.26 µm). Conclusion: Aflibercept intravitreal injection and panretinal photocoagulation may morphologically reverse retinal vein diameter and venous beading in high-risk proliferative diabetic retinopathy.

Ameliorative effects of different doses of selenium against fluoride-triggered apoptosis and oxidative stress-mediated renal injury in rats through the activation of Nrf2/HO-1/NQO1 signaling pathway.

Excess fluoride (F) exposure can cause oxidative stress in the kidney. As an antioxidant, selenium (Se) can potentially protect the kidney from F-induced injury in rats. Hence, the histopathological, renal biochemical, oxidative stress, and apoptotic-related indices upon exposure to 100 mg/L sodium fluoride (NaF) and various doses of sodium selenite (Na2SeO3; 0.5, 1, and 2 mg/L) were assessed. Our results demonstrated that F-mediated renal structural damage and apoptosis elevated the content of serum creatinine (SCr), inhibited the activity of catalase (CAT) in serum, and increased the production of reactive oxygen species (ROS) in kidney and malondialdehyde (MDA) in serum. Interestingly, 1 mg/L dietary supplementation of Se tangibly mitigated these injuries. Furthermore, F could also change the gene and protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase1 (NQO1). Concomitantly, the different concentrations of Se notably alleviated their expression. Taken together, 1-2 mg/L Se ameliorated F-induced renal injury through oxidative stress and apoptosis-related routes. The recorded ameliorative effects might be related to the activation of the Nrf2/HO-1/NQO1 signaling pathway.