An ALP-responsive, anionic iridium complex for specific recognition of osteosarcoma cells.

Poor cellular permeability greatly hampers the utilization of anionic Ir(III) complexes, though efficiently emissive and remarkably stable, in cell-based diagnosis. To overcome this barrier, we present the development of an alkaline phosphatase (ALP)-responsive, anionic, and aggregation-induced emission (AIE)-active Ir(III) complex (Ir1) for specific recognition of osteosarcoma cells. Containing phosphate moieties, Ir1 exhibits a net -1 charge, enabling charge repulsion from the cell membrane and resulting in low cellular uptake and good biocompatibility in normal osteoblast cells. Upon ALP-mediated hydrolysis of phosphate groups, the resulting dephosphorylated product, Ir2, demonstrates a positive charge and increased lipophilicity, promoting cellular uptake and activating its AIE properties for specific recognition of osteosarcoma cells that express elevated levels of ALP. This study elucidates the role of ALP as an ideal trigger for enhancing the cellular permeability of phosphate ester-containing Ir(III) complexes, thus expanding the potential of anionic Ir(III) complexes for biomedical applications.

ETS translocation variant 5 (ETV5) promotes CD4+ T cell-mediated intestinal inflammation and fibrosis in inflammatory bowel diseases.

E26 transformation-specific translocation variant 5 (ETV5) has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). However, the exact roles of ETV5 in regulating CD4+ T cell-mediated intestinal inflammation and fibrosis formation remain unclear. Here, we reveal that ETV5 overexpression induced interleukin (IL)-9 and its transcription factor IRF4 expression in IBD CD4+ T cells under T helper type 9 (Th9) cells-polarizing conditions. The silencing of IRF4 inhibited ETV5-induced IL-9 expression. CD4+ T cell-specific ETV5 deletion ameliorated intestinal inflammation and fibrosis in trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis and CD4+ T cell-transferred recombination-activating gene-1 knockout (Rag1-/-) colitis mice, characterized by less CD4+ T cell infiltration and lower fibroblast activation and collagen deposition in the colonic tissues. Furthermore, IL-9 treatment aggressive TNBS-induced intestinal fibrosis in CD4+ T cell-specific ETV5 deletion and wild-type control mice. In vitro, human intestinal fibroblasts cocultured with ETV5 overexpressed-Th9 cells expressed higher levels of collagen I and III, whereas an inclusion of anti-IL-9 antibody could reverse this effect. Ribonucleic acid sequencing analysis demonstrated that IL-9 upregulated TAF1 expression in human intestinal fibroblasts. Clinical data showed that number of α-smooth muscle actin+TAF1+ fibroblasts are higher in inflamed mucosa of patients with IBD. Importantly, TAF1 small interfering ribonucleic acid treatment suppressed IL-9-mediated profibrotic effect in vitro. These findings reveal that CD4+ T cell-derived ETV5 promotes intestinal inflammation and fibrosis through upregulating IL-9-mediated intestinal inflammatory and fibrotic response in IBD. Thus, the ETV5/IL-9 signal pathway in T cells might represent a novel therapeutic target for intestinal inflammation and fibrosis in IBD.

Investigation on biomechanical responses in bilateral semicircular canals and nystagmus in vestibulo-ocular reflex experiments under different forward-leaning angles.

Different head positions affect the responses of the vestibular semicircular canals (SCCs) to angular movement. Specific head positions can relieve vestibular disorders caused by excessive stimulating SCCs. In this study, we quantitatively explored responses of human SCCs using numerical simulations of fluid-structure interaction and vestibulo-ocular reflex (VOR) experiments under different forward-leaning angles of the head, including 0°, 10°, 20°, 30°, 40°, 50°, and 60°. It was found that the horizontal nystagmus slow-phase velocity and corresponding biomechanical responses of the cupula in horizontal SCC increased with the forward-leaning angles of the head, reached a maximum when the head was tilted 30° forward, and then gradually decreased. However, no obvious vertical or torsional nystagmus was observed in the VOR experiments. In the numerical model of bilateral SCCs, the biomechanical responses of the cupula in the left anterior SCC and the right anterior SCC showed the same trends; they decreased with the forward-leaning angles, reached a minimum at a 40° forward tilt of the head, and then gradually increased. Similarly, the biomechanical responses of the cupula in the left posterior SCC and in the right posterior SCC followed a same trend, decreasing with the forward-leaning angles, reaching a minimum at a 30° forward tilt of the head, and then gradually increasing. Additionally, the biomechanical responses of the cupula in both the anterior and posterior SCCs consistently remained lower than those observed in the horizontal SCCs across all measured head positions. The occurrence of these numerical results was attributed to the consistent maintenance of mutual symmetry in the bilateral SCCs with respect to the mid-sagittal plane containing the axis of rotation. This symmetry affected the distribution of endolymph pressure, resulting in biomechanical responses of the cupula in each pair of symmetrical SCCs exhibiting same tendencies under different forward-leaning angles of the head. These results provided a reliable numerical basis for future research to relieve vestibular diseases induced by spatial orientation of SCCs.

Ganoderma lucidum polysaccharide ameliorates cholesterol gallstone formation by modulating cholesterol and bile acid metabolism in an FXR-dependent manner.

BACKGROUND: Cholesterol gallstone (CG) disease is a worldwide common disease characterized by cholesterol supersaturation in gallbladder bile. Ganoderma lucidum polysaccharide (GLP) has been shown to possess various beneficial effects against metabolic disorders. However, the role and underlying mechanism of GLP in CG formation are still unknown. This study aimed to determine the role of GLP in ameliorating lithogenic diet (LD)-induced CG formation. METHODS: Mice were fed either a normal chow diet, a LD, or LD supplemented with GLP. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression of genes involved in cholesterol and bile acid (BA) metabolism. The BA concentrations in the ileum were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The microbiota in cecal contents were characterized using 16S ribosomal RNA (16S rRNA) gene sequencing. RESULTS: GLP effectively alleviated CG formation induced by LD. Specifically, GLP reduced the total cholesterol (TC) levels, increased the total BA levels, and decreased the cholesterol saturation index (CSI) in gallbladder bile. The protective effect of GLP was attributed to the inhibition of farnesoid X receptor (FXR) signaling, increased hepatic BA synthesis and decreased hepatic cholesterol synthesis and secretion. GLP also altered the BA composition in the ileum, reducing FXR-agonistic BAs and increasing FXR-antagonistic BAs, which may contribute to the inhibition of intestinal FXR signaling. Additionally, GLP improved dysbiosis of the intestinal flora and reduced the serum levels of hydrogen sulfide (H2S), a bacterial metabolite that can induce hepatic FXR, thereby inhibiting hepatic FXR signaling. Moreover, the protective effect of GLP against CG formation could be reversed by both the global and gut-restricted FXR agonists. CONCLUSIONS: Taken together, GLP ameliorates CG formation by regulating cholesterol and BA metabolism in an FXR-dependent manner. Our study demonstrates that GLP may be a potential strategy for the prevention against CG disease.

Targeting the E2F1/Rb/HDAC1 axis with the small molecule HR488B effectively inhibits colorectal cancer growth.

Colorectal cancer (CRC), the third most common cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in the treatment of CRC. In the present study, we designed a series of small-molecule Thiazole-based HDACis, among which HR488B bound to HDAC1 with a high affinity and exerted effective anti-CRC activity both in vitro and in vivo. Moreover, we revealed that HR488B specifically suppressed the growth of CRC cells by inducing cell cycle G0/G1 arrest and apoptosis via causing mitochondrial dysfunction, reactive oxygen species (ROS) generation, and DNA damage accumulation. Importantly, we noticed that HR488B significantly decreased the expression of the E2F transcription factor 1 (E2F1), which was crucial for the inhibitory effect of HR488B on CRC. Mechanistically, HR488B obviously decreased the phosphorylation level of the retinoblastoma protein (Rb), and subsequently prevented the release of E2F1 from the E2F1/Rb/HDAC1 complex, which ultimately suppressed the growth of CRC cells. Overall, our study suggests that HR488B, a novel and efficient HDAC1 inhibitor, may be a potential candidate for CRC therapy in the future. Furthermore, targeting the E2F1/Rb/HDAC1 axis with HR488B provides a promising therapeutic avenue for CRC.

Hyodeoxycholic acid attenuates cholesterol gallstone formation via modulation of bile acid metabolism and gut microbiota.

BACKGROUND & AIMS: Hyodeoxycholic acid (HDCA), a hydrophilic bile acid (BA), may prevent and suppress the formation of cholesterol gallstones (CGs). However, the mechanism by which HDCA prevents CGs formation remains unclear. This study aimed to investigate the underlying mechanism of HDCA in preventing CG formation. METHODS: C57BL/6J mice were fed either a lithogenic diet (LD), a chow diet, or LD combined with HDCA. The concentration of BAs in the liver and ileum were determined using liquid chromatography-mass spectrometry (LC-MS/MS). Genes involved in cholesterol and BAs metabolism were detected using polymerase chain reaction (PCR). The gut microbiota in the faeces was determined using 16S rRNA. RESULTS: HDCA supplementation effectively prevented LD-induced CG formation. HDCA increased the gene expression of BA synthesis enzymes, including Cyp7a1, Cyp7b1, and Cyp8b1, and decreased the expression of the cholesterol transporter Abcg5/g8 gene in the liver. HDCA inhibited LD-induced Nuclear farnesoid X receptor (Fxr) activation and reduced the gene expression of Fgf15 and Shp in the ileum. These data indicate that HDCA could prevent CGs formation partly by promoting BA synthesis in the liver and reduced the cholesterol efflux. In addition, HDCA administration reversed the LD-induced decrease in the abundance of norank_f_Muribaculaceae, which was inversely proportional to cholesterol levels. CONCLUSIONS: HDCA attenuated CG formation by modulating BA synthesis and gut microbiota. This study provides new insights into the mechanism by which HDCA prevents CG formation. LAY SUMMARY: In this study, we found that HDCA supplementation suppressed LD-induced CGs in mice by inhibiting Fxr in the ileum, enhancing BA synthesis, and increasing the abundance of norank_f_Muribaculaceae in the gut microbiota. HDCA can also downregulate the level of total cholesterol in the serum, liver, and bile.

Huangkui capsule attenuates diabetic kidney disease through the induction of mitophagy mediated by STING1/PINK1 signaling in tubular cells.

BACKGROUND: Mitochondria is critic to tubulopathy, especially in diabetic kidney disease (DKD). Huangkui capsule (HKC; a new ethanol extract from the dried corolla of Abelmoschus manihot) has significant clinical effect on DKD. Previous studies have shown that HKC protects kidney by regulating mitochondrial function, but its mechanism is still unclear. The latest research found that the stimulator of interferon genes (STING1) signal pathway is closely related to mitophagy. However, whether HKC induces mitophagy through targeting STING1/PTEN-Induced putative kinase (PINK1) in renal tubular remains elusive. OBJECTIVE: This study aims to clarify the therapeutic effect of HKC on renal tubular mitophagy in DKD and its potential mechanism in vivo and in vitro. METHODS: Forty male C57BL/6 mice were randomly divided into 5 groups: CON group, DKD group, HKC-L (1.0 g/kg/day, by gavage), HKC-H (2.0 g/kg/day), and LST group. Diabetes model was induced by high-fat diet (HFD) combined with intraperitoneal injection of Streptozotocin (STZ). LST (losartan) is used as a positive control drug. Then, the glomeruli, renal tubular lesions, mitochondrial morphology and function of renal tubular cells and mitophagy levels were detected in mice. In addition, a high glucose injury model was established using HK2 human renal tubular cells. Pretreate HK2 cells with HKC or LST and detect mitochondrial function, mitophagy level, and autophagic flux. In addition, small interfering RNAs (siRNAs) of STING1 and PINK1 and overexpressing pcDNA3.1 plasmids were transfected into HK-2 cells to validate the mitophagy mechanism regulated by STING1/PINK1 signaling. RESULTS: The ratio of urinary albumin to creatinine (ACR), fasting blood glucose, body weight in the early DKD mice model was increased, with damage to the glomerulus and renal tubules, mitochondrial structure and dysfunction in the renal tubules, and inhibition of STING1/PINK1 mediated mitophagy. Although the fasting blood glucose, body weight and serum creatinine levels were hardly ameliated, high dose HKC (2.0 g/kg/day) treatment significantly reduced ACR in the DKD mice to some extent, improved renal tubular injury, accurately upregulated STING1/PINK1 signaling mediated mitophagy levels, improved autophagic flux, and restored healthy mitochondrial pools. In vitro, an increase in mitochondrial fragments, fusion to fission, ROS and apoptosis, and a decrease in respiratory function, mtDNA, and membrane potential were observed in HK2 cells exposed to high glucose. HKC treatment significantly protected mitochondrial dynamics and function, which is consistent with in vivo results. Further research has shown that HKC can increase the level of mitophagy mediated by STING1/PINK1 in HK2 cells. CONCLUSIONS: Our results suggest that HKC ameliorates renal tubulopathy in DKD and induces mitophagy partly through the up-regulation of the STING1/PINK1 pathway. These findings may provide an innovative therapeutic basis for DKD treatment.

First records of the druid fly genus Clusia Haliday, 1838 (Diptera, Clusiidae), with two new species from China.

The druid fly genus Clusia was firstly recorded from China, including two new species: C. luteimacula sp. nov. from Yintiaoling Nature Reserve of Chongqing and C. sinensis sp. nov. from Wanglang of Sichuan and Mt. Taibai of Shaanxi. A key to all species of Clusia globally is presented.

Subacute thyroiditis presenting as simple acute headache was misdiagnosed as meningitis: case report and literature review.

BACKGROUND: The relationship between headache and thyrotoxicosis has been occasionally mentioned in case reports, but there are few related reports. Thus, the relationship cannot be determined. Few cases of subacute thyroiditis (SAT) presenting as simple headache have been reported. CASE PRESENTATION: This case report describes a middle-aged male patient who came to our hospital with acute headache for 10 days. He was initially misdiagnosed as meningitis due to headache, fever, and increased C-reactive protein. Routine antibacterial and antiviral therapy did not improve his symptoms. Blood test suggested thyrotoxicosis, and color ultrasound suggested SAT sonography. He was diagnosed with SAT. With the treatment of SAT, the headache was relieved after the thyrotoxicosis improved. CONCLUSION: This patient is the first detailed report of SAT presenting with simple headache, which is helpful for clinicians to differentiate and diagnose atypical SAT.

Numerical study on the distribution of nitric oxide concentration in the nasal cavity of healthy people during breathing.

BACKGROUND: In the nasal cavity, nitric oxide (NO) is involved in many physiological functions, including antibacterial and antiviral activity, promotion of nasal mucociliary clearance, and regulation of blood vessel expansion in the nasal mucosa. We investigated the distribution of NO concentration in the nasal cavity of healthy individuals during breathing. METHODS: A three-dimensional numerical model of the nasal airway, including the bilateral maxillary sinuses, was created to simulate NO distribution in the nasal cavity during normal breathing. The effect of different nasal airflow velocities and NO concentrations in the maxillary sinus on NO distribution in the nasal cavity was evaluated. The NO concentration in the nasal exhalation of 50 healthy people in Dalian was measured using an NO analyzer, and the growth rate of the NO concentration in the nasal cavity was measured under breath-holding conditions. RESULTS: The distribution of NO concentration in the nasal cavity of healthy people during breathing was obtained from numerical simulation results. Lower the airflow rate, higher was the NO concentration and greater was the diffusion range in the nasal cavity. The NO concentration in the nasal cavity increased with an increase in its concentration in the maxillary sinus, indicating a linear relationship. The NO concentration in the nasal exhalation of healthy people in Dalian and the growth rate of the NO concentration in the nasal cavity under breath-holding conditions were obtained through experiments. The numerical results correspond with the experimental results. CONCLUSIONS: The NO entered the nasal cavity mainly by diffusion and followed the convection flow of the respiratory air in the nasal cavity. NO concentration in the nasal cavity was related to the respiratory airflow velocity and NO concentration in the maxillary sinus. During inspiration, NO was present only in the nasal airway posterior to the maxillary sinus ostium, whereas during exhalation, the exhaled NO diffusely distributed throughout the nasal cavity.

CD4+ CTLs Act as a Key Effector Population for Allograft Rejection of MSCs in a Donor MHC-II Dependent Manner in Injured Liver.

Mesenchymal stromal/stem cells (MSCs) have been considered an attractive source of cytotherapy due to their promising effects on treating various diseases. Allogeneic MSCs (allo-MSCs) are extensively used in clinical trials due to their convenient preparation and credible performance. Traditionally, allo-MSCs are considered immunoprivileged with minimal immunogenicity and potent immunomodulatory capacity. However, growing evidence has suggested that allo-MSCs also induce immune response and cause rejection after transplantation, but the underlying cellular and molecular mechanisms remain to be elucidated. Here, we demonstrated that allografted MSCs upregulated MHC-II upon stimulation of IFN-γ in hepatic inflammatory environment by using mouse model of CCl4-induced liver injury. MHC-II upregulation enhanced the immunogenicity of allo-MSCs, leading to the activation of alloreactive T cells and rejection of allo-MSCs. However, MHC-II deficiency impaired the allogenic reactivity, thereby rescuing the loss of allo-MSCs. Mechanistically, CD4+ cytotoxic T lymphocytes (CTLs), rather than CD8+ CTLs, acted as the major effector for allo-MSC rejection. Under liver injury condition, the transplanted allo-MSCs upregulated CD80 and PD-L1, and CD8+ CTLs highly expressed CTLA-4 and PD-1, thereby inducing immune tolerance of CD8+ T cells to allo-MSCs. On the contrary, CD4+ CTLs minimally expressed CTLA-4 and PD-1; thus, they remain cytotoxic to allo-MSCs. Consequently, transplantation of MHC-II-deficient allo-MSCs substantially promoted their therapeutic effects in treating liver injury. This study revealed a novel mechanism of MSC allograft rejection mediated by CD4+ CTLs in injured liver, which provided new strategies for improving clinical performance of allo-MSCs in benefiting hepatic injury repair.

Identification of serum glycobiomarkers for Hepatocellular Carcinoma using lectin microarrays.

Objective: Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer and ranks third in mortality among all malignant tumors; as a result, HCC represents a major human health issue. Although aberrant glycosylation is clearly implicated in HCC, changes in serum immunoglobulin (Ig)G and IgM glycosylation have not been comprehensively characterized. In this study, we used lectin microarrays to evaluate differences in serum IgG and IgM glycosylation among patients with HCC, hepatitis B cirrhosis (HBC), or chronic hepatitis B (CHB), and healthy normal controls (NC) and aimed to establish a model to improve the diagnostic accuracy of HCC. Methods: In total, 207 serum samples collected in 2019-2020 were used for lectin microarray analyses, including 97 cases of HCC, 50 cases of HBC, 30 cases of CHB, and 30 cases of NC. Samples were randomly divided into training and validation groups at a 2:1 ratio. Training group data were used to investigate the diagnostic value of the relative signal intensity for the lectin probe combined with alpha-fetoprotein (AFP). The efficacy of models for HCC diagnosis were analyzed by receiver operating characteristic (ROC) curves. Results: In terms of IgG, a model combining three lectins and AFP had good diagnostic accuracy for HCC. The area under the ROC curve was 0.96 (P < 0.05), the sensitivity was 82.54%, and the specificity was 100%. In terms of IgM, a model including one lectin combined with AFP had an area under the curve of 0.90 (P < 0.05), sensitivity of 75.41%, and specificity of 100%. Conclusion: Estimation of serum IgG and IgM glycosylation could act as complementary techniques to improve diagnosis and shed light on the occurrence and development of the HCC.

Robust quantum state transfer by optimal invariant-based reverse engineering.

Shortening the operation time of implementing scheme and reducing the influence of harmful factors have always been the research objectives pursued by people. Based on invariant-based reverse engineering, we present a general scheme for implementing robust population transfer in a three-level system via optimal shortcut to adiabatic passage. The systematic error sensitivity is introduced to measure the robustness of the process. The smooth Rabi frequencies are expressed with some coefficients, which are also related to the systematic error sensitivity and the population of intermediate state. When the amplitude of control field is given, the transfer can be optimized within as small systematic error sensitivity as possible, i.e., the robustness against systematic errors is further improved by choosing suitable correlation coefficient. Additionally, we apply the technique to achieve robust excitation fluctuation transfer between two membranes in an optomechanical system. The relation between the fidelity of excitation fluctuation transfer and variation of effective optomechanical coupling strengths is analysed. Numerical result shows that the fidelity keeps over 0.95 even if the coupling strengths deviates from 20% of the theoretical value. Moreover, comparison with existing literature [Opt. Express29, 7998 (2021)10.1364/OE.417343], the proposed scheme possesses stronger robustness against variations of effective optomechanical coupling strengths and lower population of unwanted states. The idea may provide a promising approach for quantum information processing.

Bazi Bushen capsule attenuates cognitive deficits by inhibiting microglia activation and cellular senescence.

CONTEXT: Bazi Bushen capsule (BZBS) has anti-ageing properties and is effective in enhancing memory. OBJECTIVE: To find evidence supporting the mechanisms and biomarkers by which BZBS functions. MATERIALS AND METHODS: Male C57BL/6J mice were randomly divided into five groups: normal, ageing, ß-nicotinamide mononucleotide capsule (NMN), BZBS low-dose (LD-BZ) and BZBS high-dose (HD-BZ). The last four groups were subcutaneously injected with d-galactose (d-gal, 100 mg/kg/d) to induce the ageing process. At the same time, the LD-BZ, HD-BZ and NMN groups were intragastrically injected with BZBS (1 and 2 g/kg/d) and NMN (100 mg/kg/d) for treatment, respectively. After 60 days, the changes in overall ageing status, brain neuron morphology, expression of p16INK4a, proliferating cell nuclear antigen (PCNA), ionized calcium-binding adapter molecule 1 (Iba1), postsynaptic density protein 95 (PSD95), CD11b, Arg1, CD206, Trem2, Ym1 and Fizz1, and the senescence-associated secretory phenotype (SASP) factors were observed. RESULTS: Compared with the mice in the ageing group, the HD-BZ mice exhibited obvious improvements in strength, endurance, motor coordination, cognitive function and neuron injury. The results showed a decrease in p16INK4a, Iba1 and the upregulation of PCNA, PSD95 among brain proteins. The brain mRNA exhibited downregulation of Iba1 (p < 0.001), CD11b (p < 0.001), and upregulation of Arg1 (p < 0.01), CD206 (p < 0.05), Trem2 (p < 0.001), Ym1 (p < 0.01), Fizz1 (p < 0.05) and PSD95 (p < 0.01), as well as improvement of SASP factors. CONCLUSIONS: BZBS improves cognitive deficits via inhibition of cellular senescence and microglia activation. This study provides experimental evidence for the wide application of BZBS in clinical practice for cognitive deficits.

FXR Signaling-Mediated Bile Acid Metabolism Is Critical for Alleviation of Cholesterol Gallstones by Lactobacillus Strains.

Cholesterol gallstone (CGS) disease is characterized by an imbalance in bile acid (BA) metabolism and is closely associated with gut microbiota disorders. However, the role and mechanism by which probiotics targeting the gut microbiota attenuate cholesterol gallstones are still unknown. In this study, Limosilactobacillus reuteri strain CGMCC 17942 and Lactiplantibacillus plantarum strain CGMCC 14407 were individually administered to lithogenic-diet (LD)-fed mice for 8 weeks. Both Lactobacillus strains significantly reduced LD-induced gallstones, hepatic steatosis, and hyperlipidemia. These strains modulated BA profiles in the serum and liver, which may be responsible for the activation of farnesoid X receptor (FXR). At the molecular level, L. reuteri and L. plantarum increased ileal fibroblast growth factor 15 (FGF15) and hepatic fibroblast growth factor receptor 4 (FGFR4) and small heterodimer partner (SHP). Subsequently, hepatic cholesterol 7α-hydroxylase (CYP7A1) and oxysterol 7α-hydroxylase (CYP7B1) were inhibited. Moreover, the two strains enhanced BA transport by increasing the levels of hepatic multidrug resistance-associated protein homologs 3 and 4 (Mrp3/4), hepatic multidrug resistance protein 2 (Mdr2), and the bile salt export pump (BSEP). In addition, both L. reuteri and L. plantarum reduced LD-associated gut microbiota dysbiosis. L. reuteri increased the relative abundance of Muribaculaceae, while L. plantarum increased that of Akkermansia. The changed gut microbiota was significantly negatively correlated with the incidence of cholesterol gallstones and the FXR-antagonistic BAs in the liver and serum and with the FXR signaling pathways. Furthermore, the protective effects of the two strains were abolished by both global and intestine-specific FXR antagonists. These findings suggest that Lactobacillus might relieve CGS through the FXR signaling pathways. IMPORTANCE Cholesterol gallstone (CGS) disease is prevalent worldwide. None of the medical options for prevention and treatment of CGS disease are recommended, and surgical management has a high rate of recurrence. It has been reported that the factors involved in metabolic syndrome are highly connected with CGS formation. While remodeling of dysbiosis of the gut microbiome during improvement of metabolic syndrome has been well studied, less is known about prevention of CGS formation after regulating the gut microbiome. We used the lithogenic diet (LD) to induce an experimental CGS model in C57BL/6J mice to investigate protection against CGS formation by Limosilactobacillus reuteri strain CGMCC 17942 and Lactiplantibacillus plantarum strain CGMCC 14407. We found that these L. reuteri and L. plantarum strains altered the bile acid composition in mice and improved the dysbiosis of the gut microbiome. These two Lactobacillus strains prevented CGS formation by fully activating the hepatic and ileal FXR signaling pathways. They could be a promising therapeutic strategy for treating CGS or preventing its recurrence.

Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease.

Cellular senescence is frequently evident at etiologic sites of chronic diseases and involves essentially irreversible arrest of cell proliferation, increased protein production, resistance to apoptosis, and altered metabolic activity. Regulated cell death plays a vital role in shaping fully functional organs during the developmental process, coordinating adaptive or non-adaptive responses, and coping with long-term harmful intracellular or extracellular homeostasis disturbances. In recent years, the concept of 'diabetic tubulopathy' has emerged. tubular epithelial cells are particularly susceptible to the derangements of diabetic state because of the virtue of the high energy requirements and reliance on aerobic metabolism render. Hyperglycemia, oxidative stress, persistent chronic inflammation, glucose toxicity, advanced glycation end-products (AGEs) accumulation, lipid metabolism disorders, and lipotoxicity contribute to the cellular senescence and different patterns of regulated cell death (apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis) in tubular epithelial cells. We now explore the 'tubulocentric' view of diabetic kidney disease(DKD). And we summarize recent discoveries regarding the development and regulatory mechanisms of cellular senescence, apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis in the pathogenesis of DKD. These findings provide new perspectives on the mechanisms of DKD and are useful for designing novel therapeutic approaches for the treatment of DKD.

Highly Luminescent Nucleoside-Based N, P-Doped Carbon Dots for Sensitive Detection of Ions and Bioimaging.

The efficient detection of Fe3+ and MnO4 - in a water environment is very important and challenging due to their harmful effects on the health of humanity and environmental systems. Good biocompatibility, sensitivity, selectivity, and superior photophysical properties were important attributes of carbon dot-based CDs sensors for sensing applications. In this work, we synthesized N, P-co-doped carbon dots (N/P CDs) with guanosine 5'-monophosphate (GMP) as a green carbon source, with high fluorescence quantum yield in water (QY, 53.72%). First, the luminescent N/P CDs showed a three-state "on-off-on" fluorescence response upon the sequential addition of Fe3+ and F-, with a low detection limit of 12 nM for Fe3+ and 8.5 nM for F-, respectively. Second, the N/P CDs also exhibited desirable selectivity and sensitivity for toxic MnO4 - detection with the limit of detection of 18.2 nM, through a turn-off mechanism. Moreover, the luminescent N/P CDs successfully monitored the aforementioned ions in environmental water samples and in Escherichia coli.

Endolymphatic Hydrop Phenotype in Familial Norrie Disease Caused by Large Fragment Deletion of NDP.

Norrie disease (ND; OMIM 310600), a rare X-linked recessive genetic disorder, is characterized by congenital blindness and occasionally, sensorineural hearing loss, and developmental delay. The congenital blindness of ND patients is almost untreatable; thus, hearing is particularly important for them. However, the mechanism of hearing loss of ND patients is unclear, and no good treatment is available except wearing hearing-aid. Therefore, revealing the mechanism of hearing loss in ND patients and exploring effective treatment methods are greatly important. In addition, as a serious monogenic genetic disease, convenient gene identification method is important for ND patients and their family members, as well as prenatal diagnosis and preimplantation genetic diagnosis to block intergenerational transmission of pathogenic genes. In this study, a Norrie family with two male patients was reported. This pedigree was ND caused by large fragment deletion of NDP (norrin cystine knot growth factor NDP) gene. In addition to typical severe ophthalmologic and audiologic defects, the patients showed new pathological features of endolymphatic hydrops (EH), and they also showed acoustic nerves abnormal as described in a very recent report. PCR methods were developed to analyze and diagnose the variation of the family members. This study expands the understanding of the clinical manifestation and pathogenesis of ND and provides a new idea for the treatment of patients in this family and a convenient method for the genetic screen for this ND family.

A Novel Prognostic Ferroptosis-Related lncRNA Signature Associated with Immune Landscape in Invasive Breast Cancer.

Breast cancer (BC) represents the most common form of malignant tumors in women. However, the effectiveness of BC immunotherapy remains very low. Ferroptosis is a recently described form of programmed cell death which has unique characteristics, and associated long-chain noncoding RNAs (lncRNA) are thought to influence the occurrence and development of a variety of tumors. We identified 1,636 lncRNAs associated with ferroptosis in BC patients. 299 differentially expressed ferroptosis-related lncRNAs were subjected to univariate, LASSO regression, and multivariate Cox regression analyses to construct a ten ferroptosis-related lncRNA signature. This ten ferroptosis-related lncRNA signature performed very well in predicting survival of BC patients, and the risk score of the mRNA signature was identified as an independent prognostic factor in this cancer entity. In addition, the signature could be used to predict the immune landscape of BC patients. Low-risk patients had enriched immune-related pathways and more infiltration of most types of immune cells. The signature was also associated with the tumor mutation burden in BC. The results have allowed us to assess the potential for immunotherapy targets exposed by this model. The ferroptosis-related lncRNA risk model reported in the current study has clinical utility in BC prognosis and predicted immunotherapy response.