Qualitative Immunoglobulin Deficiency Causes Bacterial Infections in Patients with STAT1 Gain-of-Function Mutations.

PURPOSES: STAT1 is a transduction and transcriptional regulator that functions within the classical JAK/STAT pathway. In addition to chronic mucocutaneous candidiasis, bacterial infections are a common occurrence in patients with STAT1 gain-of-function (GOF) mutations. These patients often exhibit skewing of B cell subsets; however, the impact of STAT1-GOF mutations on B cell-mediated humoral immunity remains largely unexplored. It is also unclear whether these patients with IgG within normal range require regular intravenous immunoglobulin (IVIG) therapy. METHODS: Eleven patients (harboring nine different STAT1-GOF mutations) were enrolled. Reporter assays and immunoblot analyses were performed to confirm STAT1 mutations. Flow cytometry, deep sequencing, ELISA, and ELISpot were conducted to assess the impact of STAT1-GOF on humoral immunity. RESULTS: All patients exhibited increased levels of phospho-STAT1 and total STAT1 protein, with two patients carrying novel mutations. In vitro assays showed that these two novel mutations were GOF mutations. Three patients with normal total IgG levels received regular IVIG infusions, resulting in effective control of bacterial infections. Four cases showed impaired affinity and specificity of pertussis toxin-specific antibodies, accompanied by reduced generation of class-switched memory B cells. Patients also had a disrupted immunoglobulin heavy chain (IGH) repertoire, coupled with a marked reduction in the somatic hypermutation frequency of switched Ig transcripts. CONCLUSION: STAT1-GOF mutations disrupt B cell compartments and skew IGH characteristics, resulting in impaired affinity and antigen-specificity of antibodies and recurrent bacterial infections. Regular IVIG therapy can control these infections in patients, even those with normal total IgG levels.

Protective effects of the bioactive peptide from maggots against skin flap ischemia‒reperfusion injury in rats.

Ischemia‒reperfusion (I/R) injury is a frequently observed complication after flap surgery, and it affects skin flap survival and patient prognosis. Currently, there are no proven safe and effective treatment options to treat skin flap I/R injury. Herein, the potential efficacies of the bioactive peptide from maggots (BPM), as well as its underlying mechanisms, were explored in a rat model of skin flap I/R injury and LPS- or H2O2-elicited RAW 264.7 cells. We demonstrated that BPM significantly ameliorated the area of flap survival, and histological changes in skin tissue in vivo. Furthermore, BPM could markedly restore or enhance Nrf2 and HO-1 levels, and suppress the expression of pro-inflammatory cytokines, including TLR4, p-IκB, NFκB p65, p-p65, IL-6, and TNF-α in I/R-injured skin flaps. In addition, BPM treatment exhibited excellent biocompatibility with an adequate safety profile, while it exhibited superior ROS-scavenging ability and the upregulation of antioxidant enzymes in vitro. Mechanistically, the above benefits related to BPM involved the activation of Nrf2/HO-1 and suppression of TLR4/NF-κB pathway. Taken together, this study may provide a scientific basis for the potential therapeutic effect of BPM in the prevention of skin flap I/R injury and other related diseases.

Association of barium deficiency with Type 2 diabetes mellitus incident risk was mediated by mitochondrial DNA copy number (mtDNA-CN): A follow-up study.

Accumulating evidence indicates that plasma metals levels may associate with Type 2 diabetes mellitus (T2DM) incident risk. Mitochondrial function such as mitochondrial DNA copy number (mtDNA-CN) might be linked metal exposure and physiological metabolism. Mediation analysis was conducted to determine the mediating roles of mtDNA-CN in the associations of plasma metals with diabetes risk. In the present study, we investigated associations between plasma metals levels, mtDNA-CN and T2DM incident in elderly population with 6-year follow-up (2 times) study. Ten plasma metals (i.e. manganese (Mg), aluminium (Al), calcium (Ca), ferrum (Fe), barium (Ba), arsenic (As), copper (Cu), selenium (Se), titanium (Ti) and cesium (Sr) were measured by using inductively coupled plasma mass spectrometry (ICP-MS). Mitochondrial DNA copy number was measured by real-time PCR. Multivariable linear regression and logistic regression models were carried out to estimate the relationship between plasma metal concentrations, mtDNA-CN and T2DM incident risk in the current work. Plasma Ba deficiency and mtDNA-CN decline associated with T2DM incident risk during aging process. Meanwhile plasma Ba found to be positively associated with mtDNA-CN. Mitochondrial function mtDNA-CN demonstrated mediating effects in association between plasma Ba deficiency and T2DM incident risk, and 49.8% of the association was mediated by mtDNA-CN. These findings extend the knowledge of T2DM incident risk factors and highlight the point that mtDNA-CN may be linked metals element and T2DM incident risk.

Characterization, biogenesis model, and current bioinformatics of human extrachromosomal circular DNA.

Human extrachromosomal circular DNA, or eccDNA, has been the topic of extensive investigation in the last decade due to its prominent regulatory role in the development of disorders including cancer. With the rapid advancement of experimental, sequencing and computational technology, millions of eccDNA records are now accessible. Unfortunately, the literature and databases only provide snippets of this information, preventing us from fully understanding eccDNAs. Researchers frequently struggle with the process of selecting algorithms and tools to examine eccDNAs of interest. To explain the underlying formation mechanisms of the five basic classes of eccDNAs, we categorized their characteristics and functions and summarized eight biogenesis theories. Most significantly, we created a clear procedure to help in the selection of suitable techniques and tools and thoroughly examined the most recent experimental and bioinformatics methodologies and data resources for identifying, measuring and analyzing eccDNA sequences. In conclusion, we highlighted the current obstacles and prospective paths for eccDNA research, specifically discussing their probable uses in molecular diagnostics and clinical prediction, with an emphasis on the potential contribution of novel computational strategies.

In silico analysis of intestinal microbial instability and symptomatic markers in mice during the acute phase of severe burns.

BACKGROUND: Severe burns may alter the stability of the intestinal flora and affect the patient's recovery process. Understanding the characteristics of the gut microbiota in the acute phase of burns and their association with phenotype can help to accurately assess the progression of the disease and identify potential microbiota markers. METHODS: We established mouse models of partial thickness deep III degree burns and collected faecal samples for 16 S rRNA amplification and high throughput sequencing at two time points in the acute phase for independent bioinformatic analysis. RESULTS: We analysed the sequencing results using alpha diversity, beta diversity and machine learning methods. At both time points, 4 and 6 h after burning, the Firmicutes phylum content decreased and the content of the Bacteroidetes phylum content increased, showing a significant decrease in the Firmicutes/Bacteroidetes ratio compared to the control group. Nine bacterial genera changed significantly during the acute phase and occupied the top six positions in the Random Forest significance ranking. Clustering results also clearly showed that there was a clear boundary between the communities of burned and control mice. Functional analyses showed that during the acute phase of burn, gut bacteria increased lipoic acid metabolism, seleno-compound metabolism, TCA cycling, and carbon fixation, while decreasing galactose metabolism and triglyceride metabolism. Based on the abundance characteristics of the six significantly different bacterial genera, both the XGboost and Random Forest models were able to discriminate between the burn and control groups with 100% accuracy, while both the Random Forest and Support Vector Machine models were able to classify samples from the 4-hour and 6-hour burn groups with 86.7% accuracy. CONCLUSIONS: Our study shows an increase in gut microbiota diversity in the acute phase of deep burn injury, rather than a decrease as is commonly believed. Severe burns result in a severe imbalance of the gut flora, with a decrease in probiotics and an increase in microorganisms that trigger inflammation and cognitive deficits, and multiple pathways of metabolism and substance synthesis are affected. Simple machine learning model testing suggests several bacterial genera as potential biomarkers of severe burn phenotypes.

Development of a polarity-sensitive ratiometric fluorescent probe based on the intramolecular reaction of spiro-oxazolidine and its applications for in situ visualizing the fluctuations of polarity during ER stress.

Polarity is a vital element in endoplasmic reticulum (ER) microenvironment, and its variation is closely related to many physiological and pathological activities of ER, so it is necessary to trace fluctuations of polarity in ER. However, most of fluorescent probes for detecting polarity dependent on the changes of single emission, which could be affected by many factors and cause false signals. Ratiometric fluorescent probe with "built-in calibration" can effectively avoid detection errors. Here, we have designed a ratiometric fluorescent probe HM for monitoring the ER polarity based on the intramolecular reaction of spiro-oxazolidine. It forms ring open/closed isomers driven by polarity to afford ratiometric sensing. Probe HM have manifested its ratiometric responses to polarity in spectroscopic results, which could offer much more precise information for the changes of polarity in living cells with the internal built-in correction. It also showed large emission shift ( 133 nm), high selectivity and photo-stability. In biological imaging, HM could selectively accumulate in ER with high photo-stability. Importantly, HM has ability for in situ tracing the changes of ER polarity with ratiometric behavior during the ER stress process with the stimulation of tunicamycin, dithiothreitol and hypoxia, suggesting that HM is an effective molecule tool for monitoring the variations of ER polarity.

Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice.

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood-brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders.

The characteristics and prognosis of different disease patterns of multiple primary lung cancers categorized according to the 8th edition lung cancer staging system.

INTRODUCTION: The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. METHOD: We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. RESULTS: In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P < 0.05). Sex was an independent prognostic factor for sMPLC (5-year survival, female vs. male, 88.0% vs. 69.5%, P < 0.05), and in multiple tumors, the highest tumor stage was an independent prognostic factor for all categories of MPLC. CONCLUSIONS: The different disease patterns of MPLC have significantly different characteristics and prognoses. Clinicians should place treatment emphasis on the tumor with the highest stage as it is the main contributor to the prognosis of all categories of MPLC patients.

Risk prediction for severe COVID-19 progressing to critical illness and death in the ICU and efficacy analysis of using traditional Chinese medicine.

To reveal the key factors influencing the progression of severe COVID-19 to critical illness and death in the intensive care unit (ICU) and to accurately predict the risk, as well as to validate the efficacy of treatment using traditional Chinese medicine (TCM), thus providing valuable recommendations for the clinical management of patients. A total of 189 patients with COVID-19 in 25 ICUs in Chongqing, China, were enrolled, and 16 eventually died. Statistical models shown that factors influencing the progression of COVID-19 to critical illness include the severity of illness at diagnosis, the mode of respiratory support, and the use of TCM. Risk factors for death include a history of metabolic disease, the use of antiviral drugs and TCM, and invasive endotracheal intubation. The area under curve of the noncollinearity model predicted the risk of progression to critical illness and the risk of death reached 0.847 and 0.876, respectively. The use of TCM is an independent protective factor for the prevention of the progression of severe COVID-19, while uncorrectable hypoxemia and invasive respiratory support are independent risk factors, and antiviral drugs can help reduce mortality. The multifactorial prediction model can assess the risk of critical illness and death in ICU COVID-19 patients, and inform clinicians in choosing the treatment options and medications.

A pH-response-based fluorescent probe for detecting the mitophagy process by tracing changes in colocalization coefficients.

Mitochondria are not only the center of energy metabolism but also involved in regulating cellular activities. Quality and quantity control of mitochondria is therefore essential. Mitophagy is a lysosome-dependent process to clear dysfunctional mitochondria, and abnormal mitophagy can cause metabolic disorders. Therefore, it is necessary to monitor the mitophagy in living cells on a real-time basis. Herein, we developed a pH-responsive fluorescent probe MP for the detection of the mitophagy process using real-time tracing colocalization coefficients. Probe MP showed good pH responses with high selectivity and sensitivity in spectral testing. Probe MP is of positive charge, which is beneficial for accumulating into mitochondrial in living cells. Cells exhibited pH-dependent fluorescence when they were treated with different pH media. Importantly, the changes in the colocalization coefficient between probe MP and Lyso Tracker® Deep Red from 0.4 to 0.8 were achieved in a real-time manner during the mitophagy stimulated by CCCP, starvation and rapamycin. Therefore, combined with the parameter of the colocalization coefficient, probe MP is a potential molecular tool for the real-time tracing of mitophagy to further explore the details of mitophagy.

CRIF1 attenuates doxorubicin-mediated mitochondrial dysfunction and myocardial senescence via regulating PXDN.

BACKGROUND: CR6-interacting factor 1 (CRIF1), a multifunctional protein that affects mitochondrial function and cell senescence, plays a regulatory role in heart-related diseases. However, whether CRIF1 participates in myocardial senescence by regulating mitochondrial function remains unclear. METHODS: Doxorubicin (DOX)-induced C57BL/6 mice to construct mouse myocardial senescence model, and the myocardial function indicators including lactate dehydrogenase (LDH) and Creatine kinase isoform MB (CK-MB) were assessed. The expression of CRIF1 was detected by western blot. Myocardial pathological changes were examined by transthoracic echocardiography and haematoxylin and eosin (H&E) staining. Cell senescence was detected by SA-ß-gal staining. JC-1 staining was used to detect mitochondrial membrane potential. Biochemical kits were used to examine oxidative stress-related factors. Additionally, AC16 cardiomyocytes were treated with DOX to mimic the cellular senescence model in vitro. Cell activity was detected by cell counting kit-8 (CCK-8) assay. Co-immunoprecipitation (CO-IP) was used to verify the relationship between CRIF1 and peroxidasin (PXDN). RESULTS: The CRIF1 expression was significantly decreased in DOX-induced senescent mice and AC16 cells. Overexpression of CRIF1 significantly ameliorated DOX-induced myocardial dysfunction and myocardial senescence. Additionally, CRIF1 overexpression attenuated DOX-induced oxidative stress and myocardial mitochondrial dysfunction. Consistently, CRIF1 overexpression also inhibited DOX-induced oxidative stress and senescence in AC16 cells. Moreover, CRIF1 was verified to bind to PXDN and inhibited PXDN expression. The inhibitory effects of CRIF1 overexpression on DOX-induced oxidative stress and senescence in AC16 cells were partly abolished by PXDN expression. CONCLUSIONS: CRIF1 plays a protective role against DOX-caused mitochondrial dysfunction and myocardial senescence partly through downregulating PXDN.

High-resolution self-corrected single-pixel imaging through dynamic and complex scattering media: erratum.

We correct typographical errors in our paper [Opt. Express31, 23027 (2023)10.1364/OE.489808]. The corrections have no influence on the results and conclusions of the original paper.

Incidence and risk factors of depression in patients with metabolic syndrome.

BACKGROUND: Many studies have explored the relationship between depression and metabolic syndrome (MetS), especially in older people. China has entered an aging society. However, there are still few studies on the elderly in Chinese communities. AIM: To investigate the incidence and risk factors of depression in MetS patients in mainland China and to construct a predictive model. METHODS: Data from four waves of the China Health and Retirement Longitudinal Study were selected, and middle-aged and elderly patients with MetS (n = 2533) were included based on the first wave. According to the center for epidemiological survey-depression scale (CESD), participants with MetS were divided into depression (n = 938) and non-depression groups (n = 1595), and factors related to depression were screened out. Subsequently, the 2-, 4-, and 7-year follow-up data were analyzed, and a prediction model for depression in MetS patients was constructed. RESULTS: The prevalence of depression in middle-aged and elderly patients with MetS was 37.02%. The prevalence of depression at the 2-, 4-, and 7-year follow-up was 29.55%, 34.53%, and 38.15%, respectively. The prediction model, constructed using baseline CESD and Physical Self-Maintenance Scale scores, average sleep duration, number of chronic diseases, age, and weight had a good predictive effect on the risk of depression in MetS patients at the 2-year follow-up (area under the curve = 0.775, 95% confidence interval: 0.750-0.800, P < 0.001), with a sensitivity of 68% and a specificity of 74%. CONCLUSION: The prevalence of depression in middle-aged and elderly patients with MetS has increased over time. The early identification of and intervention for depressive symptoms requires greater attention in MetS patients.

Application of Chlorophyll Fluorescence Analysis Technique in Studying the Response of Lettuce (Lactuca sativa L.) to Cadmium Stress.

To reveal the impact of cadmium stress on the physiological mechanism of lettuce, simultaneous determination and correlation analyses of chlorophyll content and photosynthetic function were conducted using lettuce seedlings as the research subject. The changes in relative chlorophyll content, rapid chlorophyll fluorescence induction kinetics curve, and related chlorophyll fluorescence parameters of lettuce seedling leaves under cadmium stress were detected and analyzed. Furthermore, a model for estimating relative chlorophyll content was established. The results showed that cadmium stress at 1 mg/kg and 5 mg/kg had a promoting effect on the relative chlorophyll content, while cadmium stress at 10 mg/kg and 20 mg/kg had an inhibitory effect on the relative chlorophyll content. Moreover, with the extension of time, the inhibitory effect became more pronounced. Cadmium stress affects both the donor and acceptor sides of photosystem II in lettuce seedling leaves, damaging the electron transfer chain and reducing energy transfer in the photosynthetic system. It also inhibits water photolysis and decreases electron transfer efficiency, leading to a decline in photosynthesis. However, lettuce seedling leaves can mitigate photosystem II damage caused by cadmium stress through increased thermal dissipation. The model established based on the energy captured by a reaction center for electron transfer can effectively estimate the relative chlorophyll content of leaves. This study demonstrates that chlorophyll fluorescence techniques have great potential in elucidating the physiological mechanism of cadmium stress in lettuce, as well as in achieving synchronized determination and correlation analyses of chlorophyll content and photosynthetic function.

An exposome atlas of serum reveals the risk of chronic diseases in the Chinese population.

Although adverse environmental exposures are considered a major cause of chronic diseases, current studies provide limited information on real-world chemical exposures and related risks. For this study, we collected serum samples from 5696 healthy people and patients, including those with 12 chronic diseases, in China and completed serum biomonitoring including 267 chemicals via gas and liquid chromatography-tandem mass spectrometry. Seventy-four highly frequently detected exposures were used for exposure characterization and risk analysis. The results show that region is the most critical factor influencing human exposure levels, followed by age. Organochlorine pesticides and perfluoroalkyl substances are associated with multiple chronic diseases, and some of them exceed safe ranges. Multi-exposure models reveal significant risk effects of exposure on hyperlipidemia, metabolic syndrome and hyperuricemia. Overall, this study provides a comprehensive human serum exposome atlas and disease risk information, which can guide subsequent in-depth cause-and-effect studies between environmental exposures and human health.

Hemoglobin is associated with BMDs and risk of the 10-year probability of fractures in patients with type 2 diabetes mellitus.

Purpose: This study aimed to investigate the associations between hemoglobin (HGB) levels and bone mineral density (BMD) and fracture risk in type 2 diabetes mellitus(T2DM) population of different ages. Method: This cross-sectional study included 641 patients with T2DM (57.9% males). BMD of the femoral neck (FN), total hip (TH), and lumbar spine (LS) were measured using dual-energy X-ray absorptiometry. The 10-year probability of fracture was assessed using a fracture risk assessment tool (FRAX). HGB and other biochemical indices were measured in a certified laboratory at our hospital. Statistical analysis was performed using SPSS 26.0 and R language (R version 4.1.0). Generalized additive models (GAMs) were used to identify the associations between HGB and BMD and fracture risk. Results: Patients with osteoporosis have lower HGB levels than the non-osteoporotic population and lower FN BMD in patients with anemia than in the non-anemic population. In patients with T2DM, there was sex- and age-related variability in the correlation between HGB levels and BMDs and fracture risk. In older men, HGB level was an independent determinant of BMD and was positively correlated with FN and TH BMD. In non-older women, HGB level was an independent determinant of BMD and fracture risk, positively associated with BMDs and negatively associated with 10-year probability of fracture risk. GAMs revealed a positive linear association between HGB level and BMDs in non-older female patients but not in older male patients. Conclusion: Our study provides a new perspective on the association of HGB level and BMDs with fracture risk. Relatively high HGB levels are a protective factor for bone quality in patients with T2DM. However, the bone-protective effect of HGB is influenced by age and sex and persists only in older men and non-older women with T2DM.

Ion channel TRPV2 is critical in enhancing B cell activation and function.

The function of transient receptor potential vanilloid (TRPV) cation channels governing B cell activation remains to be explored. We present evidence that TRPV2 is highly expressed in B cells and plays a crucial role in the formation of the B cell immunological synapse and B cell activation. Physiologically, TRPV2 expression level is positively correlated to influenza-specific antibody production and is low in newborns and seniors. Pathologically, a positive correlation is established between TRPV2 expression and the clinical manifestations of systemic lupus erythematosus (SLE) in adult and child SLE patients. Correspondingly, mice with deficient TRPV2 in B cells display impaired antibody responses following immunization. Mechanistically, the pore and N-terminal domains of TRPV2 are crucial for gating cation permeation and executing mechanosensation in B cells upon antigen stimulation. These processes synergistically contribute to membrane potential depolarization and cytoskeleton remodeling within the B cell immunological synapse, fostering efficient B cell activation. Thus, TRPV2 is critical in augmenting B cell activation and function.

High-resolution ghost imaging through complex scattering media via a temporal correction: erratum.

We correct a typographical error in our Letter [Opt. Lett.47, 3692 (2022)10.1364/OL.463897]. The corrections have no influence on the results and conclusions of the original Letter.

FGF12 restrains mitochondria-dependent ferroptosis in doxorubicin-induced cardiomyocytes through the activation of FGFR1/AMPK/NRF2 signaling.

Fibroblast growth factor-12 (FGF12) has been reported to play important role in regulating heart diseases. We aimed to explore the role of FGF12 in doxorubicin (DOX)-induced myocardial injury. DOX-induced mice and DOX-induced HL-1 cells were used as the myocardial injury in vivo and in vitro. Then, FGF12, Anp, Bnp, and Myh7 expression was detected. The pathological injury in myocardium tissue was observed by H&E staining. The levels of markers related to myocardial damage and oxidative stress were assessed. Then, immunohistochemistry and immunofluorescence staining were used to detect FGF12 and 4-HNE expression. Ferroptosis were detected by Prussian blue staining and western blot. The FGFR1/AMPK/NRF2 signaling was measured by western blot. FGF12 expression was downregulated in DOX-induced mice myocardium tissues. FGF12 overexpression alleviated DOX-induced myocardial tissue pathological injury and reduced Anp, Bnp, and Myh7 expression. Additionally, the levels of CK-MB, LDH and cTnT in serum were decreased after FGF12 upregulation in DOX-induced mice. Moreover, FGF12 overexpression reduced the levels of ROS, MDA, and 4-HNE but increased SOD and GSH-Px activities. Meanwhile, FGF12 led to less deposition of iron ion, decreased ACSL4, PTGS2 and increased GPX4, FTH1 expression. Additionally, FGF12 activated the expressions of FGFR1, p-AMPK, and NRF2. Moreover, FGFR1 silencing reversed the protective effects of FGF12 overexpression on cell viability, oxidative stress, ferroptosis, and FGFR1/AMPK/NRF2 pathway. To sum up, FGF12 inhibited mitochondria-dependent ferroptosis in cardiomyocytes induced by DOX through activation of FGFR1/AMPK/NRF2 signaling. These findings clarify a new mechanism of DOX-induced cardiac injury and provide a promising target to limit the disease development.

RASFF1A inhibits the epithelial-mesenchymal transition of lens epithelial cells induced by TGFß through regulating HDAC6.

To explore the role of Ras-association domain family 1 A (RASSF1A) in TGFß2-induced changes of lens epithelial cells (LECs) behavior. The human LEC line SRA01/04 cells were treated with TGFß2 in the presence or absence of RASSF1A and histone deacetylase 6 (HDAC6). qRT-PCR and western blot were performed to analysis mRNA and proteins expression. Cell proliferation was evaluated using MTT assay and colony formation assay. Transwell and scratch-wound healing assays were conducted to detected cell migration ability. RASSF1A was downregulated in TGFß2-induced SRA01/04 cells. RASSF1A overexpression inhibited the cell viability, colony formation and migration abilities of SRA01/04 cells induced by TGFß2. Overexpression of RASSF1A suppressed TGFß2-induced EMT of SRA01/04 cells, which was manifested as inhibition of EMT-related proteins α-SMA, Vimentin, Snail and Fn expression. Moreover, RASSF1A down-regulated the expression of HDAC6. Importantly, HDAC6 reversed the effects of RASSF1A on SRA01/04 cells. These findings indicate that RASSF1A prevented TGFß2-induced proliferation, migration, and EMT of LECs by regulating HDAC6 expression, suggesting that RASSF1A holds promise as a potential target for cataracts treatment.