NOR1 promotes the osteoblastic differentiation of human periodontal ligament stem cells via TGF-ß signaling pathway.

Alveolar bone loss is a main manifestation of periodontitis. Human periodontal ligament stem cells (PDLSCs) are considered as optimal seed cells for alveolar bone regeneration due to its mesenchymal stem cell like properties. Osteogenic potential is the premise for PDLSCs to repair alveolar bone loss. However, the mechanism regulating osteogenic differentiation of PDLSCs remain elusive. In this study, we identified Neuron-derived orphan receptor 1 (NOR1), was particularly expressed in PDL tissue in vivo and gradually increased during osteogenic differentiation of PDLSCs in vitro. Knockdown of NOR1 in hPDLSCs inhibited their osteogenic potential while NOR1 overexpression reversed this effect. In order to elucidate the downstream regulatory network of NOR1, RNA-sequencing was used. We found that downregulated genes were mainly enriched in TGF-ß, Hippo, Wnt signaling pathway. Further, by western blot analysis, we verified that the expression level of phosphorylated-SMAD2/3 and phosphorylated-SMAD4 were all decreased after NOR1 knockdown. Additionally, ChIP-qPCR and dual luciferase reporter assay indicated that NOR1 could bind to the promoter of TGFBR1 and regulate its activity. Moreover, overexpression of TGFBR1 in PDLSCs could rescue the damaged osteogenic potential after NOR1 knockdown. Taken together, our results demonstrated that NOR1 could activate TGF-ß/SMAD signaling pathway and positively regulates the commitment of osteoblast lineages of PDLSCs by targeting TGFBR1 directly.

A mutation-sensitive, multiplexed and amplification-free detection of nucleic acids by stretching single-molecule tandem hairpin probes.

The detection of nucleic acid sequences in parallel with the discrimination of single nucleotide variations (SNVs) is critical for research and clinical applications. A few limitations make the detection technically challenging, such as too small variation in probe-hybridization energy caused by SNVs, the non-specific amplification of false nucleic acid fragments and the few options of dyes limited by spectral overlaps. To circumvent these limitations, we developed a single-molecule nucleic acid detection assay without amplification or fluorescence termed THREF (hybridization-induced tandem DNA hairpin refolding failure) based on multiplexed magnetic tweezers. THREF can detect DNA and RNA sequences at femtomolar concentrations within 30 min, monitor multiple probes in parallel, quantify the expression level of miR-122 in patient tissues, discriminate SNVs including the hard-to-detect G-U or T-G wobble mutations and reuse the probes to save the cost. In our demonstrative detections using mock clinic samples, we profiled the let-7 family microRNAs in serum and genotyped SARS-CoV-2 strains in saliva. Overall, the THREF assay can discriminate SNVs with the advantages of high sensitivity, ultra-specificity, multiplexing, reusability, sample hands-free and robustness.

Facile and Widely Applicable Route to Self-Adaptive Emissivity Modulation: Energy-Saving Demonstration with Transparent Wood.

The cooling power provided by radiative cooling is unwanted during cold hours. Therefore, self-adaptive regulation is desired for radiative cooling, especially in all-weather applications. However, current routes for radiative cooling regulation are constrained by substrates and complicated processing. Here, self-adaptive radiative cooling regulation on various potential substrates (transparent wood, PET, normal glass, and cement) was achieved by a Fabry-Perot structure consisting of a silver nanowires (AgNWs) bottom layer, PMMA spacer, and W-VO2 top layer. The emissivity-modulated transparent wood (EMTW) exhibits an emissivity contrast of 0.44 (ε8-13-L = ∼0.19 and ε8-13-H = ∼0.63), which thereby yields considerable energy savings across different climate zones. The emissivity contrast can be adjusted by varying the spinning parameters during the deposition process. Positive emissivity contrast was also achieved on three other industrially relevant substrates via this facile and widely applicable route. This proves the great significance of the approach to the promotion and wide adoption of radiative cooling regulation concept in the built environment.

The outer membrane protein Tp92 of Treponema pallidum delays human neutrophil apoptosis via the ERK, PI3K/Akt, and NF-κB pathways.

Syphilis is a persistent sexually transmitted disease caused by infiltration of the elusive pathogen Treponema pallidum. Despite the prevalence of human polymorphonuclear neutrophils (hPMNs) within cutaneous lesions, which are characteristic of incipient syphilis, their role in T. pallidum infection remains unclear. Tp92 is the only T. pallidum helical outer membrane protein that exhibits structural features similar to those of outer membrane proteins in other gram-negative bacteria. However, the functional mechanism of this protein in immune cells remains unclear. Neutrophils are short-lived cells that undergo innate apoptosis in response to external stimuli that typically influence this process. In this study, we determined that Tp92 impedes the activation of procaspase-3 via the ERK MAPK, PI3K/Akt, and NF-κB signaling pathways, consequently suppressing caspase-3 activity within hPMNs, and thereby preventing hPMNs apoptosis. Furthermore, Tp92 could also modulate hPMNs apoptosis by enhancing the expression of the anti-apoptotic protein Mcl-1, stimulating IL-8 secretion, and preserving the mitochondrial membrane potential. These findings provide valuable insights into the molecular mechanisms underlying T. pallidum infection and suggest potential therapeutic targets for syphilis treatment.

Long non-coding RNA MAGEA4-AS1 binding to p53 enhances MK2 signaling pathway and promotes the proliferation and metastasis of oral squamous cell carcinoma.

Long non-coding RNAs (lncRNAs) regulate the occurrence, development and progression of oral squamous cell carcinoma (OSCC). We elucidated the expression features of MAGEA4-AS1 in patients with OSCC and its activity as an OSCC biomarker. Furthermore, the impact of up-regulation of MAGEA4-AS1 on the cellular behaviors (proliferation, migration and invasion) of OSCC cells and intrinsic signal mechanisms were evaluated. Firstly, we analyzed MAGEA4-AS1 expression data in The Cancer Genome Atlas (TCGA) OSCC using a bioinformatics approach and in 45 pairs of OSCC tissues using qPCR. Then CCK-8, ethynyl deoxyuridine, colony formation, transwell and wound healing assays were conducted to assess changes in the cell proliferation, migration and invasion protential of shMAGEA4-AS1 HSC3 and CAL27 cells. The RNA sequence of MAGEA4-AS1 was identified using the rapid amplification of cDNA ends (RACE) assay. And whole-transcriptome sequencing was used to identify MAGEA4-AS1 affected genes. Additionally, dual-luciferase reporter system, RNA-binding protein immunoprecipitation (RIP), and rescue experiments were performed to clarify the role of the MAGEA4-AS1-p53-MK2 signaling pathway. As results, we found MAGEA4-AS1 was up-regulated in OSCC tissues. We identified a 418 nucleotides length of the MAGEA4-AS1 transcript and it primarily located in the cell nucleus. MAGEA4-AS1 stable knockdown weakened the proliferation, migration and invasion abilities of OSCC cells. Mechanistically, p53 protein was capable to activate MK2 gene transcription. RIP assay revealed an interaction between p53 and MAGEA4-AS1. MK2 up-regulation in MAGEA4-AS1 down-regulated OSCC cells restored MK2 and epithelial-to-mesenchymal transition related proteins' expression levels. In conclusion, MAGEA4-AS1-p53 complexes bind to MK2 promoter, enhancing the transcription of MK2 and activating the downstream signaling pathways, consequently promoting the proliferation and metastasis of OSCC cells. MAGEA4-AS1 may serve as a diagnostic marker and therapeutic target for OSCC patients.

Construction of Fe Nanoparticles Interfacial Layer on Micron Al Surface: Boosting the Efficient Energy Release of High-Energy DAP-4 as a Gradient Catalyst.

The high-energy (H2dabco)[NH4(ClO4)3] (DAP-4) with excellent energetic performance attracts wide attention from researchers. The investigation of its interaction with the Aluminum (Al) is of great importance. However, the higher ignition threshold of DAP-4 and the dense oxide layer (Al2O3) of Al severely limit the energy release efficiency of Al/DAP-4. In this study, a new idea to is first proposed to improve and adjust the thermal decomposition and combustion performance of Al/DAP-4 by constructing a highly dispersed iron (Fe) nanoparticle interfacial layer. It acts as a gradient catalyst to promote the thermal decomposition and combustion of DAP-4 and Al, and it also act as an oxygen transport channel to promote the contact and reaction of oxidizing gases with the internal reactive Al powder. It reduces the thermal decomposition temperature of Al@Fe-3/DAP-4 from 386.30 °C (Al/DAP-4) to 349.48 °C and leads to the vigorous combustion. Theoretical calculations show that Fe nanoparticle interfacial layer can facilitate the transport of oxygen through the established oxygen transport channels, and it can also significantly improve the energetic properties of Al@Fe-3/DAP-4 composites. In conclusion, the new approach is proposed to improve the performance of metal fuel/oxidizer composites by constructing interfacial layers, which is expected to promote their practical applications.

International disease burden of acute viral hepatitis among adolescents and young adults: An observational study.

Adolescents and young adults are the driving force of social development, and the prevalence of acute viral hepatitis (AVH) in this population cannot be ignored. At present, there are few studies on the disease burden of AVH in this age group, and most studies focus on chronic liver disease. In this study, we identified global trends in the burden of AVH among adolescents and young adults (15-29) to help policymakers implement precise disease interventions. In this observational study of disease trends, we collected data exclusively from the Global Burden of Disease (GBD) 2019 study. This study examined the trends in the prevalence, incidence and mortality of AVH among adolescents and young adults in 21 regions of the world from 2009 to 2019. Age-specific disease trends were analysed with a joinpoint regression model. The overall global disease burden of AVH declined. The prevalence rate per 100,000 people decreased from 316.13 in 2009 to 198.79 in 2019, the incidence rate decreased from 3245.52 in 2009 to 2091.93 in 2019, and the death rate decreased from 0.87 in 2009 to 0.43 in 2019. During the study period, the prevalence of hepatitis B virtues (HBV) in the young population decreased, but the downward trend of other types of hepatitis other than HBV was not obvious, especially HAV, which even showed an upward trend. Among adolescents and young adults aged 15-29 years, Western Saharan Africa had the highest prevalence of AVH in 2019. There were significant differences in mortality rates among different age groups; 20-24 was the age group with the highest mortality rate from 2009 to 2019, followed by the 15-19 and 25-29 age groups. Although the overall global AVH disease burden declined, some causes of AVH, such as HAV, showed an upward trend during the study period. In addition, the prevalence of AVH among adolescents and young adults in Asia and Africa was higher than that in other parts of the world and warrants more attention. Finally, more research should be conducted on mortality in the 20-24 age group.

Thermal Decomposition Mechanism of Ammonium Nitrate on the Main Crystal Surface of Ferric Oxide: Experimental and Theoretical Studies.

Understanding the decomposition process of ammonium nitrate (AN) on catalyst surfaces is crucial for the development of practical and efficient catalysts in AN-based propellants. In this study, two types of nano-Fe2O3 catalysts were synthesized: spherical particles with high-exposure (104) facets and flaky particles with high-exposure (110) facets. Through thermal analysis and particle size analysis, it was found that the nanosheet-Fe2O3 catalyst achieved more complete AN decomposition despite having a larger average particle size compared to nanosphere-Fe2O3. Subsequently, the effects of AN pyrolysis on the (110) and (104) facets were investigated by theoretical simulations. Through studying the interaction between AN and crystal facets, it was determined that the electron transfer efficiency on the (110) facet is stronger compared to that on the (104) facet. Additionally, the free-energy step diagrams for the reaction of the AN molecule on the two facets were calculated with the DFT + U method. Comparative analysis led us to conclude that the (110) facet of α-Fe2O3 is more favorable for AN pyrolysis compared to the (104) facet. Our study seeks to deepen the understanding of the mechanism underlying AN pyrolysis and present new ideas for the development of effective catalysts in AN pyrolysis.

Serum long non-coding Ribonucleic Acid H19 serves as a biomarker for systemic lupus erythematosus and participates in the disease progression.

AIM: This study aimed to investigate the expression of H19 and its possible molecular mechanism in systemic lupus erythematosus (SLE). METHODS: The expression of H19 and miR-19b in serum and peripheral blood mononuclear cells (PBMCs) were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Receiver operator characteristic (ROC) curve was constructed to evaluate the diagnostic value of serum H19 in SLE. Pearson correlation coefficient was used to analyze the correlation between serum levels of H19 and miR-19b. Flow cytometry and Cell counting kit-8 (CCK-8) assay were performed to detect cell apoptosis and viability. The levels of pro-inflammatory and anti-inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA). Luciferase reporter gene assay was conducted to verify the interaction between H19 and miR-19b. RESULTS: The expression of H19 and miR-19b in SLE group were up-regulated and down-regulated, respectively. Serum H19 has certain clinical diagnostic value in SLE. In in vitro studies, overexpression of H19 can significantly inhibit the viability of PBMCs and promote apoptosis and inflammatory response of PBMCs by interacting with miR-19b. CONCLUSIONS: The expression of H19 is upregulated in patients with SLE and plays a role in cell function and inflammation by targeting miR-19b in PBMCs, which may be one of the pathological mechanisms of SLE.

Bioactive compounds and biological functions of medicinal plant-derived extracellular vesicles.

Extracellular vesicles (EVs) are tiny lipid bilayer-enclosed membrane particles released from a variety of cell types into the surrounding environment. These EVs have massive participated in cell-to-cell communication and interspecies communication. In recent years, plant-derived extracellular vesicles (PDEVs) and "exosome-like" EVs populations found in distinct plants have attracted widespread attention. Especially, research on medicinal plant-derived extracellular vesicles (MPDEVs) are increasing, which are considered a kind of promising natural compound. This review summarizes current knowledge on MPDEVs in terms of bioactive compounds, including small RNA, protein, lipid, and metabolite, have been found on the surface and/or in the lumen of MPDEVs. Moreover, both in vitro and in vivo experiments have shown that MPDEVs exert broad biomedical functions, such as anti-inflammatory, anticancer, antioxidant, modulate microbiota, etc. MPDEVs may be a better substitute than animal-derived extracellular vesicles (ADEVs) because of safety and biocompatibility in the future.

The Trends of Gastric Cancer in China From 1990 to 2019 and Predictions to 2040: A Bayesian Age-Period-Cohort Prediction Study.

OBJECTIVES: This study aims to provide the most up-to-date temporal trends in incidence, mortality, and disability-adjusted life years (DALYs) of total gastric cancer in China from 1990 to 2019, and to predict the gastric cancer trends up to 2040. METHODS: Data for the incidence, mortality, and DALYs of stomach cancer in China from 1990 to 2019 were extracted from Global Burden of Disease Study 2019 (GBD 2019). We conducted joinpoint regression analysis to explore possible segmented changes in gastric cancer trends. We predicted gastric cancer trends up to 2040 using a Bayesian age-period-cohort model. RESULTS: The absolute incidence, mortality, and DALYs of gastric cancer increased from 1990 to 2019 in China. However, the age-standardized rates (ASRs) of incidence, mortality, and DALYs for gastric cancer decreased between 1990 and 2019, and the reductions were more pronounced for mortality and DALYs for gastric cancer. CONCLUSION: Our study generally reveals favorable declining trends of gastric cancer incidence and predicts that this will continue to 2040. However, the high contemporary incidence combined with China's aging population will likely slow or even reverse the declining trend in gastric cancer mortality.

Effect of mPEG-PLGA on Drug Crystallinity and Release of Long-Acting Injection Microspheres: In Vitro and In Vivo Perspectives.

PURPOSE: Traditional progesterone (PRG) injections require long-term administration, leading to poor patient compliance. The emergence of long-acting injectable microspheres extends the release period to several days or even months. However, these microspheres often face challenges such as burst release and incomplete drug release. This study aims to regulate drug release by altering the crystallinity of the drug during the release process from the microspheres. METHODS: This research incorporates methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide) (mPEG-PLGA) into poly(lactide-co-glycolide) (PLGA) microspheres to enhance their hydrophilicity, thus regulating the release rate and drug morphology during release. This modification aims to address the issues of burst and incomplete release in traditional PLGA microspheres. PRG was used as the model drug. PRG/mPEG-PLGA/PLGA microspheres (PmPPMs) were prepared via an emulsification-solvent evaporation method. Scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) were employed to investigate the presence of PRG in PmPPMs and its physical state changes during release. RESULTS: The addition of mPEG-PLGA altered the crystallinity of the drug within the microspheres at different release stages. The crystallinity correlated positively with the amount of mPEG-PLGA incorporated; the greater the amount, the faster the drug release from the formulation. The bioavailability and muscular irritation of the long-acting injectable were assessed through pharmacokinetic and muscle irritation studies in Sprague-Dawley (SD) rats. The results indicated that PmPPMs containing mPEG-PLGA achieved low burst release and sustained release over 7 days, with minimal irritation and self-healing within this period. PmPPMs with 5% mPEG-PLGA showed a relative bioavailability (Frel) of 146.88%. IN CONCLUSION: In summary, adding an appropriate amount of mPEG to PLGA microspheres can alter the drug release process and enhance bioavailability.

Co-delivery of Brinzolamide and Timolol from Micelles-laden Contact Lenses: In vitro and In Vivo Evaluation.

PURPOSE: Traditional eye drops exhibit a modest bioavailability ranging from 1 to 5%, necessitating recurrent application. Thus, a contact lens-based drug delivery system presents substantial benefits. Nonetheless, pharmaceutical agents exhibiting poor solubility may compromise the quintessential characteristics of contact lenses and are, consequently, deemed unsuitable for incorporation. To address this issue, the present study has engineered a novel composite drug delivery system that amalgamates micellar technology with contact lenses, designed specifically for the efficacious conveyance of timolol and brinzolamide. METHODS: Utilizing mPEG-PCL as the micellar material, this study crafted mPEG-PCL micelles loaded with brinzolamide and timolol through the film hydration technique. The micelle-loaded contact lens was fabricated employing the casting method; a uniform mixture of HEMA and EGDMA with the mPEG-PCL micelles enshrouding brinzolamide and timolol was synthesized. Following the addition of a photoinitiator, 50 µL of the concoction was deposited into a contact lens mold. Subsequently, the assembly was subjected to polymerization under 365 nm ultraviolet light for 35 min, resulting in the formation of the micelle-loaded contact lenses. RESULTS: In the present article, we delineate the construction of a micelle-loaded contact lens designed for the administration of brinzolamide and timolol in the treatment of glaucoma. The study characterizes crucial properties of the micelle-loaded contact lenses, such as transmittance and ionic permeability. It was observed that these vital attributes meet the standard requirements for contact lenses. In vitro release studies revealed that timolol and brinzolamide could be gradually liberated over periods of up to 72 and 84 h, respectively. In vivo pharmacodynamic evaluation showed a significant reduction in intraocular pressure and a relative bioavailability of 10.84 times that of commercially available eye drops. In vivo pharmacokinetic evaluation, MRT was significantly increased, and the bioavailability of timolol and brinzolamide was 2.71 and 1.41 times that of eye drops, respectively. Safety assessments, including in vivo irritation, histopathological sections, and protein adsorption studies, were conducted as per established protocols, confirming that the experiments were in compliance with safety standards. IN CONCLUSION: The manuscript delineates the development of a safe and efficacious micelle-loaded contact lens drug delivery system, which presents a novel therapeutic alternative for the management of glaucoma.

Association between periodontal diseases and chronic obstructive pulmonary disease: Evidence from sequential cross-sectional and prospective cohort studies based on UK Biobank.

AIM: To investigate the association between periodontal diseases, airflow limitation and incident chronic obstructive pulmonary disease (COPD) in a large-scale prospective UK Biobank cohort. MATERIALS AND METHODS: Our approach comprised a cross-sectional study and a prospective cohort. Periodontal diseases were determined based on the participants' self-reported dental symptoms, including painful gums, bleeding gums and loose teeth. Logistic regression and Cox proportional hazards models were used to evaluate the association of periodontal diseases with airflow limitation and incident COPD in the cross-sectional study and the prospective cohort, respectively. RESULTS: The cross-sectional study involved 495,610 participants. Multivariable analysis found that periodontal diseases were significantly associated with airflow limitation (odds ratio = 1.036, 95% confidence interval [CI]: 1.015-1.059). The cohort study included 379,266 participants with a median follow-up period of 12.68 years. An elevated risk of incident COPD was associated with the presence of periodontal diseases (hazard ratio: 1.248, 95% CI: 1.174-1.326). The effect was consistent among subgroups, including baseline age (≤65 or >65 years), sex, smoking status and diabetes mellitus. CONCLUSIONS: Periodontal diseases are associated with airflow limitation and elevated COPD incidence. Maintaining good periodontal health in patients with chronic bronchitis and emphysema may help prevent the onset of COPD.

Roles of lncLingo2 and its derived miR-876-5p in the acquisition of opioid reinforcement.

Recent studies found that non-coding RNAs (ncRNAs) played crucial roles in drug addiction through epigenetic regulation of gene expression and underlying drug-induced neuroadaptations. In this study, we characterized lncRNA transcriptome profiles in the nucleus accumbens (NAc) of mice exhibiting morphine-conditioned place preference (CPP) and explored the prospective roles of novel differentially expressed lncRNA, lncLingo2 and its derived miR-876-5p in the acquisition of opioids-associated behaviours. We found that the lncLingo2 was downregulated within the NAc core (NAcC) but not in the NAc shell (NAcS). This downregulation was found to be associated with the development of morphine CPP and heroin intravenous self-administration (IVSA). As Mfold software revealed that the secondary structures of lncLingo2 contained the sequence of pre-miR-876, transfection of LV-lncLingo2 into HEK293 cells significantly upregulated miR-876 expression and the changes of mature miR-876 are positively correlated with lncLingo2 expression in NAcC of morphine CPP trained mice. Delivering miR-876-5p mimics into NAcC also inhibited the acquisition of morphine CPP. Furthermore, bioinformatics analysis and dual-luciferase assay confirmed that miR-876-5p binds to its target gene, Kcnn3, selectively and regulates morphine CPP training-induced alteration of Kcnn3 expression. Lastly, the electrophysiological analysis indicated that the currents of small conductance calcium-activated potassium (SK) channel was increased, which led to low neuronal excitability in NAcC after CPP training, and these changes were reversed by lncLingo2 overexpression. Collectively, lncLingo2 may function as a precursor of miR-876-5p in NAcC, hence modulating the development of opioid-associated behaviours in mice, which may serve as an underlying biomarker and therapeutic target of opioid addiction.

Impact of C-reactive protein on the effect of Roxadustat for the treatment of anemia in chronic kidney disease: a systematic review of randomized controlled trials.

BACKGROUND: Chronic inflammation, reflected by an increased blood C-reactive protein (CRP) level, is common in patients with chronic kidney disease (CKD) and is involved in the development of renal anemia. This systematic review aims to investigate the impacts of CRP on the efficacy of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) in the treatment of renal anemia in patients with CKD. METHODS: We conducted a comprehensive search of electronic databases including Pubmed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and the International Clinical Trials Registry Platform (ICTRP), from their inception to May 19, 2022. We systematically reviewed evidence from randomized controlled trials using HIF-PHIs for renal anemia treatment. The mean difference (MD) in changes in hemoglobin concentration (∆Hb) before and after treatment served as the meta-analysis outcome, utilizing a random-effects model. We compared groups with CRP levels greater than or equal to the upper limit of normal (ULN) and less than the ULN. Additionally, further analysis was conducted in the CRP ≥ ULN group comparing HIF-PHIs and erythropoiesis-stimulating agents (ESA). RESULTS: A total of 7 studies from 6 publications were included in the analysis. In the comparison between the CRP ≥ ULN group and the CRP < ULN group, 524 patients from 4 studies were incorporated into the analysis. All patients received roxadustat as the primary intervention. The pooled results revealed no significant difference in ΔHb between patients with CRP ≥ ULN and CRP < ULN at baseline (Mean Difference: 0.00, 95% Confidence Interval: -0.32 to 0.33, P = 0.99). Moreover, within the CRP ≥ ULN group, three studies involving 1399 patients compared the efficacy of roxadustat and erythropoiesis-stimulating agents (ESAs). The results indicated no significant difference in ΔHb between patients treated with ESAs and HIF-PHIs (Mean Difference: 0.24, 95% Confidence Interval: -0.08 to 0.56, P = 0.14). In terms of medication dosage, an increase in ESA dose over time was observed across various studies, particularly evident in the CRP ≥ ULN group, while the dose of roxadustat remains constant over time and is not influenced by the baseline levels of CRP. CONCLUSIONS: Our systematic review demonstrates that roxadustat exhibits similar efficacy across different CRP levels. Moreover, within the CRP ≥ ULN group, roxadustat can maintain efficacy comparable to ESA without the necessity for dose escalation. TRIAL REGISTRATION: CRD42023396704.

Late-onset renal TMA and tubular injury in cobalamin C disease: a report of three cases and literature review.

BACKGROUND: Mutation of MMACHC gene causes cobalamin C disease (cblC), an inherited metabolic disorder, which presents as combined methylmalonic aciduria (MMA-uria) and hyperhomocysteinaemia in clinical. Renal complications may also be present in patients with this inborn deficiency. The most common histological change is thrombotic microangiopathy (TMA). However, to our acknowledge, renal tubular injury in the late-onset presentation of cblC is rarely been reported. This study provides a detailed description of the characteristics of kidney disease in cblC deficiency, aiming to improve the early recognition of this treatable disease for clinical nephrologists. CASE PRESENTATION: Here we described three teenage patients who presented with hematuria, proteinuria, and hypertension in clinical presentation. They were diagnosed with renal involvement due to cblC deficiency after laboratory tests revealing elevated serum and urine homocysteine, renal biopsy showing TMA and tubular injury, along with genetic testing showing heterogeneous compound mutations in MMACHC. Hydroxocobalamin, betaine, and L-carnitine were administered to these patients. All of them got improved, with decreased homocysteine, controlled blood pressure, and kidney outcomes recovered. CONCLUSIONS: The clinical diagnosis of cblC disease associated with kidney injury should be considered in patients with unclear TMA accompanied by a high concentration of serum homocysteine, even in teenagers or adults. Early diagnosis and timely intervention are vital to improving the prognosis of cobalamin C disease. CLINICAL TRIAL NUMBER: Not applicable.

5-Methyl-cytosine stabilizes DNA but hinders DNA hybridization revealed by magnetic tweezers and simulations.

5-Methyl-cytosine (5mC) is one of the most important DNA modifications and plays versatile biological roles. It is well known that 5mC stabilizes DNA duplexes. However, it remains unclear how 5mC affects the kinetics of DNA melting and hybridization. Here, we studied the kinetics of unzipping and rezipping using a 502-bp DNA hairpin by single-molecule magnetic tweezers. Under constant loading rates, 5mC increases the unzipping force but counterintuitively decreases the rezipping force at various salt and temperature conditions. Under constant forces, the non-methylated DNA hops between metastable states during unzipping and rezipping, which implies low energy barriers. Surprisingly, the 5mC DNA can't rezip after fully unzipping unless much lower forces are applied, where it rezips stochastically in a one-step manner, which implies 5mC kinetically hinders DNA hybridization and high energy barriers in DNA hybridization. All-atom molecular dynamics simulations reveal that the 5mC kinetically hinders DNA hybridization due to steric effects rather than electrostatic effects caused by the additional methyl groups of cytosines. Considering the possible high speed of DNA unzipping and zipping during replication and transcription, our findings provide new insights into the biological roles of 5mC.

Nuciferine protects hyperandrogen-injured ovarian granulosa cells by inhibiting ferroptosis via SOX2-mediated activation of the SLC7A11/GPX4 axis.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can cause menstrual irregularities, infertility, polycystic ovaries, and metabolic abnormalities. Female reproductive health and quality of life are significantly affected by PCOS, which has recently been associated with ferroptosis in granulosa cells (GCs). Nuciferine (NF) is a naturally extracted substance with multiple pharmacological activities, which is reported with anti-ferroptosis function. Herein, the influence of NF for androgen-induced ferroptosis in GCs was investigated to explore the potential value of NF on treating PCOS. 10 µM NF and 20 µM NF were employed for treating KGN cells according to cell viability results. KGN cells were treated with 10 µM dehydroepiandrosterone (DHEA) for 1 day, followed by introducing 10 µM NF and 20 µM NF for 24 h. Strikingly reduced cell viability, increased lactate dehydrogenase release and reactive oxygen species (ROS) production, enhanced apoptosis, upregulated Bax, downregulated Bcl-2, restrained malondialdehyde contents, and declined superoxide dismutase activity were observed in DHEA-treated KGN cells, which were significantly reversed by NF. Significantly repressed GPX4, SLC7A11, and SOX2 levels, as well as increased ACSL4 levels and Fe2+ levels in DHEA-treated KGN cells, were notably rescued by NF. Furthermore, the inhibitory effect of NF on ROS production and ferroptosis in DHEA-treated KGN cells was partially abrogated by silencing SOX2. Collectively, NF protected DHEA-injured ovarian GCs by inhibiting ferroptosis via upregulating SOX2.

The pro-atherogenic effects and the underlying mechanisms of chronic bisphenol S (BPS) exposure in apolipoprotein E-deficient mice.

Atherosclerosis (AS) and its related cardiovascular diseases (CVDs) remain the most frequent cause of morbidity and mortality worldwide. Researches showed that bisphenol A (BPA) exposure might exacerbate AS progression. However, as an analogue of BPA, little is known about the cardiovascular toxicity of bisphenol S (BPS), especially whether BPS exposure has the pro-atherogenic effects in mammals is still unknown. Here, we firstly constructed an apolipoprotein E knockout (ApoE-/-) mouse model and cultured cells to investigate the risk of BPS on AS and explore the underlying mechanisms. Results showed that prolonged exposure to 50 µg/kg body weight (bw)/day BPS indeed aggravated AS lesions both in the en face aortas and aortic sinuses of ApoE-/- mice. Moreover, BPS were found to be implicated in the AS pathological process: 1) stimulates adhesion molecule expression to promote monocyte-endothelial cells (ECs) adhesion with 3.6 times more than the control group in vivo; 2) increases the distribution of vascular smooth muscle cells (VSMCs) with 9.3 times more than the control group in vivo, possibly through the migration of VSMCs; and 3) induces an inflammatory response by increasing the number of macrophages (MACs), with 3.7 times more than the control group in vivo, and the release of inflammatory mediators. Furthermore, we have identified eight significant AS-related genes induced by BPS, including angiopoietin-like protein 7 (Angptl17) and lipocalin-2 (Lcn2) in ECs; matrix metalloproteinase 9 (Mmp13), secreted phosphoprotein 1 (Spp1), and collagen type II alpha 1 (Col2a1) in VSMCs; and kininogen 1 (Kng1), integrin alpha X (Itgax), and MAC-expressed gene 1 (Mpeg1) in MACs. Overall, this study firstly found BPS exposure could exacerbate mammalian AS and might also provide a theoretical basis for elucidating BPS and its analogues induced AS and related CVDs.