GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver.

Dysregulated metabolism, cell death, and inflammation contribute to the development of metabolic dysfunction-associated steatohepatitis (MASH). Pyroptosis, a recently identified form of programmed cell death, is closely linked to inflammation. However, the precise role of pyroptosis, particularly gasdermin-E (GSDME), in MASH development remains unknown. In this study, we observed GSDME cleavage and GSDME-associated interleukin-1ß (IL-1ß)/IL-18 induction in liver tissues of MASH patients and MASH mouse models induced by a choline-deficient high-fat diet (CDHFD) or a high-fat/high-cholesterol diet (HFHC). Compared with wild-type mice, global GSDME knockout mice exhibited reduced liver steatosis, steatohepatitis, fibrosis, endoplasmic reticulum stress, lipotoxicity and mitochondrial dysfunction in CDHFD- or HFHC-induced MASH models. Moreover, GSDME knockout resulted in increased energy expenditure, inhibited intestinal nutrient absorption, and reduced body weight. In the mice with GSDME deficiency, reintroduction of GSDME in myeloid cells-rather than hepatocytes-mimicked the MASH pathologies and metabolic dysfunctions, as well as the changes in the formation of neutrophil extracellular traps and hepatic macrophage/monocyte subclusters. These subclusters included shifts in Tim4+ or CD163+ resident Kupffer cells, Ly6Chi pro-inflammatory monocytes, and Ly6CloCCR2loCX3CR1hi patrolling monocytes. Integrated analyses of RNA sequencing and quantitative proteomics revealed a significant GSDME-dependent reduction in citrullination at the arginine-114 (R114) site of dynamin-related protein 1 (Drp1) during MASH. Mutation of Drp1 at R114 reduced its stability, impaired its ability to redistribute to mitochondria and regulate mitophagy, and ultimately promoted its degradation under MASH stress. GSDME deficiency reversed the de-citrullination of Drp1R114, preserved Drp1 stability, and enhanced mitochondrial function. Our study highlights the role of GSDME in promoting MASH through regulating pyroptosis, Drp1 citrullination-dependent mitochondrial function, and energy balance in the intestine and liver, and suggests that GSDME may be a potential therapeutic target for managing MASH.

Associations of ambient air pollution exposure and lifestyle factors with incident dementia in the elderly: A prospective study in the UK Biobank.

OBJECTIVE: Dementia is an important disease burden among the elderly, and its occurrence may be profoundly affected by environmental factors. Evidence of the relationship between air pollution and dementia is emerging, but the extent to which this can be offset by lifestyle factors remains ambiguous. METHODS: This study comprised 155,828 elder adults aged 60 years and above in the UK Biobank who were dementia-free at baseline. Cox proportional hazard models were conducted to examine the associations of annual average levels of air pollutants in 2010, including nitrogen dioxide (NO2), nitrogen oxides (NOX), particulate matter (PM2.5, PM10, and PMcoarse) and lifestyle factors recorded at baseline [physical activity (PA), sleep patterns, or smoking status] with incident risk of dementia, and their interactions on both multiplicative and additive scales. RESULTS: During a 12-year period of follow-up, 4,389 incidents of all-cause dementia were identified. For each standarddeviationincrease in ambient NO2, NOX or PM2.5, all-cause dementia risk increases by 1.07-fold [hazard ratio (HR) and 95 % confidence interval (CI) = 1.07 (1.04, 1.10)], 1.05-fold (95 % CI: 1.02, 1.08) and 1.07-fold (95 % CI: 1.04, 1.10), whereas low levels of PA, poor sleep patterns, and smoking are associated with an elevated risk of dementia [HR (95 % CI) = 1.17 (1.09, 1.26), 1.13 (1.00, 1.27), and 1.14 (1.07, 1.21), respectively]. Furthermore, these air pollutants show joint effects with low PA, poor sleep patterns, and smoking on the onset of dementia. The moderate to high levels of PA could significantly or marginally significantly modify the associations between NO2, NOX or PM2.5 (P-int = 0.067, 0.036, and 0.067, respectively) and Alzheimer's disease (AD), but no significant modification effects are found for sleep patterns or smoking status. CONCLUSION: The increased exposures of NO2, NOX, or PM2.5 are associated with elevated risk of dementia among elderly UK Biobank population. These air pollutants take joint effects with low PA, poor sleep patterns, and smoking on the development of dementia. In addition, moderate to high levels of PA could attenuate the incident risk of AD caused by air pollution. Further prospective researches among other cohort populations are warranted to validate these findings.

Host cell manipulation by microsporidia secreted effectors: Insights into intracellular pathogenesis.

Microsporidia are prolific producers of effector molecules, encompassing both proteins and nonproteinaceous effectors, such as toxins, small RNAs, and small peptides. These secreted effectors play a pivotal role in the pathogenicity of microsporidia, enabling them to subvert the host's innate immunity and co-opt metabolic pathways to fuel their own growth and proliferation. However, the genomes of microsporidia, despite falling within the size range of bacteria, exhibit significant reductions in both structural and physiological features, thereby affecting the repertoire of secretory effectors to varying extents. This review focuses on recent advances in understanding how microsporidia modulate host cells through the secretion of effectors, highlighting current challenges and proposed solutions in deciphering the complexities of microsporidial secretory effectors.

Green Synthesis of Polyurethane Sponge-Grafted Calcium Alginate with Carbon Ink Aerogel with High Water Vapor Harvesting Capacity for Solar-Driven All-Weather Atmospheric Water Harvesting.

Atmospheric water harvesting (AWH) technology is a new strategy for alleviating freshwater scarcity. Adsorbent materials with high hygroscopicity and high photothermal conversion efficiency are the key to AWH technology. Hence, in this study, a simple and large-scale preparation for a hygroscopic compound of polyurethane (PU) sponge-grafted calcium alginate (CA) with carbon ink (SCAC) was developed. The PU sponge in the SCAC aerogel acts as a substrate, CA as a moisture adsorber, and carbon ink as a light adsorber. The SCAC aerogel exhibits excellent water absorption of 0.555-1.40 g·g-1 within a wide range of relative humidity (40-80%) at 25 °C. The SCAC aerogel could release adsorbed water driven by solar energy, and more than 92.17% of the adsorbed water could be rapidly released over a wide solar intensity range of 1.0-2.0 sun. In an outdoor experiment, 57.517 g of SCAC was able to collect 32.8 g of clean water in 6 h, and the water quality meets the drinking water standards set by the World Health Organization. This study suggests a new approach to design promising AWH materials and infers the potential practical application of SCAC aerogel-based adsorbents.

Notopterygium Incisum Extract Promotes Apoptosis by Preventing the Degradation of BIM in Colorectal Cancer.

OBJECTIVE: Colorectal cancer (CRC), a prevalent malignancy worldwide, has prompted extensive research into anticancer drugs. Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities. This study investigated the effects of Notopterygium incisum, a traditional Chinese medicine named Qianghuo (QH), on CRC cells and the underlying mechanism. METHODS: The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2. Propidium iodide (PI) staining was utilized to detect cell cycle progression, and PE Annexin V staining to detect apoptosis. Western blotting was conducted to examine the levels of apoptotic proteins, including B-cell lymphoma 2-interacting mediator of cell death (BIM), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX) and cleaved caspase-3, as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide. The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis. The in vivo effects of QH extract on tumor growth were observed using a xenograft model. Lastly, APCMin+ mice were used to study the effects of QH extract on primary intestinal tumors. RESULTS: QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation, perturbation of cell cycle progression, and induction of apoptosis. Mechanistically, QH extract significantly increased the stability of BIM proteins, which undergo rapid degradation under unstressed conditions. Knockdown of BAX, the downstream effector of BIM, significantly rescued QH-induced apoptosis. Furthermore, the in vitro effect of QH extract was recapitulated in vivo. QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APCMin+ mice. CONCLUSION: QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.

A systematic investigation of peracetic acid oxidation and polymeric coagulants re-flocculation to enhance activated sludge dewatering: Multi-porous skeleton structures.

In this research, the effects of peracetic acid (PAA), polymeric flocculants, and their combined conditioning on improving the dewatering performance were comprehensively evaluated. The results showed that sludge cake moisture content, capillary suction time (CST), and specific resistance to filtration (SRF) were 70.6%, 48.1 s, and 3.42 × 1012 m/kg after adding 0.10 g/gMLSS PAA for 50 min, representing reductions of 12.60%, 40.32%, and 33.98%, respectively. Additionally, conditioning of sludge with polyferric sulfate (PFS), polyaluminum chloride (PAC), and cationic polyacrylamide (CPAM) enhanced sludge properties in the following order: CPAM > PAC > PFS. After the PAA oxidation and re-flocculation process, the optimal dosages of PFS, PAC, and CPAM were reduced to 1.5 g/L, 0.9 g/L, and 0.04 g/L, respectively. The sludge dewatering performance significantly improved, with sludge cake moisture content measuring 65.8%, 66.3%, and 61.7%, respectively. Moreover, the spatial multi-porous skeleton structures were formed via re-flocculation to improve the sludge dewatering. Furthermore, economic evaluation validated that the pre-oxidation and re-flocculation process could be considered an economically viable option. These research findings could serve as a valuable reference for practical engineering applications.

Evaluation of protective immunity induced by a DNA vaccine encoding SAG2 and SRS2 against Toxoplasma gondii infection in mice.

Toxoplasma gondii is an important protozoan pathogen, which can cause severe diseases in the newborns and immunocompromised individuals. Developing an effective vaccine against Toxoplasma infection is a critically important global health priority. Immunofluorescence staining analysis revealed that TgSAG2 and TgSRS2 are membrane associated and displayed on the surface of the parasite. Immunizations with pBud-SAG2, pBud-SRS2 and pBud-SAG2-SRS2 DNA vaccines significantly increased the production of specific IgG antibodies. Immunization with pBud-SAG2-SRS2 elicited cellular immune response with higher concentrations of IFN-γ and IL-4 compared to the control group. Antigen-specific lymphocyte proliferations in the pBud-SRS2 and pBud-SAG2-SRS2 groups were significantly higher compared to that in the control group. Furthermore, 30 % of mice immunized with pBud-SAG2-SRS2 survived after the challenge infection with virulent T. gondii RH tachyzoites. This study revealed that immunization with pBud-SAG2-SRS2 induced potent immune responses, and has the potential as a promising vaccine candidate for the control of T. gondii infection.

m6A demethylase OsALKBH5 is required for double-strand break formation and repair by affecting mRNA stability in rice meiosis.

N6-methyladenosine (m6A) RNA modification is the most prevalent messenger RNA (mRNA) modification in eukaryotes and plays critical roles in the regulation of gene expression. m6A is a reversible RNA modification that is deposited by methyltransferases (writers) and removed by demethylases (erasers). The function of m6A erasers in plants is highly diversified and their roles in cereal crops, especially in reproductive development essential for crop yield, are largely unknown. Here, we demonstrate that rice OsALKBH5 acts as an m6A demethylase required for the normal progression of male meiosis. OsALKBH5 is a nucleo-cytoplasmic protein, highly enriched in rice anthers during meiosis, that associates with P-bodies and exon junction complexes, suggesting that it is involved in regulating mRNA processing and abundance. Mutations of OsALKBH5 cause reduced double-strand break (DSB) formation, severe defects in DSB repair, and delayed meiotic progression, leading to complete male sterility. Transcriptome analysis and m6A profiling indicate that OsALKBH5-mediated m6A demethylation stabilizes the mRNA level of multiple meiotic genes directly or indirectly, including several genes that regulate DSB formation and repair. Our study reveals the indispensable role of m6A metabolism in post-transcriptional regulation of meiotic progression in rice.

Mitochondrial DNA copy number mediated the associations between perfluoroalkyl substances and breast cancer incidence: A prospective case-cohort study.

Epidemiologic studies have reported the relationships between perfluoroalkyl substances (PFASs) and breast cancer incidence, yet the underlying mechanisms are not well understood. This study aimed to elucidate the mediation role of mitochondrial DNA copy number (mtDNAcn) in the relationships between PFASs exposure and breast cancer risk. We conducted a case-cohort study within the Dongfeng-Tongji cohort, involving 226 incident breast cancer cases and a random sub-cohort (n = 990). Their plasma concentrations of six PFASs [including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)], and peripheral blood levels of mtDNAcn, were detected at baseline by using ultraperformance liquid chromatography-tandem mass spectrometry and quantitative real-time PCR, respectively. Linear regression and Barlow-weighted Cox models were employed separately to assess the relationships of mtDNAcn with PFASs and breast cancer risk. Mediation analysis was further conducted to quantify the mediating effects of mtDNAcn on PFAS-breast cancer relationships. We observed increased blood mtDNAcn levels among participants with the highest PFNA and PFHpA exposure [Q4 vs. Q1, ß(95%CI) = 0.092(0.022, 0.162) and 0.091(0.022, 0.160), respectively], while no significant associations were observed of PFOA, PFDA, PFOS, or PFHxS with mtDNAcn. Compared to participants within the lowest quartile subgroup of mtDNAcn, those with the highest mtDNAcn levels exhibited a significantly increased risk of breast cancer and postmenopausal breast cancer [Q4 vs. Q1, HR(95%CI) = 3.34(1.80, 6.20) and 3.71(1.89, 7.31)]. Furthermore, mtDNAcn could mediate 14.6 % of the PFHpA-breast cancer relationship [Indirect effect, HR(95%CI) = 1.02(1.00, 1.05)]. Our study unveiled the relationships of PFNA and the short-chain PFHpA with mtDNAcn and the mediation role of mtDNAcn in the PFHpA-breast cancer association. These findings provided insights into the potential biological mechanisms linking PFASs to breast cancer risk.

ARHGAP4 Inhibits Proliferation and Growth of SW620 Colon Cancer Cells by Cell Cycle and Differentiation Pathways.

The aim of this study is to explore the mechanism by which ARHGAP4 regulates the proliferation and growth of colon cancer cells, and it relates to the metastasis of colorectal cancer (CRC). Various techniques including western blot, CCK8, qRT-PCR, RNA seq assay, plate cloning, subcutaneous tumorigenesis assays, and bioinformatics tools were employed to identify genes that were upregulated or downregulated upon ARHGAP4 knockdown and their involvement in tumor cell proliferation and growth. The expression of ARHGAP4 in T and M stages of CRC uses immunohistochemistry. The expression levels of ARHGAP4 were found to be high in SW620, SW480, and HCT116 cell lines, while they were being low in HT29, LoVo, and NCM460 cell lines. Depletion of ARHGAP4 resulted in inhibited proliferation and growth in SW620 cells and inhibited subcutaneous tumorigenesis in nude mice, whereas overexpression of ARHGAP4 promoted proliferation and growth in HT29 cells and promoted subcutaneous tumorigenesis in nude mice. A total of 318 upregulated genes and 637 downregulated genes were identified in SW620 cells upon ARHGAP4 knockdown. The downregulated genes were primarily associated with cell cycle pathways, while the upregulated genes were enriched in differentiation-related pathways. Notable upregulated genes involved in cell differentiation included KRT10, KRT13, KRT16, IVL, and CD24, while significant downregulation was observed in genes related to the cell cycle such as CCNA2, CDKN2C, CDKN3, CENPA, and CENPF. ARHGAP4 expression is markedly elevated in the M1 stage of CRC compared to the M0 stage, suggesting ARHGAP4 linked to the metastatic in CRC. ARHGAP4 regulates the proliferation and growth of colon cancer cells by up- and downregulated cell cycle and differentiation-related molecules, which may be related to the metastasis of CRC.

Unveiling the Roles of Alloyed Boron in Hexavalent Chromium Removal Using Borohydride-Synthesized Nanoscale Zerovalent Iron: Electron Donor and Antipassivator.

Nanoscale zerovalent iron synthesized using borohydride (B-NZVI) has been widely applied in environmental remediation in recent decades. However, the contribution of boron in enhancing the inherent reactivity of B-NZVI and its effectiveness in removing hexavalent chromium [Cr(VI)] have not been well recognized and quantified. To the best of our knowledge, herein, a core-shell structure of B-NZVI featuring an Fe-B alloy shell beneath the iron oxide shell is demonstrated for the first time. Alloyed boron can reduce H+, contributing to more than 35.6% of H2 generation during acid digestion of B-NZVIs. In addition, alloyed B provides electrons for Fe3+ reduction during Cr(VI) removal, preventing in situ passivation of the reactive particle surface. Meanwhile, the amorphous oxide shell of B-NZVI exhibits an increased defect density, promoting the release of Fe2+ outside the shell to reduce Cr(VI), forming layer-structured precipitates and intense Fe-O bonds. Consequently, the surface-area-normalized capacity and surface reaction rate of B-NZVI are 6.5 and 6.9 times higher than those of crystalline NZVI, respectively. This study reveals the importance of alloyed B in Cr(VI) removal using B-NZVI and presents a comprehensive approach for investigating electron pathways and mechanisms involved in B-NZVIs for contaminant removal.

Tazarotene-induced Gene 1 Induces Melanoma Cell Death by Triggering Endoplasmic Reticulum Stress Response.

BACKGROUND: This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth. METHODS: The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between TIG1 expression and its downstream genes was analyzed in a melanoma tissue array. RESULTS: TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between TIG1 expression and the expression of HERPUD1, BIP, and DDIT3. Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth. CONCLUSIONS: TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.

A systematic review on reporting quality of economic evaluations for negotiated glucose-lowering drugs in China national reimbursement drug list.

BACKGROUND: This study aimed to examine the reporting quality of existing economic evaluations for negotiated glucose-lowering drugs (GLDs) included in China National Reimbursement Drug List (NRDL) using the Consolidated Health Economic Evaluation Reporting Standards 2013 (CHEERS 2013). METHODS: We performed a systematic literature research through 7 databases to identify published economic evaluations for GLDs included in the China NRDL up to March 2021. Reporting quality of identified studies was assessed by two independent reviewers based on the CHEERS checklist. The Kruskal-Wallis test and Mann-Whitney U test were performed to examine the association between reporting quality and characteristics of the identified studies. RESULTS: We have identified 24 studies, which evaluated six GLDs types. The average score rate of the included studies was 77.41% (SD:13.23%, Range 47.62%-91.67%). Among all the required reporting items, characterizing heterogeneity (score rate = 4.17%) was the least satisfied item. Among six parts of CHEERS, results part scored least at 0.55 (score rate = 54.79%) because of the incompleteness of characterizing uncertainty. Results from the Kruskal-Wallis test and Mann-Whitney U test showed that model choice, journal type, type of economic evaluations, and study perspective were associated with the reporting quality of the studies. CONCLUSIONS: There remains room to improve the reporting quality of economic evaluations for GLDs in NRDL. Checklists such as CHEERS should be widely used to improve the reporting quality of economic researches in China.

Evolution of hormonal therapy for prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy after skin cancer in men in Australia. Its management varies according to tumour stage. Due to the significant dependence on androgen receptor signalling, agents that interfere with this pathway (most commonly medical castration in the form of androgen deprivation therapy [ADT]) are the mainstay treatment of advanced disease. OBJECTIVE: This review provides a contemporary update on ADT, with further discussion of emerging novel therapies for primary care. DISCUSSION: ADT is currently indicated for the treatment of metastatic prostate cancer, disease recurrence following attempted local curative therapy, as well as combined use with radiotherapy for intermediate/high-risk disease. There has been rapid development of new pharmaceuticals targeting the androgen receptor. These are reviewed historically with an emphasis placed on emerging therapies, their common side effects, and how to manage them in the general practice setting.

Dopaminergic inhibition of the inwardly rectifying potassium current in direct pathway medium spiny neurons in normal and parkinsonian striatum.

Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel ( Kir ) being a key determinant of striatal medium spiny neuron (MSN) activity that also profoundly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. Here we show that in normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently strongly increasing D1-MSN spike firing that is behavior-promoting; this DA excitation of D1-MSNs is stronger when the DA depletion is more severe. The DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl 2 ). In behaving parkinsonian mice, BaCl 2 microinjection into the dorsal striatum stimulates movement but occludes the motor stimulation of D1R agonism. Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates D1R agonistic behavioral stimulation in normal and parkinsonian animals.

Chronic fluoxetine treatment desensitizes serotoninergic inhibition of GABA inputs and the intrinsic excitability of dorsal raphe serotonin neurons.

Dorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical to normal brain function such mood and emotion. Serotonin reuptake inhibitors (SSRIs) increase the synaptic and extracellular 5-HT level and are effective in treating depression. Treatment of two weeks or longer is often required for SSRIs to exert clinical benefits. The cellular mechanism underlying this delay was not fully understood. Here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons; this GABAergic regulation was reduced by 5-HT, which was prevented by G-protein-activated inwardly rectifying potassium (Girk) channel inhibitor tertiapin-Q, indicating a contribution of 5-HT activation of Girk channels in GABAergic presynaptic axon terminals. Equally important, after 14 days of treatment of fluoxetine, a widely used SSRI type antidepressant, this 5-HT inhibition of GABAergic inputs was substantially downregulated. Furthermore, the chronic fluoxetine treatment substantially downregulated the 5-HT activation of the inhibitory Girk current in 5-HT neurons. Taken together, our results suggest that chronic fluoxetine administration, by blocking 5-HT reuptake and hence increasing the extracellular 5-HT level, can downregulate the function of 5-HT1B receptors on the GABAergic afferent axon terminals synapsing onto 5-HT neurons, allowing extrinsic, behaviorally important GABA neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulate somatic 5-HT autoreceptor-activated Girk channel-mediated hyperpolarization and decrease in input resistance and intrinsic excitability, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity, potentially contributing to the antidepressant effect of SSRIs.

Correction: Tumor Immunotherapy-Related Information on Internet-Based Videos Commonly Used by the Chinese Population: Content Quality Analysis.

[This corrects the article DOI: 10.2196/50561.].

Hyperbaric Lidocaine Aggravates Diabetic Neuropathic Pain by Targeting p38 MAPK/ERK and PINK1/Parkin-Mediated Mitophagy Signaling Pathway.

BACKGROUND: Diabetic neuropathic pain (DNP) is a complication of diabetes mellitus (DM). Hyperbaric lidocaine (HL), a local anesthetics drug, has neurotoxicity. The present study aims to study the effect and molecular mechanisms of HL on spinal nerve injury in DNP. METHODS: The DNP rat model was established through a high-fat-glucose diet in combination with Streptozotocin (STZ) administration. SB203580 and PD98059 were utilized to inhibit p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The mechanical paw withdrawal threshold (PWT) and the thermal paw withdrawal latency (PWL) were tested to evaluate rats' mechanical allodynia and thermal hyperalgesia. Hematoxylin-eosin (H&E) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end Labeling (TUNEL) staining were performed to evaluate the pathological changes and neuron apoptosis in spinal cord tissues of L4-5. Western blotting analysis and reverse transcription-polymerase chain reaction (RT-qPCR) assay were used to measure the levels of proteins and mRNAs, respectively. RESULTS: PWT and PWL were decreased in DNP rats with serious spinal nerve injury. HL administration downregulated the PWT and PWL and aggravated spinal nerve injury in DNP rats, but isobaric lidocaine had no effects on these changes. Meanwhile, p38 MAPK/ERK signaling and PTEN-induced kinase 1 (PINK1)-mediated mitophagy were activated in DNP, which was enhanced by HL but not isobaric lidocaine. Blocking p38 MAPK/ERK signaling could effectively attenuate HL-induced spinal nerve injury and inhibit mitophagy. CONCLUSION: In summary, HL can aggravate spinal cord tissue damage in DNP rats by inducing PINK1-mediated mitophagy via activating p38 MAPK/ERK signaling. Our data provide a novel insight that supports the potential role of p38 MAPK/ERK signaling in acting as a therapeutic target for HL-induced neurotoxicity.

Assess the Outcomes of Transcatheter Aortic Valve Replacement in Bicuspid Valve with Mixed Disease versus Predominant Aortic Stenosis.

Purpose: In mixed aortic valve disease (MAVD), the results of transcatheter aortic valve replacement (TAVR) are conflicting. There is limited data on the outcomes of TAVR in patients with bicuspid aortic valve (BAV) and MAVD. The objective of this study is to compare outcomes after TAVR in BAV patients with MAVD and predominant aortic stenosis (PAS). Patients and Methods: Patients with BAV who underwent TAVR between January 2016 and April 2023 were included. The primary outcome was device success. The secondary endpoints were periprocedural mortality and other complications as defined by the Valve Academic Research Consortium-3 (VARC-3). Propensity score matching was used to minimize potential confounding. Results: A total of 262 patients were included in this study, 83 of whom had MAVD. The median age was 72 years, and 55.7% were male. The baseline comorbidity risk files were comparable between the two groups. Patients with MAVD had more mitral regurgitation, tricuspid regurgitation and pulmonary hypertension, larger annular and left ventricular outflow tract dimensions, and more severe calcification than PAS. In the unmatched population, MAVD patients had similar device success rate (69.9% vs 79.9%, P=0.075) and 30-day mortality (3.6% vs 3.4%, P=1) compared to PAS. Propensity score matching resulted in 66 patient pairs. Device success rate were still comparable in the matched population. Other clinical outcomes, including stroke, bleeding (type 2-4), major vascular complications, acute kidney injury (stage 2-4) and permanent pacemaker implantation, were comparable between the two groups. Multivariable logistic regression analysis did not show MAVD to be an independent negative predictor of device success. At one year, survival was similar between patients with MAVD and those with PAS. Conclusion: For the bicuspid valve, patients with MAVD had a more challenging anatomy. MAVD patients associated with comparable 30-day clinical outcomes after TAVR compared to PAS patients in patients with BAV.

Tat-dependent conditionally replicating adenoviruses expressing diphtheria toxin A for specifically killing HIV-1-infected cells.

HIV-1 infection remains a public health problem with no cure. Although antiretroviral therapy (ART) is effective for suppressing HIV-1 replication, it requires lifelong drug administration due to a stable reservoir of latent proviruses and may cause serious side effects and drive the emergence of drug-resistant HIV-1 variants. Gene therapy represents an alternative approach to overcome the limitations of conventional treatments against HIV-1 infection. In this study, we constructed and investigated the antiviral effects of an HIV-1 Tat-dependent conditionally replicating adenovirus, which selectively replicates and expresses the diphtheria toxin A chain (Tat-CRAds-DTA) in HIV-1-infected cells both in vitro and in vivo. We found that Tat-CRAds-DTA could specifically induce cell death and inhibit virus replication in HIV-1-infected cells mediated by adenovirus proliferation and DTA expression. A low titer of progeny Tat-CRAds-DTA was also detected in HIV-1-infected cells. In addition, Tat-CRAds-DTA showed no apparent cytotoxicity to HIV-1-negative cells and demonstrated significant therapeutic efficacy against HIV-1 infection in a humanized mouse model. The findings in this study highlight the potential of Tat-CRAds-DTA as a new gene therapy for the treatment of HIV-1 infection.