Specific Mechanisms Research Articles

Molecular transformation of petroleum compounds by hydroxyl radicals produced upon oxidation of reduced nontronite

At redox interfaces, the interaction between oxygen and structural Fe(II) in minerals produces hydroxyl radicals (●OH); however, the specific reactivity and mechanisms of oxidation of complex petroleum compounds by ●OH remain poorly understood. This study investigates the interaction mechanisms between ●OH generated from reduced nontronite, an Fe-rich clay mineral (NAu-2), and petroleum compounds by employing a suite of wet chemistry, gas chromatography mass spectrometry and Fourier transform-ion cyclotron resonance-mass spectrometry, as well as theoretical calculations. The results showed that the intrinsic structure, composition, solubility, and adsorption of petroleum molecules onto reduced NAu-2 significantly influenced their reactivity with ●OH. Specifically, the aromatic fraction of a crude oil sample exerted a minimal influence on the oxidation rate of structural Fe(II) in reduced NAu-2, but enhanced the production of ●OH by generating environmentally persistent free radicals. ●OH reacted more with water-soluble dissolved organic matter from oil compared to polar compounds. The newly generated molecules by ●OH exhibited a preference for the insoluble (polar) phase. The oxidation of petroleum hydrocarbons by ●OH was mediated through hydrogen atom abstraction and radical adduct formation, followed by dehydrogenation, hydroxylation, and carboxylation reactions. Consequently, the abundance of oxygen-containing compounds in polar compounds increased. However, specific oxidation pathways differed depending on the nature of petroleum compounds. Our results provide insights that oxidation of petroleum compounds by ●OH is vital for mitigating the negative impacts from hydrocarbon contamination and for evaluating the role of these processes in the carbon cycle in redox-active environments.

Abstract A028: Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer cells

Abstract Ovarian cancer (OVCA) is the most lethal gynecologic malignancy, often detected at an advanced stage. OVCA progression involves transcoelomic metastasis, where tumor cells disseminate into the peritoneal ascites. Malignant cells in the ascites adapt to survive under Anchorage-Independent (A-I) conditions by altering the expression of genes escalating anoikis (A-I cell death) resistance and metastasis. Our lab has shown that OVCA cells manipulate their transcriptomic profile to promote the expression of anoikis resistance genes in A-I. Expression profiling of genes upregulated in A-I revealed the transcription factor SRY-Box Transcription Factor 2 (SOX2) to be highly upregulated in response to OVCA cell detachment. While we have previously demonstrated that SOX2 is necessary for the A-I survival of OVCA cells, the specific mechanism underlying SOX2-dependent A-I survival remains unknown. RNA-sequencing studies performed in the high-grade serous ovarian cancer cell line, OVCAR3, revealed that the Leucine-rich repeat-containing G-protein coupled receptor 5, LGR5, is the most significantly upregulated gene in A-I compared to attached conditions. Importantly, amongst those genes that are upregulated in A-I, LGR5 is significantly downregulated following SOX2 knockdown in A-I. LGR5 is an ‘orphan’ G-protein coupled receptor known to modulate canonical Wnt signaling upon interacting with its ligand R-spondin1 (RSPO1). Time-course experiments in OVCAR3 cells revealed a striking increase in LGR5 expression that peaked after 24 hours in A-I. Furthermore, siRNA mediated knockdown of SOX2 downregulated LGR5 expression only in A-I, suggesting that LGR5 is a potential SOX2 target under A-I conditions. Interestingly, bioinformatics analysis of the existing OVCA datasets from the Cancer Genome Atlas showed increased expression of RSPO1, which correlated with a significant decrease in the overall survival of OVCA patients. Interaction of LGR5 with its ligand RSPO1 is crucial for the receptor to signal through the Wnt pathway to promote cell survival and cancer stemness. Although SOX2 and LGR5 are established markers of cancer stemness in various tumor types, their direct relationship in promoting tumor progression and regulation of OVCA A-I cell survival remains unknown. Our data suggests that increased SOX2 and LGR5 expression could drive OVCA cell survival under A-I conditions. Our current studies focus on understanding the molecular mechanisms behind SOX2-driven regulation of LGR5 and the role of LGR5 in driving OVCA A-I cell survival. Citation Format: Shriya Kamlapurkar, Coryn Stump, Mythreye Karthikeyan, Nadine Hempel. Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A028.

Exercise Improves Heart Function after Myocardial Infarction: The Merits of AMPK.

AMPK is considered an important protein signaling pathway that has been shown to exert prominent cardioprotective effects on the pathophysiological mechanisms of numerous diseases. Following myocardial infarction, severe impairment of cardiac function occurs, leading to complications such as heart failure and arrhythmia. Therefore, protecting the heart and improving cardiac function are important therapeutic goals after myocardial infarction. Currently, there is substantial ongoing research on exercise-centered rehabilitation training, positioning exercise training as a significant nonpharmacological approach for preventing and treating numerous cardiovascular diseases. Previous studies have reported that exercise can activate AMPK phosphorylation and upregulate the AMPK signaling pathway to play a cardioprotective role in coronary artery disease, but the specific mechanism involved remains to be elucidated. This review discusses the role and mechanism of the exercise-mediated AMPK pathway in improving postinfarction cardiac function through existing studies and describes the mechanism of exercise-induced myocardial repair of AMPK from multiple perspectives to formulate a reasonable and optimal exercise rehabilitation program for the prevention and treatment of myocardial infarction patients in the clinic.

(064) Argonaute 2 Restores Erectile Function by Enhancing Angiogenesis and Reducing Reactive Oxygen Species Production in Streptozotocin (STZ)-Induced Type-1 Diabetic Mice

Abstract Introduction Diabetes mellitus (DM), a primary cause of erectile dysfunction (ED), is a pancreatic β-cell dysfunction that leads to insulin deficiency and resistance, resulting in microvascular complications. Argonaute 2 (Ago2), a catalytic engine in mammalian RNA interference, is involved in neurovascular regeneration under inflammatory conditions. Objective In the present study, we aimed to determine whether an exogenous injection of Ago2 proteins can improve erectile function in STZ-induced type-1 diabetic mice and explore the specific mechanisms of Ago2 in the process. Methods Eight-week-old male C57BL/6 mice were used for in vivo study. The detailed mechanisms were evaluated in age-matched control or STZ-induced type-1 diabetic mice. Mouse cavernous endothelial cells and human umbilical vein endothelial cells were used for in vitro study. The function of Ago2 in high-glucose condition was evaluated by tube formation assay, migration assay, immunofluorescence stain and western blot experiments. Results We report that Ago2 administration can effectively improve penile erection by enhancing cavernous endothelial cell angiogenesis and survival under diabetic conditions. We found that although Ago2 is highly expressed around blood vessels and nerves, it is significantly reduced in the penis tissue of diabetic mice. Exogenous administration of the Ago2 protein restored erectile function in diabetic mice by reducing reactive oxygen species production-signaling pathways (inducing eNOS Ser1177/NF-κB Ser536 signaling) and improving cavernous endothelial angiogenesis, migration, and cell survival. Our study provides new evidence that Ago2 mediation may be a promising therapeutic strategy and a new approach for diabetic ED treatment. Conclusions Our study provides new insights into Ago2 function and may represent a new therapeutic approach for ED and other vascular and neurological diseases. Disclosure No.

Role and regulation of FOXO3a: new insights into breast cancer therapy.

Breast cancer is the most common malignancy in the world, particularly affecting female cancer patients. Enhancing the therapeutic strategies for breast cancer necessitates identifying molecular drug targets that effectively eliminate tumor cells. One of these prominent targets is the forkhead and O3a class (FOXO3a), a member of the forkhead transcription factor subfamily. FOXO3a plays a pivotal role in various cellular processes, including apoptosis, proliferation, cell cycle regulation, and drug resistance. It acts as a tumor suppressor in multiple cancer types, although its specific role in cancer remains unclear. Moreover, FOXO3a shows promise as a potential marker for tumor diagnosis and prognosis in breast cancer patients. In addition, it is actively influenced by common anti-breast cancer drugs like paclitaxel, simvastatin, and gefitinib. In breast cancer, the regulation of FOXO3a involves intricate networks, encompassing post-translational modification post-translational regulation by non-coding RNA (ncRNA) and protein-protein interaction. The specific mechanism of FOXO3a in breast cancer urgently requires further investigation. This review aims to systematically elucidate the role of FOXO3a in breast cancer. Additionally, it reviews the interaction of FOXO3a and its upstream and downstream signaling pathway-related molecules to uncover potential therapeutic drugs and related regulatory factors for breast cancer treatment by regulating FOXO3a.

Mendelian randomization study on causal association of FAM210B with drug-induced lupus.

Due to the complexity of drug-induced lupus (DIL) pathogenesis, more susceptibility factors need to be discovered. FAM210B is a new mitochondrial protein whose function has not been fully elucidated. This study will explore whether there is a correlation between FAM210B and the risk of DIL. At first, we extracted three FAM210B genetic variants from the GTEx database (n = 948), and extracted their corresponding genome-wide association study (GWAS) summary statistics from DIL (101 DIL cases and 218691 controls). Then, we performed a Mendelian randomization (MR) study to evaluate the causal association of the expression of FAM210B with DIL using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. We successfully extracted three FAM210B single-nucleotide polymorphisms (SNPs) (rs116032784, rs34361943 and rs33923703) from the GTEx_Analysis_v8_eQTL data that can reduce FAM210B expression. The results of the MR analysis showed that genetically reduced expression of FAM210B was significantly associated with increased risk of DIL in European ancestry based on the IVW method (β = 1.037, p = 0.001, odds ratio [OR] = 2.821, 95% confidence interval [CI]:1.495-5.322). MR analysis showed a causal relationship between FAM210B expression and the risk of DIL disease. Our results suggested that FAM210B may be a marker that can mark susceptibility of DIL in the future. It provides evidence for the study of DIL, but its specific mechanism of action in DIL needs to be further studied. Key Points •This is the first MR analysis to examine the association between FAM210B and DIL. •The findings of this study suggested that reduced FAM210B expression is associated with the increased risk of DIL. •FAM210B may be a marker that can mark susceptibility of DIL in the future.

Betaine Alleviates High-Fat Diet Induced Excessive Lipid Deposition in Gibel Carp Hepatopancreas and L8824 Cells by Enhancing VLDL Secretion through HNF4α/MTTP Pathway.

Betaine, a methyl donor, plays a crucial role in lipid metabolism. Previous studies have shown that appropriate betaine supplementation in a high-fat diet reduces triglycerides (TG) of serum and hepatopancreas in fish. However, the underlying mechanism remains unclear. This study examined whether betaine can enhance the secretion of very low-density lipoprotein (VLDL) and sought to identify the specific mechanisms through which this enhancement occurs. A lipid accumulation model was established in gibel carp and L8824 cells using a high-fat diet and oleic acid, respectively. Different doses of betaine (1, 4, and 16 g/kg in the diet; 400 μmol in cell culture) were administered, and measurements were taken for lipid deposition, gene expression of HNF4α, MTTP, and ApoB, as well as the regulation of Mttp and Apob promoters by HNF4α. The results showed that betaine supplementation mitigated lipid droplet accumulation, TG levels, and VLDL production induced by the high-fat diet in gibel carp hepatopancreas and L8824 cells. Moreover, betaine not only increased VLDL content in the cell culture supernatant but also reversed the inhibitory effects of the high-fat diet on protein expression of MTTP, ApoB, and HNF4α in both gibel carp hepatopancreas and L8824 cells. Additionally, HNF4α exhibits transactivating activity on the promoter of Mttp in gibel carp. These findings suggest that betaine supplementation exerts its effects through the HNF4α/MTTP/ApoB pathway, promoting the assembly and secretion of VLDL and effectively reducing lipid accumulation in the hepatopancreas of farmed gibel carp fed a high-fat diet.

Cysteine and thiosulfate promoted cadmium immobilization in strain G303 by the formation of extracellular CdS

Bacteria have evolved a variety of strategies to defend themselves against cadmium toxicity, however, the specific mechanisms involved in the enhancement of bacterial cadmium resistance by sulfur sources are unclear. In this study, a novel cadmium (Cd)-tolerant bacterium, Stenotrophomonas geniculata G303, was isolated from activated sludge. The growth of strain G303 under diverse Cd concentrations was investigated, and the minimum inhibitory concentration of Cd was found to be 1 mM. Strain G303 effectively remove 94.7 % of Cd after 96 h of culture. Extracellular CdS was detected using multiple methods, with the CdS formed being aggregated in the biofilm. The addition of cysteine and thiosulfate to the medium significantly enhanced the Cd resistance and removal capacity of strain G303. Integrated genomic and proteomic analyses revealed that heavy metal transporters cooperate to resist Cd stress. Cysteine and thiosulfate improved Cd tolerance in strain G303 by upregulating nitrogen and energy metabolism. Proteins associated with nitrate reduction likely played a pivotal role in cysteine and thiosulfate metabolism. Notably, cysteine synthase and the SUF system played crucial roles in CdS formation. This study systematically explored the impact of cysteine and thiosulfate on the Cd resistance of strain G303, deepening our understanding of the microbial response mechanism to heavy metals.

Phosphorylated CPI-17 and MLC2 as Biomarkers of Coronary Artery Spasm-Induced Sudden Cardiac Death.

Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.

TET1 inhibits the migration and invasion of cervical cancer cells by regulating autophagy

ABSTRACT Methylation modifications play pertinent roles in regulating gene expression and various biological processes. The silencing of the demethylase enzyme TET1 can affect the expressions of key oncogenes or tumour suppressor genes, thus contributing to tumour formation. Nonetheless, how TET1 affects the progression of cervical cancer is yet to be elucidated. In this study, we found that the expression of TET1 was significantly downregulated in cervical cancer tissues. Functionally, TET1 knockdown in cervical cancer cells can promote cell proliferation, migration, invasion, cervical xenograft tumour formation and EMT. On the contrary, its overexpression can reverse the aforementioned processes. Moreover, the autophagy level of cervical cancer cells can be enhanced after TET1 knockdown. Mechanistically, methylated DNA immunoprecipitation (MeDIP)-sequencing and MeDIP quantitative real-time PCR revealed that TET1 mediates the methylation of autophagy promoter regions. These findings suggest that TET1 affects the autophagy of cervical cancer cells by altering the methylation levels of NKRF or HIST1H2AK, but the specific mechanism needs to be investigated further.

A summary of initiatives to address teacher shortages in hard-to-staff schools in the Anglosphere

ABSTARCT This article brings together a number of key issues that emerge in research around the problem of teacher shortages in hard-to-staff schools. It offers a broad overview of the hard-to-staff schooling sector as discussed in recent academic literature and provides a context-specific overview of the literature around workforce shortages in hard-to-staff schools with relevancy for high poverty contexts. In line with Williams et al. (2022) position on “Local Strategies, Global Inspiration,” this paper focuses on the problem of teacher shortages in hard-to-staff schools in Australia while looking to both Australian and broader Anglosphere literature (p.120) to reconsider responses to teacher recruitment and retention. The paper begins with a survey of the current state of this issue of workforce shortages in hard-to-staff schools in Australia. Turning our attention to literature from both Australia and Anglosphere countries, the summary then focuses on the specific initiatives and mechanisms employed for recruiting and retaining teachers in hard-to-staff schools, particularly the organisational contributions of Initial Teacher Education that support recruitment into hard-to-staff schools. The article concludes by highlighting limitations and critiques of hard-to-staff initiatives in the literature to inform policy and organisational considerations when addressing the issue of teacher shortages going forward.

Modulating the Activity of the Human Organic Cation Transporter 2 Emerges as a Potential Strategy to Mitigate Unwanted Toxicities Associated with Cisplatin Chemotherapy.

Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro- and ototoxicity. The human organic cation transporter 2 (hOCT2), found in abundance in the basolateral membrane domain of renal proximal tubules and the Corti organ, plays a crucial role in the initiation of nephro- and ototoxicity associated with CDDP by facilitating its uptake in kidney and ear cells. Given its limited presence in cancer cells, hOCT2 emerges as a potential druggable target for mitigating unwanted toxicities associated with CDDP. Potential strategies for mitigating CDDP toxicities include competing with the uptake of CDDP by hOCT2 or inhibiting hOCT2 activity through rapid regulation mediated by specific signaling pathways. This study investigated the interaction between the already approved cationic drugs disopyramide, imipramine, and orphenadrine with hOCT2 that is stably expressed in human embryonic kidney cells. Regarding disopyramide, its influence on CDDP cellular transport by hOCT2 was further characterized through inductively coupled plasma isotope dilution mass spectrometry. Additionally, its potential protective effects against cellular toxicity induced by CDDP were assessed using a cytotoxicity test. Given that hOCT2 is typically expressed in the basolateral membrane of polarized cells, with specific regulatory mechanisms, this work studied the regulation of hOCT2 that is stably expressed in Madin-Darby Canine Kidney (MDCK) cells. These cells were cultured in a matrix to induce the formation of cysts, exposing hOCT2 in the basolateral plasma membrane domain, which was freely accessible to experimental solutions. The study specifically tested the regulation of ASP+ uptake by hOCT2 in MDCK cysts through the inhibition of casein kinase II (CKII), calmodulin, or p56lck tyrosine kinase. Furthermore, the impact of this manipulation on the cellular toxicity induced by CDDP was examined using a cytotoxicity test. All three drugs-disopyramide, imipramine, and orphenadrine-demonstrated inhibition of ASP+ uptake, with IC50 values in the micromolar (µM) range. Notably, disopyramide produced a significant reduction in the CDDP cellular toxicity and platinum cellular accumulation when co-incubated with CDDP. The activity of hOCT2 in MDCK cysts experienced a significant down-regulation under inhibition of CKII, calmodulin, or p56lck tyrosine kinase. Interestingly, only the inhibition of p56lck tyrosine kinase demonstrated the capability to protect the cells against CDDP toxicity. In conclusion, certain interventions targeting hOCT2 have demonstrated the ability to reduce CDDP cytotoxicity, at least in vitro. Further investigations in in vivo systems are warranted to ascertain their potential applicability as co-treatments for mitigating undesired toxicities associated with CDDP in patients.

Direct carbonization of cellulose toward hydroxyl-rich porous carbons for pseudocapacitive energy storage

Designing carbon materials with specific oxygen-containing functional groups is very attractive for the precise decoration of carbon electrode materials and the basic understanding of specific charge storage mechanisms, which contributes to the further development of high-performance carbon materials for energy storage and conversion applications. In this contribution, a hydroxyl-rich micropore-dominated porous carbon material was obtained by direct carbonization of cellulose. The content of oxygen atoms in hydroxyl form in the obtained carbon is nearly 6 at.%. With the pyrolysis temperature changed, the macroscopic morphology, the specific surface area, surface functional groups, and graphitization degree of the carbon materials were changed strongly. Besides, the carbon material obtained with a carbonization temperature of 900 °C (C9) showed enhanced specific capacitance in sulfuric acid, sodium hydroxide, and sodium sulfate aqueous electrolytes, which mainly originates from the contribution of pseudocapacitance. The pseudocapacitance mainly depends on the presence of surface hydroxyl functional groups. Besides, the pseudocapacitance value of C9 material in neutral electrolytes (151.34 F g−1) is about twice that in acidic (75.9 F g−1) and alkaline (75.78 F g−1) electrolytes.

Shikonin suppresses rheumatoid arthritis by inducing apoptosis and autophagy via modulation of the AMPK/mTOR/ULK-1 signaling pathway

BackgroundThe overproliferation of fibroblast-like synoviocytes (FLS) contributes to synovial hyperplasia, a pivotal pathological feature of rheumatoid arthritis (RA). Shikonin (SKN), the active compound from Lithospermum erythrorhizon, exerts anti-RA effects by diverse means. However, further research is needed to confirm SKN's in vitro and in vivo anti-proliferative functions and reveal the underlying specific molecular mechanisms. PurposeThis study revealed SKN's anti-proliferative effects by inducing both apoptosis and autophagic cell death in RA FLS and adjuvant-induced arthritis (AIA) rat synovium, with involvement of regulating the AMPK/mTOR/ULK-1 pathway. MethodsSKN's influences on RA FLS were assessed for proliferation, apoptosis, and autophagy with immunofluorescence staining (Ki67, LC3B, P62), EdU incorporation assay, staining assays of Hoechst, Annexin V-FITC/PI, and JC-1, transmission electron microscopy, mCherry-GFP-LC3B puncta assay, and western blot. In AIA rats, SKN's anti-arthritic effects were assessed, and its impacts on synovial proliferation, apoptosis, and autophagy were studied using Ki67 immunohistochemistry, TUNEL, and western blot. The involvement of AMPK/mTOR/ULK-1 pathway was examined via western blot. ResultsSKN suppressed RA FLS proliferation with reduced cell viability and decreased Ki67-positive and EdU-positive cells. SKN promoted RA FLS apoptosis, as evidenced by apoptotic nuclear fragmentation, increased Annexin V-FITC/PI-stained cells, reduced mitochondrial potential, elevated Bax/Bcl-2 ratio, and increased cleaved-caspase 3 and cleaved-PARP protein levels. SKN also enhanced RA FLS autophagy, featuring increased LC3B, reduced P62, autophagosome formation, and activated autophagic flux. Autophagy inhibition by 3-MA attenuated SKN's anti-proliferative roles, implying that SKN-induced autophagy contributes to cell death. In vivo, SKN mitigated the severity of rat AIA while also reducing Ki67 expression, inducing apoptosis, and enhancing autophagy within AIA rat synovium. Mechanistically, SKN modulated the AMPK/mTOR/ULK-1 pathway in RA FLS and AIA rat synovium, as shown by elevated P-AMPK and P-ULK-1 expression and decreased P-mTOR expression. This regulation was supported by the reversal of SKN's in vitro and in vivo effects upon co-administration with the AMPK inhibitor compound C. ConclusionSKN exerted in vitro and in vivo anti-proliferative properties by inducing apoptosis and autophagic cell death via modulating the AMPK/mTOR/ULK-1 pathway. Our study revealed novel molecular mechanisms underlying SKN's anti-RA effects.

Amylovis-201 enhances physiological memory formation and rescues memory and hippocampal cell loss in a streptozotocin-induced Alzheimer's disease animal model

Alzheimer's disease is the most common neurodegenerative disease, and its treatment is lacking. In this work, we tested Amylovis-201, a naphthalene-derived compound, as a possible therapeutic candidate for the treatment of AD. For this purpose, we performed three experiments. In the first and third experiment, animals received a bilateral administration of streptozotocin and, starting 24 h after injection, a daily dose of Amylovis-201 (orally), for 17 days or for the whole time of the experiment respectively (28 days), after which learning and memory, as well as the number of hippocampal dentate gyrus cells, were assessed. In the second experiment, healthy animals received a single dose of Amylovis-201, 10 min or 5 h after the learning section to assess whether this substance could promote specific mechanisms involved in memory trace formation. Our data show that, administration of a single dose of Amylovis-201, 10 min after the end of training, but not at 5 h, produces a prolongation in memory duration, probably because it modulates specific mechanisms involved in memory trace consolidation. Furthermore, daily administration of Amylovis-201 to animals with bilateral intracerebroventricular injection of STZ produces a reduction in the loss of the hippocampus dentate gyrus cells and an improvement in spatial memory, probably because Amylovis-201 can interact with some of the protein kinases of the insulin signaling cascade, also involved in neural plasticity, and thereby halt or reverse some of the effects of STZ. Taking to account these results, Amylovis-201 is a good candidate for the therapeutic treatment of AD.

Prenatal diesel exhaust exposure alters hippocampal synaptic plasticity in offspring.

Diesel exhaust particles (DEPs) are major air pollutants emitted from automobile engines. Prenatal exposure to DEPs has been linked to neurodevelopmental and neurodegenerative diseases associated with aging. However, the specific mechanism by DEPs impair the hippocampal synaptic plasticity in the offspring remains unclear. Pregnant C57BL/6 mice were administered DEPs solution via the tail vein every other day for a total of 10 injections, then the male offsprings were studied to assess learning and memory by the Morris water maze. Additionally, protein expression in the hippocampus, including CPEB3, NMDAR (NR1, NR2A, NR2B), PKA, SYP, PSD95, and p-CREB was analyzed using Western blotting and immunohistochemistry. The alterations in the histomorphology of the hippocampus were observed in male offspring on postnatal day 7 following prenatal exposure to DEPs. Furthermore, 8-week-old male offspring exposed to DEPs during prenatal development exhibited impairments in the Morris water maze test, indicating deficits in learning and memory. Mechanistically, the findings from our study indicate that exposure to DEPs during pregnancy may alter the expression of CPEB3, SYP, PSD95, NMDAR (NR1, NR2A, and NR2B), PKA, and p-CREB in the hippocampus of both immature and mature male offspring. The results offer evidence for the role of the NMDAR/PKA/CREB and CPEB3 signaling pathway in mediating the learning and memory toxicity of DEPs in male offspring mice. The alterations in signaling pathways may contribute to the observed damage to synaptic structure and transmission function plasticity caused by DEPs. The findings hold potential for informing future safety assessments of DEPs.

Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis

(Background): Cadmium is an environmental pollutant associated with several liver diseases. Baicalin and N-Acetylcysteine have antioxidant and hepatoprotective effects. (Purpose): However, it is unclear whether baicalin and N-Acetylcysteine can alleviate Cadmium -induced liver fibrosis by regulating metabolism, or whether they exert a synergistic effect. (Study design): We treated Cadmium-poisoned mice with baicalin, N-Acetylcysteine, or baicalin+ N-Acetylcysteine. We studied the effects of baicalin and N-Acetylcysteine on Cadmium-induced liver fibers and their specific mechanisms. (Methods): We used C57BL/6J mice, and AML12, and HSC-6T cells to establish in vitro assays and in vivo models. (Results): Metabolomics was used to detect the effect of baicalin and N-Acetylcysteine on liver metabolism, which showed that compared with the control group, the Cadmium group had increased fatty acid and amino acid levels, with significantly reduced choline and acetylcholine contents. Baicalin and N-Acetylcysteine alleviated these Cadmium-induced metabolic changes. We further showed that choline alleviated Cadmium -induced liver inflammation and fibrosis. In addition, cadmium significantly promoted extracellular leakage of lactic acid, while choline alleviated the cadmium -induced destruction of the cell membrane structure and lactic acid leakage. Western blotting showed that cadmium significantly reduced mitochondrial transcription factor A (TFAM) and Choline Kinase α(CHKα2) levels, and baicalin and N-Acetylcysteine reversed this effect. Overexpression of Tfam in mouse liver and AML12 cells increased the expression of CHKα2 and the choline content, alleviating and cadmium-induced lactic acid leakage, liver inflammation, and fibrosis. (Conclusion): Overall, baicalin and N-Acetylcysteine alleviated cadmium-induced liver damage, inflammation, and fibrosis to a greater extent than either drug alone. TFAM represents a target for baicalin and N-Acetylcysteine, and alleviated cadmium-induced liver inflammation and fibrosis by regulating hepatic choline metabolism.

N-acetylcysteine and Hydroxychloroquine Ameliorate ADMA-Induced Fetal Growth Restriction in Mice via Regulating Oxidative Stress and Autophagy.

Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR.

The Effect of Social Media Forwarding on Subjective Well-Being in Chinese Older Adults: A Moderated Mediation Model.

In the intersection of the aging and information era, the development of digital aging significantly influences the well-being of older individuals. Given the divergent findings in various studies exploring the effects of social media use on mental health, this study specifically examined the impact of forwarding, a prevalent social media behavior among older individuals, focusing on the effects of use intensity on their subjective well-being (SWB) and the specific mechanisms involved. A total of 323 Chinese older adults completed the questionnaire. SPSS along with Hayes Process Models 4 and 7 was employed to test the hypotheses. The results indicated that social media forwarding intensity significantly and positively predicted SWB of older adults. This association was partially mediated by perceived social support (PSS) and self-esteem. Gender served as a moderator, highlighting that the positive predictive effects of forwarding intensity on PSS and self-esteem were more pronounced for older men than for older women. Further, the findings confirmed the existence of the moderated mediating effect such that the impact of forwarding on SWB was mediated through both PSS and self-esteem for older men, while, for older women, it was solely mediated by PSS. This study revealed the positive impact of forwarding, a user-friendly social media function, on the well-being of older adults and elucidated the specific mechanisms through a moderated mediation model. In light of these findings, we propose customizing the development of age-friendly social media functions to address the diverse psychological needs of older adults, taking into account gender differences. These findings may offer valuable insights for constructing digital age-friendly platforms and fostering active aging development.

MicroRNA-5010-5p ameliorates high-glucose induced inflammation in renal tubular epithelial cells by modulating the expression of PPP2R2D

IntroductionWe previously reported the significant upregulation of eight circulating exosomal microRNAs (miRNAs) in patients with diabetic kidney disease (DKD). However, their specific roles and molecular mechanisms in the kidney remain...