Potential Reversibility Research Articles

Renovascular hypertension - a primer for the radiologist.

Renovascular hypertension (RVHT) is an important cause of secondary hypertension, accounting for approximately 75% of cases. This pictorial review describes the imaging modalities used to diagnose RVHT, including ultrasound, computed tomography angiography, and magnetic resonance angiography, provides their benefits and limitations, and explores the imaging findings, diagnostic criteria, and management of multiple causes of RVHT. Atherosclerosis is the most common cause of RVHT, particularly in older individuals, while fibromuscular dysplasia is more prevalent in younger females. Less common discussed etiologies include polyarteritis nodosa, extrinsic compression, Page kidney, dissection, renal artery (RA) thrombus, and RA aneurysms. This paper also highlights the importance of recognizing anatomical variants and rare conditions that can impact diagnosis and management. While RVHT represents a minority of hypertension cases, its potential reversibility makes accurate diagnosis crucial. Treatment approaches vary based on etiology and may include medical management, angioplasty, stenting, or surgical intervention. This review aims to enhance radiologists' understanding of RVHT, facilitating improved diagnosis and patient care.

Multi-omics analysis of the biological function of the VEGF family in colon adenocarcinoma.

The vascular endothelial growth factor (VEGF) family plays a crucial role in cancer progression, but the prognostic significance and biological functions of VEGF family members in colon adenocarcinoma (COAD) remain unclear. Using data from The Cancer Genome Atlas, Gene Expression Omnibus, Gene Set Cancer Analysis, cBioPortal, GeneMANIA, String, MethSurv and starBase database, we identified vascular endothelial growth factor B (VEGFB) as a key gene associated with COAD prognosis, with its abnormal expression linked to methylation dysregulation. In vitro experiments confirmed VEGFB expression was significantly higher in colon cancer tissues compared to normal tissues, as shown by Real-time quantitative PCR and immunohistochemistry. Cell Counting Kit-8 and colony formation assay showed that decreased VEGFB expression in SW480 cells resulted in decreased cell viability and proliferation ability. Scratch assay showed that VEGFB downregulation impaired SW480 cell migration. In addition, our research suggests that VEGFB not only promotes angiogenesis but is also involved in the tumor microenvironment and immune regulation. The SHNG17-miR-375-VEGFB regulatory axis provides a potential therapeutic target for COAD, highlighting VEGFB's role in immune activation during anti-angiogenic therapy and potential reversal of drug resistance.

Socioeconomic inequalities linked to the transitioning to neurocognitive disorders and mortality

Research on socioeconomic position (SEP) and mild neurocognitive impairment, considered a transient state between normal cognitive function and dementia is limited. The purpose of this study was to determine the role of SEP in transitioning between different cognitive states and mortality risk. Using nationally representative English data and utilising a multistate model association between SEP and the risk of transitioning from no cognitive impairment (NOCI) to Cognitive impairment no dementia (CIND), dementia and death were investigated. The potential reverse transition from CIND to NOCI was also explored. The probabilities of transitioning between cognitive states and time spent in each state differed significantly between those with lower and higher levels of SEP. Higher wealth was associated with a reverse transition from CIND to NOCI [HR = 1.56, CI (1.42,1.72)]. Socioeconomic advantage might protect against the progression to the early stages of neurocognitive disorders (CIND) and facilitate the potential reversion from mild cognitive impairment to a healthy cognitive state in later life. Lower levels of education affect the risk of mortality after the onset of dementia.

The WE-RISE™ multi-domain intervention: a feasibility study for the potential reversal of cognitive frailty in Malaysian older persons of lower socioeconomic status

BackgroundCognitive frailty (CF) is an emerging concern among older persons, particularly within lower socioeconomic statuses (SES) populations. Currently, there is limited evidence on the potential reversibility of CF through multi-domain interventions within this demographic. This study aimed to investigate the effectiveness of the WE-RISE™ multi-domain intervention in addressing the potential reversibility of CF among community-dwelling older persons of lower SES, the intervention effects on multiple health dimensions, and to determine if WE-RISE™ is of low cost.MethodsThis 24-week randomised controlled trial included 55 community-dwelling older persons of lower SES with CF, who were randomised into either the WE-RISE™ intervention group (n = 27), or the control group receiving usual care (n = 28). The WE-RISE™ intervention comprised of 12 weeks of instructor led, community-based intervention, followed by 12 weeks of WE-RISE™@Home. CF status, cognitive and physical function, nutrition, disability, health-related quality of life, exercise self-efficacy and depression were assessed at baseline, 12th and 24th weeks. Changes in CF status was analysed descriptively, while intervention effects were analyzed with split plot ANOVA. The cost of the WE-RISE™ intervention was calculated using activity-based costing.ResultsAt baseline, all participants in both the intervention and control groups (100%) were classified as CF. Following 12 weeks of the WE-RISE™ intervention, 74.1% of participants in the experimental group no longer met the criteria for cognitive frailty, with 63% maintaining this improvement at 24 weeks. In contrast, the CF status of participants in the control group remained largely unchanged, with only 10.7% showing improvement at 12 weeks and falling to 3.6% at 24 weeks. Significant intervention effects were observed for cognition, physical function, body composition, disability, health-related quality of life and self-perceived exercise self-efficacy (p < 0.05) following participation in WE-RISE™. The cost per intervention session was RM4.06 (≈ RM3.88), and the cost per subject for 48 sessions was RM194.74 (≈ RM187.01).ConclusionThe WE-RISE™ multi-domain intervention has demonstrated potential in reversing CF among older persons of lower SES, leading to significant improvements across multiple health dimensions at a low cost. WE-RISE™ shows promise to enrich the well-being of ageing societies, contribute to societal health, and ensure equitable access to healthcare, supporting broader implementation by enhancing equitable access to health programs and addressing the needs of older persons, WE-RISE™.Trial registrationThis trial was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12619001055190) on the 29th of July 2019 – retrospectively registered.

Quantitative Design of Cathode Materials for Ion Battery from a Reductionist Perspective

AbstractThe quantitative design of functionalities for functional materials is highly attractive for materials research, which must be based on a thorough understanding of the behavior of fundamental particles. Reductionism advocates for the understanding of complex materials through dissection into the constituent parts, providing a robust framework for investigating functional materials. In an ion battery system, this review utilizes reductionism to deconstruct cathode materials into phase, atom, and even electron, building the intrinsic connections between the macroscopic properties and fundamental particles across four degrees of freedom. This aims to enable the quantitative design of cathode materials. Specifically, the microscopic origins of the macroscopic properties, that is, capacity, potential, rate, and cycling reversibility, based on lattice, charge, orbital, and spin degrees of freedom are elucidated. Additionally, current strategies are summarized and proposed future development directions for improving these properties. These insights contribute to achieving the goal of quantitative design of energy storage materials.

DNA methylation at AHRR as a master predictor of smoke exposure and a biomarker for sleep and exercise

BackgroundDNA methylation profiling may provide a more accurate measure of the smoking status than self-report and may be useful in guiding clinical interventions and forensic investigations. In the current study, blood DNA methylation profiles of nearly 800 Polish individuals were assayed using Illuminia EPIC and the inference of smoking from epigenetic data was explored. In addition, we focused on the role of the AHRR gene as a top marker for smoking and investigated its responsiveness to other lifestyle behaviors.ResultsWe found > 450 significant CpGs associated with cigarette consumption, and overrepresented in various biological functions including cell communication, response to stress, blood vessel development, cell death, and atherosclerosis. The model consisting of cg05575921 in AHRR (p = 4.5 × 10–32) and three additional CpGs (cg09594361, cg21322436 in CNTNAP2 and cg09842685) was able to predict smoking status with a high accuracy of AUC = 0.8 in the test set. Importantly, a gradual increase in the probability of smoking was observed, starting from occasional smokers to regular heavy smokers. Furthermore, former smokers displayed the intermediate DNA methylation profiles compared to current and never smokers, and thus our results indicate the potential reversibility of DNA methylation after smoking cessation. The AHRR played a key role in a predictive analysis, explaining 21.5% of the variation in smoking. In addition, the AHRR methylation was analyzed for association with other modifiable lifestyle factors, and showed significance for sleep and physical activity. We also showed that the epigenetic score for smoking was significantly correlated with most of the epigenetic clocks tested, except for two first-generation clocks.ConclusionsOur study suggests that a more rapid return to never-smoker methylation levels after smoking cessation may be achievable in people who change their lifestyle in terms of physical activity and sleep duration. As cigarette smoking has been implicated in the literature as a leading cause of epigenetic aging and AHRR appears to be modifiable by multiple exogenous factors, it emerges as a promising target for intervention and investment.

Complete retinal pigment epithelium and outer retinal atrophy: Is it really an end-stage atrophy?

Geographic atrophy (GA), a late manifestation of age-related macular degeneration (AMD), leads to irreversible vision loss. Early identification of precursor lesions, such as incomplete and complete retinal pigment epithelium and outer retinal atrophy (iRORA and cRORA), is crucial for predicting GA formation. The latter stage has been associated with irreversible and progressive changes, and the eventual development of a dense scotoma on the compromised area. We present an 80-year-old woman with AMD in both eyes, demonstrating progressive changes over a 2-year follow-up. While the right eye developed cRORA with vision decline, the left eye exhibited unexpected restoration of the outer retinal layers within the cRORA lesion. This finding challenges the notion of "end-stage atrophy" in GA development and highlights the potential reversibility of early atrophic lesions. Recognizing these dynamics has implications for the development of targeted therapies aimed at preserving vision in AMD's early stages.

Role of molybdenum compounds in enhancing denitrification: Structure-activity relationship and the regulatory mechanisms

The effect and regulatory mechanisms of molybdenum compounds (MoO2, MoS2, MoSe2 and MoSi2) on denitrification were investigated by structure-activity relationships, electrochemical characteristics, microbial metabolism analysis and bacterial community distribution. All the assessed molybdenum compounds exhibited the enhancement effect on denitrification, in the order of MoS2 > MoSi2 > MoSe2 > MoO2, with MoS2 increasing 7.08-fold in 12 h. Analysis of structure-activity relationships suggested that the molybdenum compounds with lower negative redox potential and higher redox reversibility were favorable for promoting denitrification. According to the morphology observation, the interactions between Mo compounds and denitrifying bacteria may be beneficial to extracellular electron transfer. Molybdenum compounds with electron transfer capability facilitated an increase in electron capacitance from 835.1 to 1011.3 μF, promoting the electron exchange rate during denitrification. In the denitrification electron transport chain, the molybdenum compounds upregulated nicotinamide adenine dinucleotide and denitrifying enzyme activity, as well as facilitated the abundance of quinone pools, ATP translocation, and cytochrome c related proteins. Moreover, Mo compounds enriched functional bacteria such as electroactive bacteria and denitrifying functional bacteria. Notably, Mo ions in molybdenum compounds may provide active sites for nitrate reductase, optimizing the electron distribution of the denitrification process and thus improved the partial denitrification efficiency. This work aimed to further understand the regulatory mechanisms of molybdenum on denitrification electron transfer in the compound state and to anticipate the catalytic role of Mo compounds for sustainable water treatment.

The effect of norepinephrine on ovarian dysfunction by mediating ferroptosis in mice model.

Studies have shown that stress is associated with ovarian dysfunction. Norepinephrine (NE), a classic stress hormone involved in the stress response, is less recognized for its role in ovarian function. In this study, an NE-treated mouse model is induced by intraperitoneal injection of NE for 4 weeks. Compared with normal control mice, NE-treated mice show disturbances in the estrous cycle, decreased levels of anti-Mullerian hormone (AMH) and estradiol (E2), and increased level of follicle-stimulating hormone (FSH). Additionally, the numbers of primordial follicles, primary follicles, secondary follicles, and antral follicles are decreased, whereas the number of atretic follicles is increased in NE-treated mice, indicating NE-induced ovarian dysfunction. RNA sequencing further reveals that genes associated with ferroptosis are significantly enriched in NE-treated ovarian tissues. Concurrently, the levels of reactive oxygen species (ROS), ferrous ions, and malondialdehyde (MDA) are increased, whereas the expression level of glutathione peroxidase 4 (GPX4) is decreased. To elucidate the mechanism of NE-induced ferroptosis in ovaries and the potential reversal by Coenzyme Q10 (CoQ10), an antioxidant, we conduct both in vitro and in vivo experiments. In vitro, the granulosa cell line KGN, when treated with NE, shows decreased cell viability, reduced expression of GPX4, elevated levels of ferrous ion and ROS, and increased MDA level. However, these NE-induced changes are reversed by the addition of CoQ10. Compared with the NE group, the NE-treated mice supplemented with CoQ10 present increased GPX4 level and decreased iron, ROS, and MDA levels. Moreover, the differential expression of genes associated with ferroptosis induced by NE is ameliorated by CoQ10 in NE-treated mice. Additionally, CoQ10 improves ovarian function, as evidenced by increased ovarian weight, more regular estrous cycles, and an increase in follicles at various stages of growth in NE-treated mice. In conclusion, NE induces ovarian dysfunction by triggering ferroptosis in ovarian tissues, and CoQ10 represents a promising approach for protecting reproductive function by inhibiting ferroptosis.

A coupled plasma-thermal model for hollow cathode power decomposition and parametric analysis

Abstract A 2D axisymmetric transient coupled plasma-thermal model is developed to simulate the plasma behavior during the self-sustained discharge of hollow cathodes, which presents a complete hollow cathode structure and energy transfer processes in multiphysics fields. The model has been validated by quantitative agreement between the simulation results and experimental data on the plasma and emitter temperature at the NSTAR cathode. The effects of thermal protection design, operating conditions, and geometric design on the cathode performance are analysed through electric and thermal power decomposition. The parametric analysis shows that the optimal thermal protection design is to use a 1/3 thickness cathode tube with 4 layers of radiation shielding close to the tube, which reduces 43.7% conductive and 61.1% radiative heat dissipation, respectively. Increasing the inlet flow rate counter-intuitively reduces the emitter temperature due to the potential reversal in the diffusion electric field dominated region, revealing that the flow rate can be traded for the dual optimisation of lifetime and power consumption. Under high current conditions, the IAT effect dominates the plume resistance to increase the discharge voltage after an inflexion point, which is the main factor limiting the cathode performance. A large internal radius gives a uniform low emission and helps to prolong life, while the orifice length should be avoided to be longer than 4 times the orifice radius due to the significantly enhanced Joule heating in the narrow orifice. The orifice radius determines the power deposition due to electron and ion bombardment through potential penetration. For high-current discharger cathodes dominated by electron bombardment, large or through-orifice designs are preferred, while for low-current neutralizer cathodes dominated by electron bombardment, small-orifice designs are recommended.

Investigation of Photoinduced Deterioration in Shadow Puppet Artifacts Collected from the National Shadow Pupperty Museum in Chengdu, China

Shadow puppet artifacts are a special type of cultural heritage made from animal skin, possessing significant cultural and artistic value. However, there is insufficient attention to the scientific preservation of these artifacts, and systematic research on their protection is lacking. In particular, light as an important factor and related conservation studies are weak. This study investigates the photoinduced deterioration of shadow puppet artifacts from the National Shadow Pupperty Museum in Chengdu collection. Based on the xenon arc lamp are a common method of light aging, the modern rawhide samples were aged by the xenon arc lamp to simulate photoinduced deterioration. After artificial light aging, the samples were stored in a stable environment (with temperature maintained at 22 ± 2°C and relative humidity maintained at 50 ± 5%RH) for 150 days. It attempts to avoid further deterioration of the samples due to drastic cyclic changes in the environment. And continuously observe changes in characteristics during this process to verify the potential reversibility of photoinduced deterioration. Comprehensive assessments were conducted to gauge the extent of deterioration. In order to assess the deterioration, a series of analytical techniques were used. Moisture gain or loss was inferred from mass changes, and colorimetric measurements were measured using the CIELAB formula. Macroscopic and microscopic morphological damage was documented through camera, stereo microscope, and scanning electron microscope observations. Fourier transform infrared spectroscopy (FTIR) assessed amide bond degradation and moisture loss, while thermogravimetry/differential thermogravimetry (TG/DTG) evaluated collagen denaturation and thermal stability. The results indicated that prolonged light exposure caused significant deterioration, including color fading, moisture evaporation, and structural damage such as shrinkage and cracking. The findings indicate that light exposure is a crucial factor in the preservation of shadow puppet artifacts. Therefore, it is essential to implement careful management strategies in museum environments to ensure the protection of these artifacts.

The construction of an inflammation classification model for HDPCs applied in guiding pulpotomy based on single-cell Raman spectroscopy

The immune defense and the repair function of the pulp tissue serve as the biological foundation of pulpotomy. The precise evaluation of the pulp inflammation extent and determining its reversibility are essential for the success of pulpotomy. The objective of this study was to classify the molecular-level of dental pulp cell physiology and inflammatory state based on the biochemical changes obtained by single-cell Raman spectroscopy. Firstly, we differentiated the growth of HDPCs (human dental pulp cells) under physiological states by employing Raman spectroscopy with multivariate statistical analysis. Raman spectroscopy reflected the biochemical changes at different growth phases, including the lag phase, log phase, and stationary phase. Secondly, we evaluated the optimal concentration and duration of Porphyromonas gingivalis lipopolysaccharide (P.g.LPS) stimulation to establish a six-level inflammation classification model of HDPCs. Thirdly, we performed label-free characterization of biological component changes in cells of different inflammation grades by Raman spectroscopy. As a result, the differences of peaks in the region 600–1800 cm−1 demonstrated the biochemical molecular alterations in the different inflammation grades of HDPCs. As inflammation progresses in steps, protein peaks increased first and then decreased, while lipid and nucleic acid peaks gradually decreased compared to unstimulated cells. However, when the inflammatory stimulation reached grade V, the changes in the biological properties were characterized by a recovery in protein and lipid content, and a decrease in nucleic acid content. We then established the diagnostic model using the Raman spectra of HDPCs in physiological and inflammatory states, which had a prediction accuracy of 100 % and 97.4 %, respectively. Finally, we determined the reversibility threshold of HDPCs at different grades of inflammation. We observed that the inflammation of grade I and II cells had potential reversibility and could be attempted to be retained. In conclusion, Raman spectroscopy combined with multivariate statistical analysis has potential possibility to effectively distinguish the degree of inflammation in the dental pulp, thus providing new tools and perspectives on pulpotomy in clinical practice.

Inhibition of Epithelial-Mesenchymal Transition and Migration in Cisplatin-resistant Cancer Through Combined Treatment With Cisplatin and SH003.

This study investigated the synergistic effects of combining cisplatin and SH003 treatment on the viability, apoptosis, cytotoxicity, migration and epithelial-mesenchymal transition (EMT) in cisplatin-resistant cancer cell lines YD-8/CIS, YD-9/CIS and YD-38/CIS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess cell viability, while trypan blue exclusion assay was used to evaluate cytotoxicity. Flow cytometry and western blot analysis measured apoptotic cell death. Wound-healing assays evaluated cell migration and EMT markers. Combination index (CI) plots were used to evaluate the combinatory effects of the treatment. Combination therapy significantly reduced cell viability more effectively than each agent alone, as demonstrated by the MTT assay, with CI plots confirming notable synergism. Trypan blue exclusion assays indicated increased cell death and cytotoxicity in combination treatment than in both monotherapies, although the increase was not significant. Flow cytometry and western blot analysis revealed no significant synergistic effect on apoptotic cell death. However, wound-healing assays revealed that the combination of cisplatin and SH003 significantly inhibited cell migration and regulated EMT markers, indicating the potential reversal of EMT. Combining cisplatin and SH003 therapy may potentially be a more effective strategy for treating cisplatin-resistant cancer by increasing cytotoxicity and inhibiting metastasis. Further research is required to elucidate the underlying mechanisms and evaluate the in vivo efficacy of this combination therapy.

Anlotinib reverses osimertinib resistance via inhibiting epithelial-to-mesenchymal transition and angiogenesis in non-small cell lung cancer.

In the present, we aimed to investigate the effect of anlotinib on the potential reversal of osimertinib resistance by inhibiting the formation of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In a clinical case, anlotinib reversed osimertinib resistance in Non-small cell lung cancer (NSCLC). We performed an immunohistochemical experiment on tumor tissues from three non-small cell lung cancer patients exhibiting osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A (VEGFA) before and after osimertinib resistance. The results revealed the downregulation of E-cadherin, coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance, compared with the expression in tissues of patients before taking osimertinib. Subsequently, we established osimertinib-resistant cell lines and found that the osimertinib-resistant cells acquired the EMT features. Then, we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT. The expression levels of VEGFA and micro-vessels were analyzed in the combination group in vitro. Finally, we explored the reversal of osimertinib resistance in combination with anlotinib in vivo with 20 nude mice. The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of resistant cells, which also inhibited tumor growth, exerted anti-tumor activity, and ultimately reversed osimertinib resistance in mice. The co-administration of osimertinib and anlotinib demonstrated their synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients, ultimately reversing osimertinib resistance.

Abstract A060: Breast cancer-associated leukocyte DNA methylation profile in obese African-American women

Abstract Background: DNA methylation (DNAme) is a stable epigenetic mark leading to reduced gene expression. However, genome-wide DNAme profile is susceptible to disease. Therefore, specific genetic DNAme profiles could potentially serve as biomarkers associated with breast cancer (BC) and obesity as its comorbidity. Incidentally, BC-related mortality is higher in African-American women, causing a significant health disparity. In this study, we profiled obesity and breast cancer-related leukocyte DNAme in African-American women to explore methylation- associated biomarkers in these women. Methods: We used 10 African-American women with confirmed breast cancer diagnosis and 10 otherwise healthy African-American women with known Body Mass Index (BMI) &amp;gt; 30 (Obese). DNA was extracted from the buffy coat of peripheral blood using Qiagen DNA extraction kits. We used the next-generation sequencing technology to perform reduced presentation bisulfite sequencing (RRBS) using the Tecan Ovation RRBS kit. We sequenced the libraries on a NextSeq 550 at our Precision Medicine Unit. Single-end 75bp reads were generated and processed using Bismark and mapped against the GRCh38 human genome, and differentially methylated regions (DMR) were derived using MethylKit using a 1 kb window. Gene Ontology and Disease association studies were conducted using DAVID and relapsed-free survival in Kmplot. Additionally, we compared the gene sets with obese and normal DMRs that had previously been obtained similarly. Results: We found that 83% of the DMRs were in the promoter/upstream regions of the nearest genes, and 96% of DMRs were part of CpG islands, indicating potential regulatory functions of these regions. Gene ontology analysis revealed that the DMR-associated genes were also overrepresented in breast carcinoma, Type 2 Diabetes, Obesity, and Tobacco usage, according to the DisGeNET and GAD disease associations databases. Genes with DMRs in their upstream or promoter regions - include PRDM16, PTBP1, RAB1A (lower methylation in cancer with obesity), and Multiple ribosomal genes along with RRAF, XKR4 (higher methylation in cancer with obesity). We observed lower methylation profiles in multiple genes in samples with cancer, which were higher in obese samples without cancer.Conclusion: Our study suggests that a distinct peripheral DNA methylation profile is associated with minority women suffering from both cancer and obesity. Our data show that showed that breast cancer modulates leucocyte DNA methylation profile in obese individuals towards that of a more normal BMI, causing a partial reversal. This potential reversal is primarily in the upstream regions of the genes detected for methylation. The DMR genes in cancer with obesity are significantly associated with overall survival in breast cancer, thus indicating a potential link in understanding the crosstalk between obesity and cancer. Citation Format: Pranabananda Dutta, Yanyuan Wu, Jaydutt V. Duta. Breast cancer-associated leukocyte DNA methylation profile in obese African-American women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A060.

Correction to “Structure–Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents”

Correction to “Structure–Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents”

Lifestyle interventions in cardiometabolic HFpEF: dietary and exercise modalities.

Heart failure with preserved ejection fraction (HFpEF) is rapidly growing as the most common form of heart failure. Among HFpEF phenotypes, the cardiometabolic/obese HFpEF - HFpEF driven by cardiometabolic alterations - emerges as one of the most prevalent forms of this syndrome and the one on which recent therapeutic success have been made. Indeed, pharmacological approaches with sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have proved to be effective due to metabolic protective effects. Similarly, lifestyle changes, including diet and exercise are crucial in HFpEF management. Increasing evidence supports the important role of diet and physicalactivity in the pathogenesis, prognosis, and potential reversal of HFpEF. Metabolic derangements and systemic inflammation are key features of HFpEF and represent the main targets of lifestyle interventions. However, the underlying mechanisms of the beneficial effects of these interventions in HFpEF are incompletely understood. Hence,there is an unmet need of tailored lifestyle intervention modalities for patients with HFpEF. Here we present the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms.

Investigation of Metaplasticity Associated with Transcranial Focused Ultrasound Neuromodulation in Humans.

Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30-60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS.

Serum C-reactive protein to albumin ratio as a reliable marker of diabetic neuropathy in type 2 diabetes mellitus.

In various diseases characterized by inflammation, the C-reactive protein to albumin ratio (CAR) serves as a marker of inflammation. Type 2 diabetes mellitus (T2DM) is frequently complicated by diabetic neuropathy (DN) and timely diagnosis is crucial for treatment and potential reversal of this complication. Since both DN and T2DM are associated with chronic, low-grade inflammation, our study aimed to evaluate CAR levels in type 2 diabetic subjects with DN and compare them to those in subjects without DN. Patients presenting to our institutional outpatient clinics were divided into two groups based on the presence of DN. Data on characteristics and laboratory measures, including CAR,were compared between the DN and non-DN groups. The median CAR in the DN and non-DN groups was 2.19% (range 0.2%-49%) and 0.56% (range 0.02%-5.8%), respectively (P < 0.001). CAR showed significant positive correlations with weight (r = 0.19, P = 0.01), body mass index (BMI) (r = 0.11, P = 0.03), waist circumference (r = 0.10, P = 0.046), fasting glucose (r = 0.14, P = 0.004), serum creatinine (r = 0.25, P < 0.001), triglyceride (r = 0.17, P < 0.001), and LDL-cholesterol (r = 0.13, P = 0.001) levels, and an inverse correlation with estimated glomerular filtration rate (eGFR) (r = -0.16, P < 0.001). Additionally, CAR demonstrated a sensitivity of 78% and specificity of 73% for predicting DN at a threshold of 1.02% (area under curve [AUC] 0.84, 95% confidence interval [CI] 0.82-0.87, P < 0.001). High CAR levels were independently associated with an increased risk of DN (odds ratio [OR] 1.34, 95% CI 1.08-1.62, P < 0.001). Elevated CAR levels may thus be considered a potential marker for DN in T2DM patients.

Associations between single nucleotide polymorphisms of cytokines and hepatitis B virus-related liver cirrhosis: A case-controlstudy.

Various inflammatory and immune cytokines play key roles in the progression of hepatitis B virus (HBV)-related liver cirrhosis (LC). This study explored the relationship between single nucleotide polymorphisms (SNPs) in cytokines with the combined effect of polymorphisms and gender-polymorphisms interaction and LC risk. In this study, a case-control design was used, samples were selected from 45 patients with hepatitis B-related cirrhosis and 45 age-gender-matched chronic HBV-infected patients without cirrhosis attending the tumor hospital of Wuwei Academy of Medical Sciences. Fifteen SNPs were examined using a real-time polymerase chain reaction allelic discrimination system. Logistic regression was utilized to assess cytokine-associated SNPs and the association between SNPs and LC progression in HBV-infected patients. The multivariate-adjusted logistic model revealed that the GG/AG dominant model (OR, 16.38; 95% CI, 1.13-236.70) and G allele (OR, 5.93; 95% CI, 0.98-36.01) of rs1800896 were associated with an increased risk of cirrhosis in CHB patients. Instead, rs2227306 CT presented a reduced cirrhosis risk (OR, 0.22; 95% CI, 0.04-1.38). Rs2055979 AA/AC was negatively associated with the risk of cirrhosis, potentially reversed in males (p = 0.021). Rs1799964 CC/CT was positively related to the risk of cirrhosis but reduced the risk of cirrhosis in males (OR, 0.13; 95% CI, 0.022-0.808; p = 0.028). Both rs1799964 TT and rs1799724 CT/TT genotype showed a synergistic effect in reducing the risk of cirrhosis with rs1800896 AA (OR, 0.08; 95% CI, 0.01-1.43 and OR, 0.12; 95% CI, 0.01-2.21). Polymorphisms rs1800896 and rs2227306 are potentially associated with the risk of cirrhosis. For the first time, the study highlights that the rs2055979 AA/AC and rs1799964 CC/CT polymorphism interact with gender and its potential reversal of cirrhosis risk in males. Furthermore, rs1800896 AA showed a synergistic effect with rs1799964 TT and rs1799724 CT/TT to prevent the progression of HBV infection to cirrhosis.