3,3'-Diindolylmethane inhibits the proliferation of esophageal squamous cell carcinoma cells via downregulation of STIM1.

3,3'-Diindolylmethane (DIM) is a natural phytochemical derived from cruciferous plants that has inhibitory effects on a wide range of tumor cells; however, its relevant effects on esophageal cancer cells have been poorly studied. Therefore, in the present study, a pharmacology network approach was used to predict the possible core targets of DIM acting on esophageal cancer. Subsequently, using in vitro experiments, TE-1 human esophageal cancer cells were treated with different concentrations of DIM (0, 40, 60 and 80 µM) for 24 h. Changes in cell activity were detected by Cell Counting Kit-8 assay, and changes in the expression levels of stromal interaction molecule 1 (STIM1) and apoptosis-related proteins, B-cell lymphoma-2 (Bcl-2) and Bax, were assessed by western blotting, followed by the upregulation of STIM1 by thapsigargin (Tg). Network pharmacology analysis showed that there were 39 potential core targets of DIM in esophageal cancer. The results of the in vitro experiments showed that DIM could inhibit the viability of esophageal cancer cells, downregulate the expression of STIM1 and Bcl-2 proteins and upregulate the expression of Bax protein, all in a concentration-dependent manner. The results also demonstrated that toxic carotenoids were agonist against STIM1 protein and upregulated STIM1 and Bax protein expression. After agonizing STIM1 protein expression using Tg, DIM was able to counteract the expression trend of STIM1, Bcl-2 and Bax protein in TE-1 cells. In summary, DIM induced apoptosis and inhibited the viability of esophageal cancer cells by downregulating the expression of STIM1 protein; therefore, the natural phytochemical, DIM, may be a potential substance for the early prevention and treatment of esophageal cancer cells.

Mechanisms of QiShenYiQi in Inhibiting Blood-Brain Barrier Damage Following Stroke: A Network Pharmacology and Experimental Study.

BACKGROUND AND PURPOSE: QiShenYiQi (QSYQ) has shown promise in the treatment of blood-brain barrier (BBB) damage following stroke. However, the identification of its bioactive components and the underlying molecular mechanisms of action remain unknown. This study aimed to investigate the active ingredients and mechanisms involved in the inhibitory effects of QSYQ on BBB damage after ischemic stroke based on network pharmacology and experimental verification. MATERIALS AND METHODS: The chemical composition and target information of QSYQ were obtained from the Traditional Chinese Medicine Systems Pharmacology and Analysis Platform. BBB injury-related targets were identified by screening databases, and the overlapping targets with QSYQ were collected. Cytoscape software was utilized to construct protein-protein interaction (PPI) networks. Molecular docking analysis was conducted using AutoDock software. Animal experiments were carried out to verify the protective effect of QSYQ on BBB and explore potential molecular mechanisms. RESULTS: A total of 131 active ingredients in QSYQ and 154 common targets related to QSYQ and BBB damage were identified. Analysis of the PPI network revealed key targets including ALB, INS, ACTB, TP53, and CASP3 against BBB injury. Molecular docking analysis indicated favorable binding interactions between dihydrotanshinlactone, tanshinone IIA, salviolone, and their respective target proteins, such as FOS, INS, CASP3, and JUN. In animal experiments, QSYQ demonstrated effective inhibition of BBB damage, and this effect may be attributed to the regulation of ALB, INS, TP53, and CASP3. CONCLUSION: This study provides intriguing insights into the mechanisms by which QSYQ protects against BBB injury following ischemic stroke. Key targets, including ALB, INS, TP53, and CASP3, could be potentially involved in the beneficial effects of QSYQ.

Germacrane-type sesquiterpenes from Pilea cavaleriei Levl. subsp. cavaleriei.

The first systematic investigation of germacrane-type sesquiterpenes from Pilea cavaleriei Levl. subsp. cavaleriei was conducted. Eleven undescribed germacrane analogues named cavalinols A-K were identified. Their planar structures were determined by extensive analysis of 1D and 2D NMR spectroscopic data, and the absolute configurations were further determined by X-ray single crystal diffraction, Mosher method, and time dependent density functional theory (TDDFT) electron circular dichroism (ECD) calculation, with the aid from DFT NMR calculation and NOESY experiment. Except for the common 10-memebered ring, ten new compounds contained a p-coumaroyl sidechain connected to C-8 of the nucleus skeleton. All the isolated compounds were screened for anti-inflammatory activity in LPS stimulated RAW 264.7 cells, and compounds 5 and 6 showed moderate activity.

Development and Validation of a Prognostic Nomogram for HR+ HER- Breast Cancer.

Purpose: We aimed to develop a nomogram to predict prognosis of HR+ HER2- breast cancer patients and guide the application of postoperative adjuvant chemotherapy. Methods: We identified 310 eligible HR+ HER- breast cancer patients and randomly divided the database into a training group and a validation group. The endpoint was disease free survival (DFS). Concordance index (C-index), area under the curve (AUC) and calibration curves were used to evaluate predictive accuracy and discriminative ability of the nomogram. We also compared the predictive accuracy and discriminative ability of our nomogram with the eighth AJCC staging system using overall data. Results: According to the training group, platelet-to-lymphocyte ratio (PLR), tumor size, positive lymph nodes and Ki-67 index were used to construct the nomogram of DFS. The C-index of DFS was 0.708 (95% CI: 0.623-0.793) in the training group and 0.67 (95% CI: 0.544-0.796) in the validation group. The calibration curves revealed great consistencies in both groups. Conclusion: We have developed and validated a novel and practical nomogram that can provide individual prediction of DFS for patients with HR+ HER- breast cancer. This nomogram may help clinicians in risk consulting and guiding the application of postoperative adjuvant chemotherapy.

De novo urinary incontinence and lower urinary tract symptoms after colpocleisis: A single-center prospective study.

Background: Colpocleisis is one of traditional surgical procedures for elderly and frail women with advanced pelvic organ prolapse. The occurrence of de novo urinary incontinence following colpocleisis was considered to impair the postoperative quality of life. The incidence of de novo urinary incontinence after colpocleisis has been reported to be ranging from 6.6 % to 27 %. There was an absence of prospective large-sample study to investigate the accurate incidence of de novo urinary incontinence following colpocleisis and the impact on the quality of life till now. Purpose: s The primary objective was to report the incidence of de novo urinary incontinence after colpocleisis. The second objectives were to evaluate the long-term quality of life in patients with de novo urinary incontinence, and to conduct detailed pre- and post-operative evaluations of lower urinary tract symptoms. Methods: This prospective study included 253 patients with symptomatic pelvic organ prolapse who underwent colpocleisis between 2009 and 2021. De novo urinary incontinence was defined as the occurrence of urinary incontinence 3 months postoperatively. All patients were required to complete the Urinary Distress Inventory questionnaire and the Urinary Impact Questionnaire for the evaluation of patients' quality of life, and the Patient Global Impression of Improvement questionnaire for the evaluation of patients' satisfaction. Results: 245 patients (245/253, 96·8 %) completed the 3-month follow-up, and were included in the final analysis. The incidence of de novo urinary incontinence was 5.4 % (10/185). There was no significant difference in the Urinary Distress Inventory -6 scores (22.50 vs. 10.30, P = 0.276) or the subjective satisfaction rate (100 % vs. 98.9 %, P = 0.250) between the patients with or without de novo urinary incontinence at the long-term follow-up. The incidence of voiding difficulty was significantly reduced after colpocleisis (27.8 % vs. 0.0 %, P < 0.001). The patients' quality of life indicated by Urinary Distress Inventory-6 and Urinary Impact Questionnaire-7 scores were significantly improved postoperatively (26.27 vs. 13.39, and 19.13 vs. 6.05, P < 0.05). Conclusion: The incidence of de novo urinary incontinence after colpocleisis was very low. Patients' quality of life, and low urinary tract symptoms were significantly improved after colpocleisis.

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

GLP-2 ameliorates D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a signaling pathway in C2C12 cells and mice.

BACKGROUND: The study aimed to investigate the effect of Glucagon-like peptide-2 (GLP-2) on muscle aging in vivo and in vitro. METHODS: Six-week-old C57BL/6J mice were administered with D-galactose (200 mg/kg/day, intraperitoneally) for 8weeks, followed by daily subcutaneous injections of GLP-2 (300 or 600 µg/kg/day) for 4weeks. Skeletal muscle function and mass were evaluated using relative grip strength and muscle weight. The sizes and types of muscle fibers and apoptosis were assessed through histological analysis, immunofluorescence staining, and TUNEL staining, respectively. C2C12 myotubes were treated with D-galactose (40 mg/mL) and GLP-2. Protein expression of differentiation-related myogenic differentiation factor D (MyoD), myogenin (MyoG), and myosin heavy chain (Myhc), degradation-related Muscle RING finger 1 (MuRF-1), and muscle atrophy F-box (MAFbx)/Atrogin-1, and apoptosis-related B-cell leukemia/lymphoma 2 (Bcl-2) and Bax, were assessed using western blots. The Pi3k inhibitor LY294002 was applied to investigate whether GLP-2 regulated myogenesis and myotube aging via IGF-1/Pi3k/Akt/FoxO3a signaling pathway. RESULTS: The results demonstrated that GLP-2 significantly reversed the decline in muscles weight, relative grip strength, diameter, and cross-sectional area of muscle fibers induced by D-galactose in mice. Apart from suppressing the expressions of MuRF-1 and Atrogin-1 in the muscles and C2C12 myotubes, GLP-2 significantly increased the expressions of MyoD, MyoG, and Myhc compared to the D-galactose. GLP-2 significantly suppressed cell apoptosis. Western blot analysis indicated that the regulation of GLP-2 may be attributed to the activation of theIGF-1/Pi3k/Akt/FoxO3a phosphorylation pathway. CONCLUSIONS: This study suggested that GLP-2 ameliorated D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a pathway.

The Immunomodulatory effect of exosomes in diabetes: a novel and attractive therapeutic tool in diabetes therapy.

Exosomes carry proteins, metabolites, nucleic acids and lipids from their parent cell of origin. They are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Therefore, exosomes are often modified in reaction to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic perturbations such as obesity and diabetes, all of which involve a significant inflammatory aspect. Here, we discuss how immune cell-derived exosomes origin from neutrophils, T lymphocytes, macrophages impact on the immune reprogramming of diabetes and the associated complications. Besides, exosomes derived from stem cells and their immunomodulatory properties and anti-inflammation effect in diabetes are also reviewed. Moreover, As an important addition to previous reviews, we describes promising directions involving engineered exosomes as well as current challenges of clinical applications in diabetic therapy. Further research on exosomes will explore their potential in translational medicine and provide new avenues for the development of effective clinical diagnostics and therapeutic strategies for immunoregulation of diabetes.

Gel Properties and Protein Structures of Minced Pork Prepared with κ-Carrageenan and Non-Meat Proteins.

Problems with minced pork include water release and low gel strength. This study aimed to investigate the effect of treatments with κ-carrageenan (κ-CAR), egg white powder (EWP), wheat gluten (WG), soy isolate protein (SPI), and a combination of these treatments on the gel properties and protein structures of minced pork. The cooking loss and trapped water within minced pork increased when additives were incorporated; in particular, the SPI group reached 1.31 ± 0.01% and 91.42 ± 0.20%. The hardness and chewiness of minced pork reached their maximum values (38.91 ± 0.80 N, 14.73 ± 0.41 N) when the WG was added. The κ-CAR/WG-minced pork gel network structure was the densest and most stable, characterized by increased hydrophobic interactions, disulfide bonds in the mince gel, and enthalpy value. The α-helix content with κ-CAR/WG treatment decreased from 27% to 7.8%, transforming into other secondary structures. This suggests that the addition of κ-CAR/WG can be a more effective combination for improving the quality of minced pork.

Photo/Mechanical/Acidic Multi-Stimuli Responses and Information Encryption Design of Acylhydrazone Derivative.

Stimuli-responsive crystalline materials have received much attention for being potential candidates of smart materials. However, the occurrence of polymorphism-driven stimuli responses in crystalline materials remains interesting but rare. Herein, three polymorphs of an acylhydrazone derivative, N'-[(E)-(1-benzofuran-2-yl) methylidene] pyridine -4-carbohydrazide (BFMP) were prepared. Form-1 undergoes a photomechanical response via E→Z photoisomerization under UV irradiation, accompanied by a decrease in fluorescence intensity and a change from colorless to yellow. Two types of Z→E thermal isomerization mechanisms with significant differences in conversion rate were observed at different temperatures in form-1. The solid-melt-solid transition has a faster conversion rate compared to the solid-solid transition due to freedom from lattice confinement. The transition from form-2 to form-3 can be achieved under grinding, coupled with a significant decrease in fluorescence intensity. The similar molecular stacking pattern of form-2 and form-3 provides a structural basis for the grinding-induced crystalline transition behavior. In addition, the presence of the pyridine moiety imparts an acidochromic property. The combination of photochromism and acidochromism explores the possible applications of acylhydrazone derivatives in information encryption.

Causal associations of male infertility with stroke: a two-sample Mendelian randomization study.

Background: Stroke is a devastating global health issue, with high mortality and disability rates. The increasing prevalence of male infertility among reproductive-aged men has become a growing concern worldwide. However, the relationship between male infertility and stroke incidence remains uncertain. This study aimed to address this knowledge gap by employing a Mendelian randomization (MR) approach. Method: Utilizing genetic instrumental variables derived from a genome-wide association study (GWAS) on male infertility and stroke, a two-sample MR design was implemented. Five different analysis methods, with inverse-variance weighted as the primary approach, were used to examine the genetic causal associations between male infertility and various stroke subtypes. Heterogeneity analysis, pleiotropy tests, and leave-one-out validation were conducted to assess heterogeneity, evaluate pleiotropy, and ensure the robustness of the findings. Result: The results indicate a potential lower risk of small vessel stroke associated with male infertility (odds ratio, 95% confidence interval: 0.82, 0.68 to 0.99, p=0.044), although no significant impact on other stroke subtypes was observed. The study exhibited low heterogeneity and no apparent pleiotropy; however, the stability of the results was not optimal. Conclusion: Male infertility might potentially confer a protective effect against small vessel stroke risk. Caution is warranted due to potential confounding factors. Additional studies are necessary to confirm these findings and provide further validation.

Neuropilin-1-Targeted Nanomedicine for Spatiotemporal Tumor Suppression through Photodynamic Vascular Damage and Antiangiogenesis.

Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG8-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) in situ for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.

Association of coffee intake with bone mineral density: a Mendelian randomization study.

Background: In observational studies, the relationship between coffee intake and bone mineral density (BMD) is contradictory. However, residual confounding tends to bias the results of these studies. Therefore, we used a two-sample Mendelian randomization (MR) approach to further investigate the potential causal relationship between the two. Methods: Genetic instrumental variables (IVs) associated with coffee intake were derived from genome-wide association studies (GWAS) of the Food Frequency Questionnaire (FFQ) in 428,860 British individuals and matched using phenotypes in PhenoScanner. Summarized data on BMD were obtained from 537,750 participants, including total body BMD (TB-BMD), TB-BMD in five age brackets ≥60, 45-60, 30-45, 15-30, and 0-15 years, and BMD in four body sites: the lumbar spine, the femoral neck, the heel, and the ultradistal forearm. We used inverse variance weighting (IVW) methods as the primary analytical method for causal inference. In addition, several sensitivity analyses (MR-Egger, Weighted median, MR-PRESSO, Cochran's Q test, and Leave-one-out test) were used to test the robustness of the results. Results: After Bonferroni correction, Coffee intake has a potential positive correlation with total body BMD (effect estimate [Beta]: 0.198, 95% confidence interval [Cl]: 0.05-0.35, P=0.008). In subgroup analyses, coffee intake was potentially positively associated with TB-BMD (45-60, 30-45 years) (Beta: 0.408, 95% Cl: 0.12-0.69, P=0.005; Beta: 0.486, 95% Cl: 0.12-0.85, P=0.010). In addition, a significant positive correlation with heel BMD was also observed (Beta: 0.173, 95% Cl: 0.08-0.27, P=0.002). The results of the sensitivity analysis were generally consistent. Conclusion: The results of the present study provide genetic evidence for the idea that coffee intake is beneficial for bone density. Further studies are needed to reveal the biological mechanisms and offer solid support for clinical guidelines on osteoporosis prevention.

Remnant cholesterol and the risk of carotid plaque in hypertension: results from a community-based screening among old adults in Hangzhou, China.

Elevated remnant cholesterol (RC) is considered a risk factor for atherosclerotic cardiovascular disease, but the evidence on this association applies to the Chinese population with hypertension is limited. We aimed to explore the association between RC levels and carotid plaque in old adults with hypertension. 8523 hypertensive patients aged ≥ 60 years with serum lipids and carotid ultrasonography data were included in this community-based screening. Fasting RC was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDLC). The associations of RC levels with carotid plaque risk were evaluated using Logistic regression and restricted cubic spline models. Carotid plaque was screened in 4821 (56.56%) subjects. After multivariable-adjusted, RC was significantly related to carotid plaque [Odd ratio (OR)] = 1.043 per 0.1 mmol/L increase, 95% confidence interval (CI): 1.030-1.056). The highest versus the lowest quartile of RC was 1.928 (1.673-2.223) for carotid plaque. A nonlinear association was found between serum RC levels and the risk of carotid plaque (P for nonlinearity < 0.001). Moreover, an RC > 0.78 mmol/L differentiated patients at a higher risk of carotid plaque compared to those at lower concentrations, regardless of whether LDLC was on target at 2.59 mmol/L. In old adults with hypertension, elevated RC was positively associated with carotid plaque, independent of LDLC and other conventional risk factors.

The combination of allantoin, bisabolol, D-panthenol and dipotassium glycyrrhizinate mitigates UVB-induced PGE2 synthesis by keratinocytes.

OBJECTIVE: Erythema, characterized by the redness of the skin, is a common skin reaction triggered by various endogenous and exogenous factors. This response is often a result of the activation of underlying inflammatory mechanisms within the skin. The objective of this study is to investigate the potential benefits of applying a combination of skincare ingredients, namely allantoin, bisabolol, D-panthenol and dipotassium glycyrrhizinate (AB5D), in the modulation of inflammatory factors associated with erythema. Additionally, the study aims to elucidate the mechanisms by which these ingredients exert their combined actions to alleviate erythema-associated inflammation. METHODS: Human epidermal keratinocytes were exposed to UVB and subsequently treated with AB5D. Transcriptomics profiling was performed to analyse the dose-response effect of AB5D treatment on keratinocytes. The quantitation of inflammatory mediators, including PGE2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα, was performed on cultured media. Additionally, the oxygen radical absorbance capacity (ORAC) assay was carried out to evaluate the total antioxidant capacity of both individual ingredients and the AB5D combination. To assess the in-vitro antioxidant effects of AB5D against UVB-induced oxidative stress in hTERT keratinocytes, real-time quantitation of mitochondrial superoxide was measured through live-cell imaging. RESULTS: The application of AB5D to UVB-exposed keratinocytes downregulated gene sets associated with inflammatory responses, highlighting the anti-inflammatory properties of AB5D. Specifically, AB5D effectively reduced the production of PGE2 , leading to the downregulation of inflammatory cytokines. Moreover, our findings indicate that AB5D exhibits antioxidative capabilities, functioning as both an antioxidant agent and a regulator of antioxidant enzyme expression to counteract the detrimental effects of cellular oxidative stress. CONCLUSION: We demonstrated that AB5D can reduce UVB-induced PGE2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα as well as mitochondrial superoxide. These findings suggest that AB5D may alleviate erythema by modulating inflammation via PGE2 and through antioxidation mechanisms.

L'érythème, caractérisé par une rougeur sur la peau, est une réaction cutanée fréquente déclenchée par divers facteurs endogènes et exogènes. Il s'agit d'une réponse qui résulte souvent de l'activation des mécanismes inflammatoires sous-jacents dans la peau. OBJECTIF: cette étude vise à étudier les bénéfices potentiels de l'application d'une association d'ingrédients de soins cutanés, à savoir l'allantoïne, le bisabolol, le D-panthénol et le glycyrrhizinate dipotassique (AB5D) dans la modulation des facteurs inflammatoires associés à l'érythème. En outre, l'étude vise à élucider les mécanismes par lesquels ces ingrédients exercent leurs actions combinées pour soulager l'inflammation associée à l'érythème. MÉTHODES: les kératinocytes épidermiques humains ont été exposés aux UVB et traités par la suite par AB5D. Un profilage transcriptomique a été effectué pour analyser l'effet dose-réponse du traitement par AB5D sur les kératinocytes. La quantification des médiateurs inflammatoires, y compris PGE2, IL-1α, IL-6, IL-8, IL-1RA et TNFα, a été effectuée sur des milieux de culture. En outre, le dosage de la capacité d'absorption des radicaux oxygénés (Oxygen Radical Absorbance Capacity, ORAC) a été effectué pour évaluer la capacité antioxydante totale des deux ingrédients individuels et de l'association AB5D. Pour évaluer les effets antioxydants in vitro de l'AB5D contre le stress oxydatif induit par les UVB dans les kératinocytes hTERT, on a mesuré la quantification en temps réel du superoxyde mitochondrial par des tests d'imagerie des cellules vivantes. RÉSULTATS: l'application de l'AB5D aux ensembles de gènes régulés à la baisse exposés aux kératinocytes UVB associés à des réponses inflammatoires, a mis en évidence les propriétés anti-inflammatoires de l'AB5D. Plus précisément, l'AB5D a efficacement réduit la production de PGE2, entraînant une régulation négative des cytokines inflammatoires. En outre, nos résultats indiquent que l'AB5D présente des capacités antioxydantes. Il fonctionne à la fois comme un agent antioxydant et comme un régulateur de l'expression enzymatique antioxydante pour contrer les effets néfastes du stress oxydatif cellulaire. CONCLUSION: nous avons montré que l'AB5D pouvait réduire la PGE2 induite par les UVB, l'IL-1α, l'IL-6, IL-8, IL-1RA et le TNFα, ainsi que le superoxyde mitochondrial. Ces résultats suggèrent que l'AB5D pourrait soulager l'érythème en modulant l'inflammation via la PGE2 et via des mécanismes d'antioxydation.

Dopamine D2 receptor antagonist modulates rTMS-induced pain experiences and corticospinal excitability dependent on stimulation targets / El antagonista del receptor de dopamina D2 modula las experiencias de dolor inducidas por rTMS y la excitabilidad corticoespinal dependiendo de los objetivos de estimulación

Both the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) rTMS have the potential to reduce certain chronic pain conditions. However, the analgesic mechanisms remain unclear, in which M1- and DLPFC-rTMS may have different impact on the release of dopamine receptor D2 neurotransmissions (DRD2). Using a double-blind, randomised, sham- and placebo-controlled design, this study investigated the influence of DRD2 antagonist on rTMS-induced analgesia and corticospinal excitability across the M1 and DLPFC. Healthy participants in each group (M1, DLPFC, or Sham) received an oral dose of chlorpromazine or placebo before the delivery of rTMS in two separate sessions. Heat pain and cortical excitability were assessed before drug administration and after rTMS intervention. DRD2 antagonist selectively abolished the increased heat pain threshold induced by DLPFC stimulation and increased pain unpleasantness. The absence of analgesic effects in DLPFC stimulation was not accompanied by plastic changes in the corticospinal pathway. In contrast, DRD2 antagonist increased corticospinal excitability and rebalanced excitation-inhibition relationship following motor cortex stimulation, although there were no clear changes in pain experiences. These novel findings together highlight the influence of dopaminergic neurotransmission on rTMS-induced analgesia and corticospinal excitability dependent on stimulation targets.(AU)

Efficacy of natural products on premature ovarian failure: a systematic review and meta-analysis of preclinical studies.

OBJECTIVE: This study aims to investigate the effects of natural products on animal models of premature ovarian failure (POF). METHODS: We conducted comprehensive literature searches and identified relevant studies that examined the protective effects of natural products on experimental POF. We extracted quantitative data on various aspects such as follicular development, ovarian function, physical indicators, oxidative stress markers, inflammatory factors, and protein changes. The data was analyzed using random-effects meta-analyses, calculating pooled standardized mean differences and 95% confidence intervals. Heterogeneity was assessed using the I2 statistic, and bias was estimated using the SYRCLE tool. RESULTS: Among the 879 reviewed records, 25 articles met our inclusion criteria. These findings demonstrate that treatment with different phytochemicals and marine natural products (flavonoids, phenols, peptides, and alkaloids, etc.) significantly improved various aspects of ovarian function compared to control groups. The treatment led to an increase in follicle count at different stages, elevated levels of key hormones, and a decrease in atretic follicles and hormone levels associated with POF. This therapy also reduced oxidative stress (specifically polyphenols, resveratrol) and apoptotic cell death (particularly flavonoids, chrysin) in ovarian granulosa cells, although it showed no significant impact on inflammatory responses. The certainty of evidence supporting these findings ranged from low to moderate. CONCLUSIONS: Phytochemicals and marine natural product therapy (explicitly flavonoids, phenols, peptides, and alkaloids) has shown potential in enhancing folliculogenesis and improving ovarian function in animal models of POF. These findings provide promising strategies to protect ovarian reserve and reproductive health. Targeting oxidative stress and apoptosis pathways may be the underlying mechanism.

Sensory manipulation as a countermeasure to robot teleoperation delays: system and evidence.

In the realm of robotics and automation, robot teleoperation, which facilitates human-machine interaction in distant or hazardous settings, has surged in significance. A persistent issue in this domain is the delays between command issuance and action execution, causing negative repercussions on operator situational awareness, performance, and cognitive load. These delays, particularly in long-distance operations, are difficult to mitigate even with the most advanced computing advancements. Current solutions mainly revolve around machine-based adjustments to combat these delays. However, a notable lacuna remains in harnessing human perceptions for an enhanced subjective teleoperation experience. This paper introduces a novel approach of sensory manipulation for induced human adaptation in delayed teleoperation. Drawing from motor learning and rehabilitation principles, it is posited that strategic sensory manipulation, via altered sensory stimuli, can mitigate the subjective feeling of these delays. The focus is not on introducing new skills or adapting to novel conditions; rather, it leverages prior motor coordination experience in the context of delays. The objective is to reduce the need for extensive training or sophisticated automation designs. A human-centered experiment involving 41 participants was conducted to examine the effects of modified haptic cues in teleoperations with delays. These cues were generated from high-fidelity physics engines using parameters from robot-end sensors or physics engine simulations. The results underscored several benefits, notably the considerable reduction in task time and enhanced user perceptions about visual delays. Real-time haptic feedback, or the anchoring method, emerged as a significant contributor to these benefits, showcasing reduced cognitive load, bolstered self-confidence, and minimized frustration. Beyond the prevalent methods of automation design and training, this research underscores induced human adaptation as a pivotal avenue in robot teleoperation. It seeks to enhance teleoperation efficacy through rapid human adaptation, offering insights beyond just optimizing robotic systems for delay compensations.

An ultra-soft conductive elastomer for multifunctional tactile sensors with high range and sensitivity.

Flexible tactile sensors have become important as essential tools for facilitating human and object interactions. However, the materials utilized for the electrodes of capacitive tactile sensors often cannot simultaneously exhibit high conductivity, low modulus, and strong adhesiveness. This limitation restricts their application on flexible interfaces and results in device failure due to mechanical mismatch. Herein, we report an ultra-low modulus, highly conductive, and adhesive elastomer and utilize it to fabricate a microstructure-coupled multifunctional flexible tactile sensor. We prepare a supramolecular conductive composite film (SCCF) as the electrode of the tactile sensor using a supramolecular deep eutectic solvent, polyvinyl alcohol (PVA) solution, poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS), and MXene suspension. We employ a polyvinylidene fluoride-hexafluoropropylene (PVDF-HFP) film containing 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMIM:TFSI) as the dielectric layer to fabricate capacitive sensors with an electrical double layer structure. Furthermore, we enhance the performance of the device by incorporating coupled pyramid and dome microstructures, which endow the sensor with multi-directional force detection. Our SCCF exhibits extremely high conductivity (reaching 710 S cm-1), ultra-low modulus (0.8 MPa), and excellent interface adhesion strength (>120 J m-2). Additionally, due to the outstanding conductivity and unique structure of the SCCF, it possesses remarkable electromagnetic shielding ability (>50 dB). Moreover, our device demonstrates a high sensitivity of up to 1756 kPa-1 and a wide working range reaching 400 kPa, combining these attributes with the requirements of an ultra-soft human-machine interface to ensure optimal contact between the sensor and interface materials. This innovative and flexible tactile sensor holds great promise and potential for addressing various and complex demands of human-machine interaction.

Poly(Glutamic Acid-Lysine) Hydrogels with Alternating Sequence Resist the Foreign Body Response in Rodents and Non-Human Primates.

The foreign body response (FBR) to implanted biomaterials and biomedical devices can severely impede their functionality and even lead to failure. The discovery of effective anti-FBR materials remains a formidable challenge. Inspire by the enrichment of glutamic acid (E) and lysine (K) residues on human protein surfaces, a class of zwitterionic polypeptide (ZIP) hydrogels with alternating E and K sequences to mitigate the FBR is prepared. When subcutaneously implanted, the ZIP hydrogels caused minimal inflammation after 2 weeks and no obvious collagen capsulation after 6 months in mice. Importantly, these hydrogels effectively resisted the FBR in non-human primate models for at least 2 months. In addition, the enzymatic degradability of the gel can be controlled by adjusting the crosslinking degree or the optical isomerism of amino acid monomers. The long-term FBR resistance and controlled degradability of ZIP hydrogels open up new possibilities for a broad range of biomedical applications.