Dose-response Analysis Research Articles

Histological and clinical dose-response analysis of radiofrequency microneedling treatment for skin rejuvenation

Radiofrequency microneedling (RFMN) is a commonly used fractional device to treat skin laxity and rhytids. Several studies investigated its histological and clinical effects. However, the role of the applied energy per needle (EPN) and total energy in the outcome remains unclear. The aim of the present study is to analyze the correlation between applied energy and resulting histological and clinical volume effects of RFMN treatment for skin rejuvenation. Ex vivo porcine skin was treated with a RFMN system equipped with insulated needles. Histological measurements of coagulation volumes were correlated with the delivered EPN, ranging from 20 mJ to 100 mJ. For the clinical investigation, a cohort of patients received treatment on the lower face and submental area. Absolute volume changes were calculated using computer-aided three-dimensional analysis. Pearson’s and Spearman’s correlation coefficients r were determined. Histologic analysis revealed a strong positive correlation between EPN and coagulation volume (r = 0.976; p < 0.005). A total of 30 patients, with a mean age of 55.9 ± 8.7 years, were recruited and received 1.7 ± 0.8 sessions (1–3) with a total energy of 1518.2 ± 784.1 J. Three-dimensional imaging revealed a strong logistic correlation with the total energy applied across all sessions (r = 0.676; p < 0.001). Analysis showed a positive association between the number of sessions and volume change. Study findings indicate a very strong and strong correlation between the applied energy and the resulting histological and clinical outcome in RFMN treatment, respectively. The introduction of coagulation volume as a matrix in RFMN treatments enables medical doctors to tailor and adjust treatment plan to the individual patient.

Assessment of six insulin resistance surrogate indexes for predicting stroke incidence in Chinese middle-aged and elderly populations with abnormal glucose metabolism: a nationwide prospective cohort study

BackgroundEstimate glucose disposal rate (eGDR), Chinese visceral adiposity index (CVAI), triglyceride-glucose (TyG), TyG-body mass index (TyG-BMI), metabolic score for insulin resistance (METS-IR), and atherogenic index of plasma (AIP) are considered surrogate indexes of insulin resistance (IR). There is a lack of studies comparing the predictive values of different IR surrogate indexes for stroke risk among individuals with abnormal glucose metabolism. This study aimed to investigate the relationships between six IR surrogate indexes and stroke risk in individuals with abnormal glucose metabolism, evaluate their predictive abilities for stroke risk.MethodsData from the China Health and Retirement Longitudinal Study (CHARLS) were analysed in this study. Multivariate logistic regression models were applied to analyse the relationships of IR surrogate indexes with stroke risk. The dose-response relationships between IR surrogate indexes and stroke risk were explored using restricted cubic splines. The areas under the curve (AUCs) of IR surrogate indexes were calculated by receiver operating characteristic (ROC) analysis.ResultsAfter adjusting for potential confounders, we observed that each standard deviation (SD) increase in eGDR was associated with a reduced risk of stroke, with an adjusted odds ratio (OR) of 0.746 [95% confidence interval (CI): 0.661–0.842]. In contrast, each SD increase in CVAI, TyG, TyG-BMI, METS-IR, and AIP were associated with an increased risk of stroke, with adjusted ORs (95% CIs) of 1.232 (1.106–1.373), 1.246 (1.050–1.479), 1.186 (1.022–1.376), 1.222 (1.069–1.396), and 1.193 (1.050–1.355), respectively. Dose-response analyses showed that eGDR, CVAI, TyG-BMI and METS-IR were linearly associated with stroke risk (Pnonlinear ≥ 0.05), whereas TyG and AIP were nonlinearly associated with stroke risk (Pnonlinear < 0.05). According to ROC analysis, The AUC of eGDR for predicting stroke risk in the overall population with abnormal glucose metabolism (AUC: 0.612, 95% CI: 0.584–0.640) was significantly higher than that of other indexes.ConclusionThe six IR surrogate indexes were closely associated with high risk of stroke in individuals with abnormal glucose metabolism. The eGDR showed promising potential in predicting stroke risk in Chinese middle-aged and elderly populations with abnormal glucose metabolism.

Sex-specific associations between estimated glucose disposal rate and cognitive decline in middle-aged and older adults in China: a longitudinal cohort study

BackgroundInsulin resistance (IR) is recognized as a potential modifiable risk factor for cognitive decline, but findings within Asian populations have been inconsistent. Given the high prevalence of dementia and its substantial economic burden in China, large-scale longitudinal studies are essential to elucidate the complex relationship between IR and cognitive function.MethodsThis longitudinal cohort study included 8,734 middle-aged and older adults (median age: 58 years; 53.6% females) from the China Health and Retirement Longitudinal Study (CHARLS), followed from 2011 to 2018. Estimated glucose disposal rate (eGDR) was used to assess IR and was calculated using waist circumference, hypertension status, and HbA1c levels. Participants were categorized into tertiles based on eGDR levels (Tertile 1: lowest; Tertile 3: highest). Cognitive function was calculated as the sum of episodic memory and executive function scores, which was then standardized to a Z-score. Linear mixed-effects models and dose-response analyses were performed to evaluate the association between baseline eGDR and cognitive changes in the total population and stratified by sex.ResultsHigher eGDR levels were significantly associated with slower global cognitive decline (Tertile 3 vs. Tertile 1: β = 0.007; 95% CI: 0.000–0.014; P = 0.047). This association was stronger in females (Tertile 3 vs. Tertile 1: β = 0.011; 95% CI: 0.002–0.021; P = 0.021), while no significant association was observed in males. Dose-response analyses indicated a linear positive relationship between baseline eGDR and global cognitive function in the total population and in females, but not in males. Similar patterns were found for episodic memory and executive function, with significant associations predominantly in females.ConclusionHigher eGDR was significantly associated with slower cognitive decline, particularly among women. These findings underscore the potential of eGDR as a marker for identifying and mitigating cognitive decline and highlight the importance of sex-specific strategies to address insulin resistance and promote cognitive health.

A cohort study on the risk of diabetic retinopathy in type 2 diabetes patients with serum TG/HDL-C ratio.

Diabetic retinopathy (DR) is a leading cause of vision impairment in type 2 diabetes. This study aims to clarify the association between baseline triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and DR risk in type 2 diabetes patients to aid in prevention and treatment strategies. This retrospective cohort study included 1049 patients with type 2 diabetes who met the inclusion criteria and underwent health examinations at our hospital from January 2017 to December 2023. All patients completed seven follow-up visits within seven years. Baseline data from 2017 were utilized for the analysis. The Kaplan-Meier method and the Cox proportional hazards regression model and restricted cubic spline (RCS) method were employed to analyze the association between baseline serum TG/HDL-C ratio and the risk of DR. A total of 1049 patients were included in the cohort, with a median follow-up period of seven years. During the follow-up period, 124 new cases of DR were identified, with an incidence rate of 11.8 %. The incidence of DR showed an upward trend with increasing baseline TG/HDL-C ratio. After adjusting for various potential confounding factors in the Cox proportional hazards regression model, high TG/HDL-C ratio levels were identified as a risk factor for DR (HR=3.04, 95 % CI 1.55-5.98, P = 0.0029).In the dose-response relationship analysis, a significant nonlinear relationship was observed between the TG/HDL-C ratio and the risk of diabetic retinopathy (DR) (nonlinear P value = 0.029). The risk of DR significantly increased when the TG/HDL-C ratio reached 3.3 (HR = 1.56, 95 % CI: 1.17-2.10, P = 0.003) and then leveled off. High TG/HDL-C ratio is closely associated with the occurrence of DR and has a certain predictive value for the onset of DR. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to confidentiality agreements with the funding organization.

The effect of tart cherry juice (TCJ) supplementation on exercise-induced muscle damage (EIMD) in an athletic population

Introduction: This systematic review and meta-analysis quantified the effect of tart cherry juice (TCJ) supplementation on exercise-induced muscle damage (EIMD). Evidence supported TCJ’s beneficial effects on muscular function and inflammatory biomarkers interleukin (IL)-6 and IL-8. Method: PubMed, Scopus, and Web of Science were searched up to January 2024. Risk of bias was assessed using RevMan® software. Mean differences and 95% confidence intervals (CIs) of maximal voluntary isometric contraction (MVIC), inflammatory markers, creatine kinase (CK), and visual analog scale (VAS) score were pooled using fixed- or random-effect models. Heterogeneity was assessed using Chi-square or I 2 statistics. Results: Ten trials were included in the analysis. TCJ supplementation significantly improved MVIC [weighted mean difference (WMD) = 9.13%, 95% CI (6.42–11.84), I 2 = 62.3%] and decreased IL-6 [WMD = −0.4 pg/ml, 95% CI (−0.68 to −0.11), I 2 = 62.2%] and IL-8 [WMD = −0.3 pg/ml, 95% CI (−0.6 to −0.0), I 2 = 46.3%]. No significant changes were found in CK, C-reactive protein, IL-1β, tumor necrosis factor-alpha, or VAS score. Dose–response analysis revealed a significant non-linear association between daily TCJ dose and MVIC effect size. Conclusion: TCJ supplementation may improve muscle function and some inflammatory biomarkers in EIMD. Further high-quality studies with larger sample sizes are needed to determine TCJ’s long-term effects.

Lipid Levels and Lung Cancer Risk: Findings from the Taiwan National Data Systems from 2012 to 2018

BackgroundLipids are known to be involved in carcinogenesis, but the associations between lipid profiles and different lung cancer histological classifications remain unknown.MethodsIndividuals who participated in national adult health surveillance from 2012 to 2018 were included. For patients who developed lung cancer during follow-up, a 1:2 control group of nonlung cancer participants was selected after matching. Multivariate conditional logistic regression was used to explore the associations between lipid profiles, different lung cancer histological classifications and epidermal growth factor receptor mutation statuses. Subgroup, sensitivity, and dose‒response analyses were also performed.ResultsA total of 4,704,853 participants (30,337 lung cancer participants and 4,674,516 nonlung cancer participants) were included. In both the main and sensitivity analyses, the associations remained constant between lower high-density lipoprotein (HDL) cholesterol levels and a higher risk of lung cancer (main analysis: odds ratio: 1.13 [1.08–1.18]) and squamous cell carcinoma (1.29 [1.16–1.43]). Hypertriglyceridemia was associated with a lower risk of adenocarcinoma (0.90 [0.84–0.96]) and a higher risk of small cell lung cancer (1.31 [1.11–1.55]). Hypercholesterolemia was associated with a lower risk of squamous cell carcinoma (0.84 [0.76–0.94]). In the subgroup analysis, lower HDL cholesterol levels were associated with greater risk across most subgroups. HDL cholesterol levels also demonstrated a dose‒response association with the development of lung cancer.ConclusionsThe distinct associations between specific lipid profiles and lung cancer subtypes suggest that lipid metabolism may play different mechanistic roles in lung cancer development.

Antiviral effects and mechanism of Qi pi pill against influenza viruses.

Qi pi pill (QPP), which contains Renshen, Baizhu, Fuling, Gancao, Chenpi, Shanyao, Lianzi, Shanzha, Liushenqu, Maiya, and Zexie, was recommended for preventing and treating COVID-19 in Shandong Province (China). However, the mechanism by which QPP treats infectious diseases remains unclear. This study aims to investigate the therapeutic effect of QPP invitro and on acute influenza infection in mice, exploring its mechanism of action against influenza A virus (IAV). The invitro activity of QPP was assessed using dose-response curve analysis and titer reduction assay, and its antiviral mechanism was identified invitro by real-time polymerase chain reaction (PCR), time-of-addition, and enzymatic assays. The antiviral efficacy of QPP was further evaluated invivo using BALB/c mice infected with IAV. At the same time, each single Chinese herbal medicine in QPP was evaluated to preliminarily identify those with antiviral effects. In vitro results showed that QPP exhibited a higher potency antiviral effect against both influenza A and B viruses, inhibiting viral RNA replication and release by targeting RNA-dependent RNA polymerase and neuraminidase. Additionally, QPP significantly decreased the expression of inflammatory cytokines in A549 cells. Invivo study revealed that QPP significantly reduced the lung index and viral load in lung tissue of mice infected with IAV. Renshen, Gancao, Zexie, and Lianzi were the Chinese herbal medicines from QPP that showed anti-IAV activity. The antiviral activity of QPP targets IAV replication and release, cytokine modulation in host cells, and provides protection in mice with acute influenza infection.

Dose-response analysis of music intervention for improving delirium in intensive care unit patients: A systematic review and meta-analysis.

Delirium is a common and severe condition among adult intensive care unit (ICU) patients. Music intervention, as a non-pharmacological approach, has the potential to reduce delirium, but the optimal dosage and type of intervention remain unclear. To explore the effects of music intervention at different doses and types on reducing delirium in ICU patients. This study was conducted as a systematic review and meta-analysis. Databases including Cochrane Library, EBSCO, Embase, PubMed, Web of Science, Airiti Library, China National Knowledge Infrastructure and Wanfang Data were searched until 29 February 2024. Study quality was assessed using the Cochrane Risk of Bias 2.0 criteria. Data were analysed using RevMan 5.4.1 and Comprehensive Meta-Analysis 3.0. Fourteen studies involving 1434 ICU patients were included. Four studies were of good quality (low risk of bias), seven were of moderate quality (unclear risk) and three were of low quality (high risk). Pooled analysis showed that music interventions significantly reduced the risk of delirium (12 studies, RR = .49, 95% confidence interval [CI] [.40, .61]). Slow-tempo music had the strongest effect (11 studies, RR = .46, 95% CI [.37, .57]). The optimal intervention dosage involves conducting music interventions twice daily (12 studies, RR = .46, 95% CI [.34, .63]), with each session lasting 30 min (12 studies, RR = .41, 95% CI [.30, .55]). Additionally, a pooled analysis showed that a 7-day music intervention (6 studies, RR = .43, 95% CI [.26, .71]) was the most effective in reducing the risk of delirium. Music intervention reduces delirium in ICU patients, especially with two 30-min sessions daily for 7 days. However, the certainty of evidence is low, highlighting the need for further high-quality research. Music intervention is a simple, non-invasive method that may help reduce delirium in ICU patients. However, given the low certainty of the current evidence, it should be used cautiously, and further research is needed to validate its effectiveness before routine implementation.

It's about time: moving away from statistical analysis of ecotoxicity data.

Environmental risk assessment of chemicals (ERA) relies on single-species laboratory testing to establish the toxic properties of a compound. However, ERA is not concerned with toxicity under laboratory conditions: it needs to assess the impacts of the compound in the real world. Data-driven statistical analyses (e.g., hypothesis testing and interpolation) are the common approaches for analysing toxicity data, but such approaches are the wrong tool for the job at hand. ERA does not need a statistical description of the effects in the toxicity test (at the end of the standardised test duration), it needs to extrapolate from the laboratory test to longer and time-varying exposure. Such extrapolation requires mechanistic process models, providing a simplified representation of the mechanisms underlying toxicity. Any useful model for the toxicity process should explicitly consider both dose (e.g., exposure concentration) and time. In the history of effects analysis for ERA, the factor of time does not get as much attention as the dose, hence common use of the term 'dose-response analysis'. However, this is a historical oversight: time is a crucial factor for understanding toxicity and thereby essential for meaningful extrapolation from laboratory to field. Mechanistic models for ecotoxicity, considering both dose and time, have been around for quite some time and are classified as toxicokinetic-toxicodynamic (TKTD) models. TKTD models are starting to find their way into pesticide ERA in Europe, next to the classical statistical approaches. In this opinion paper, I argue that it is about time to leave statistical analysis of toxicity data behind us. Statistics remains important for ERA's effects assessment, but its role lies in the definition of appropriate 'error models', explaining the deviations between model output and observations, which is essential for parameter estimation, uncertainty quantification, and error propagation. The 'process model', essential for extrapolation, firmly belongs to TKTD modelling.

Nonlinear Relationship Between Body Mass Index and Liver Transplant Outcomes: A Dose-Response Meta-Analysis.

Weight management was recommended to have more access to transplantation and improve transplant outcomes after liver transplantation (LT). However, the dose-response relationship between body mass index (BMI) and transplant outcomes has not been clearly defined. PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to October 20th, 2019. Dose-response meta-analyses was conducted to establish the dose-response relationship pattern. Twenty-three observational studies were eligible. In the pair-wise analysis, compared with normal BMI, HRs in underweight, overweight, obesity-I, obesity-II, and obesity-III were 2.13, 0.96, 1.06, 1.36, and 1.97 for patient death, and 3.08, 1.02, 1.25, 1.58, and 2.90, for graft loss. In the dose-response analysis, U-shaped relationships were observed between BMI and both patient and graft survival (P < .001, P < .001). Referring to 17.5kg/m2, the patient death risk decreased to 0.72 (95% CI: 0.62-0.84) in 27kg/m2 and then increased to 1.44 (95% CI:1.09-1.90) in 28.7-42kg/m2. Comparing to 17.5kg/m2, individuals in 26.7-28.0kg/m2 had the least risk of graft loss with HR of 0.62 (95% CI:0.48-0.80) and increased to 1.64 (95% CI:1.03-2.61) in 42kg/m2. Subgroup analyses by age, sex, sample size, duration of follow-up, location, publication year, and study type presented similar results. Underweight and severe obesity are associated with a significantly increased risk of graft loss and patient death after liver transplantation. Overweight, especially BMI of 26-28 kg/m2, may have extra survival benefit. Weight management before liver transplantation may be necessary.

The association between blood selenium and metabolic syndrome in adults: a systematic review and dose-response meta-analysis of epidemiologic studies.

Although the relationship between selenium and metabolic syndrome (MetS) was previously investigated, the findings were inconsistent. Therefore, we performed a systematic review and dose-response meta-analysis to summarize the association between blood selenium and MetS in adults. A comprehensive search was conducted in Medline (PubMed), ISI Web of Science, Scopus, and motor engineering of Google Scholar up to October 1st, 2024. Observational studies which reported the risk of MetS in relation to blood selenium in adults were included. The protocol of the current analysis was registered at PROSPERO as CRD42024486035. Overall, 16,779 participants and 6,471 cases with MetS from 5 cross-sectional and 7 case-control studies were included in the current systematic review and meta-analysis. The findings showed that participants with the highest blood values of selenium (mean: 268.5 μg/L) in comparison to those with the lowest values (mean: 75.27 μg/L) had 40% higher risk of MetS. Nevertheless, this association was not significant (95%CI: 0.99-1.97). Due to a significant between-study heterogeneity (I2 = 90.4%, p < 0.001), subgroup analysis was conducted based on potential confounders. However, this association was only significant in a few subgroups with low number effect sizes. Linear dose-response analysis illustrated each 50 μg/L increment in circulating selenium was related to 7% higher risk of MetS (RR: 1.07, 95%CI: 0.99, 1.15) However, this association was not statistically significant. Additionally, non-linear dose-response analysis indicated a U-shaped association between blood selenium and risk of MetS with the lowest risk at 160 ug/L of blood selenium (p < 0.001). There is a U-shaped relationship between blood selenium levels risk of MetS. However, more longitudinal studies are needed to verify the causality of findings and clarify the underlying mechanisms.

The Longitudinal Effect of Sugar-Sweetened Beverage Consumption and Risk of All-Cause and Cause-Specific Mortality in Korean Adults: Results From the Health Examinees Study

Objective High consumption of sugar-sweetened beverages (SSBs) is associated with an increased risk of all-cause and cardiovascular disease (CVD) mortality; however, the data and results for Asian populations, particularly in Korea, are limited and unclear. Therefore, this research aimed to investigate the association between types of SSB consumption and risk of all-cause and cause-specific mortality in South Korean adults. Methods This prospective study included Korean adults aged 40 to 79 who participated in the Health Examinees Study. The baseline survey was conducted from 2004 to 2013, and death data were obtained until December 2022. A food frequency questionnaire was used to assess SSB intake, and all-cause, CVD, and cancer mortality were estimated. The SSB included total SSB, soda, and other drinks (Korean traditional SSB). Results A total of 126,856 participants were included (mean [standard deviation]: age, 53.1 [8.3] years; 82,311 [64.9%] women). During a mean follow-up of 11.0 years, 5741 all-cause, 936 CVD, and 2662 cancer deaths were recorded. Increased soda consumption was associated with higher all-cause mortality (1–3 servings/wk: hazard ratio [HR], 1.125; 95% confidence interval [CI], 1.003–2.263; ≥3 servings/wk: HR, 1.190, 95% CI, 1.011–1.401), compared with low soda intake (never–<1 serving/wk). However, there was no association between total SSB consumption and other drinks with all-cause and cause-specific mortality. In the dose–response analysis, a trend in which a higher risk of all-cause and CVD cancers was observed with increasing soda intake. Conclusion In this large prospective study, soda intake of >1 serving/wk was associated with an increased risk of all-cause mortality among Korean adults. However, there was no association between total SSB or other drinks and mortality. As the consumption of SSBs increases in the Korean population, appropriate control strategies are needed to reduce SSB consumption and the disease burden.

Serum Uric Acid and Bone Health in Middle-Aged and Elderly Hypertensive Patients: A Potential U-Shaped Association and Implications for Future Fracture Risk.

The influence of serum uric acid (SUA) on bone metabolism, as suggested by previous studies, remains a contentious issue. SUA plays a complex role in bone health and hypertension, making it challenging to discern its impact on the skeletal status of middle-aged and elderly hypertensive patients. This study aims to elucidate the effects of SUA on bone health, with a particular focus on its association with osteoporosis and the risk of fractures. Multiple linear regression analyzed SUA levels against bone mineral density (BMD) and future fracture risk. Additionally, multivariate logistic regression was used to examine the association between SUA and osteoporosis. Dose-response relationship analysis was conducted using generalized smooth curve fitting (GSCF) and restricted cubic spline (RCS) methods. With the exception of the total femur region, SUA and BMD showed a positive connection. GSCF analysis revealed an inverted U-shaped relationship between SUA and BMD, alongside a U-shaped trend with FRAX scores. Moreover, RCS analysis indicated a U-shaped relationship between osteoporosis risk and SUA levels, with higher risks identified in the first and third tertiles compared to the second tertile. In individuals with middle-aged and older hypertension, SUA is substantially linked to bone health. The identification of an inverted U-shaped relationship with BMD and U-shaped relationships with FRAX scores and osteoporosis risk highlights the nuanced influence of SUA. These findings suggest that both low and high SUA levels may adversely affect bone health, emphasizing the need for further research.

Exposure to Drinking Water Trihalomethanes and Risk of Cancer: A Systematic Review of the Epidemiologic Evidence and Dose-Response Meta-Analysis.

Chlorination is a widespread method for drinking water disinfection that has the drawback of introducing potentially carcinogenic chemical by-products to drinking water. We systematically evaluated the epidemiologic evidence of exposure to trihalomethane (THM) disinfection by-products and risk of cancer. We conducted a systematic review and meta-analysis of epidemiologic studies that assessed the association of exposure to residential concentrations of THMs with risk of cancer in adults. A protocol was preregistered in PROSPERO (CRD42023435491). PubMed, Embase, Web of Science, and Cochrane were searched for publications up to April 2024. Study selection and risk of bias appraisal using the National Toxicology Program Office of Health Assessment and Translation (NTP OHAT) tool was done in duplicate. Summary risk estimates were assessed using random effects meta-analysis and one-stage dose-response meta-analysis. The literature search resulted in 2,022 records, of which 29 publications assessing 14 different cancers were eligible for inclusion. Summary relative risks (RRs) were estimated for bladder cancer and colorectal cancer based on 5,860 and 9,262 cases and 84,371 and 90,272 participants, respectively. The summary RR of bladder cancer for the highest exposed compared with the lowest was 1.33 (95% CI: 1.04, 1.71), and in the dose-response analysis, RRs were statistically significant above THM concentrations of . For colorectal cancer, the summary RR was 1.15 (95% CI: 1.07, 1.24). According to the World Cancer Research Fund criteria, we found limited-suggestive evidence that THM in drinking water increases the risk of bladder and colorectal cancer at levels below current regulatory limits in the US and EU, indicating that these fail to protect against cancer in the general population. https://doi.org/10.1289/EHP14505.

The Transcription Factor SOX18 Inhibitor Small Molecule 4 Is a Potential Treatment of Cancer-Induced Lymphatic Metastasis and Lymphangiosarcoma.

Malignant tumors release growth factors, promoting lymphangiogenesis in primary tumors and draining sentinel lymph nodes, ultimately facilitating lymph node metastasis. As a malignant lymphatic tumor entity, lymphangiosarcomas are characterized by low survival rates and limited treatment options. The transcription factor SOX18 plays a crucial role in both lymphatic endothelial cell differentiation and cancer-induced lymphangiogenesis. In this invitro study, we investigated the potential therapeutic effect of a small molecule called Sm4, which inhibits SOX18, on lymphatic endothelial and lymphangiosarcoma cells invitro. Human dermal lymphatic endothelial cells (HDLECs), lymphangiosarcoma cells (MO-LAS), and other endothelial cell lines were cultured. We found that Sox18 exhibited high mRNA expression levels in both HDLEC and MO-LAS. Sm4 treatment decreased the Sox18 expression level at the mRNA and protein levels in both HDLEC and MO-LAS significantly, a phenomenon confirmed through immunofluorescence images. Additionally, Sm4 treatment suppressed the expression of key lymphatic phenotype markers (Prox1, Flt4, and Lyve1) and hindered migration in both HDLEC and MO-LAS, all while maintaining cell viability. These findings suggest that targeting SOX18 with Sm4 may hold potential as a therapeutic strategy for lymphangiosarcoma and cancer-induced lymphatic metastasis. Further invitro studies are warranted to investigate the mechanisms and conduct dose-response analyses to evaluate Sm4's potential as a targeted therapy for lymphangiosarcoma and cancer-induced lymphangiogenesis in the future.

N-Palmitoylethanolamide enhances antinociceptive effect of tramadol in neuropathic rats.

The efficacy of opioids in the treatment of chronic pain is limited; however, the adverse effects they produce are considerable. N-palmitoylethanolamide (PEA), a bioactive lipid mediator with structural similarities to endocannabinoids, has exhibited notable anti-inflammatory and analgesic effects in preclinical models. The objective of this study was to investigate the antinociceptive properties, motor coordination (MC), and constipation effects of tramadol and PEA in combination within a neuropathic pain model. The antinociceptive effects of tramadol (TRA) and PEA in various combination ratios were assessed using a CCI model of neuropathic pain in 126 male Wistar rats, divided into 21 groups: vehicles, GBP (1.0-177.78 mg/kg), TRA (1.0-31.62 mg/kg), PEA (0.0316-10 mg/kg), or TRA (1.0-10 mg/kg) with PEA (0.0316-1.0 mg/kg), all compounds were administered orally. The results of the dose-response analyses indicated that PEA was approximately five and eightfold more potent than tramadol in producing anti-hyperalgesic and anti-allodynic effects, respectively. The results of the surface of synergistic interaction (SSI) analysis indicated that the combination of TRA 10 mg/kg + PEA 0.0316 mg/kg exhibited the most pronounced anti-hyperalgesic effects and the most favorable anti-allodynic outcomes among the various combinations. No significant differences in MC or constipation were observed between the vehicle and optimal combination group. The results of this study demonstrate that sub-antinociceptive doses of tramadol, when combined with PEA, significantly enhance the antinociceptive efficacy of tramadol without the induction of typical opioid-associated side effects. These findings propose a novel approach to the treatment of pain.

Effect of multiple counselling contacts along the continuum of care on use of postpartum family planning in a cohort of Ethiopian women: a dose-response analysis

ObjectiveDose-response analysis of the effect of each additional contact where family planning (FP) was discussed during antenatal, delivery, postnatal or immunisation visits on the uptake of postpartum family planning (PPFP)...

Micellar Choline-Acetyltransferase Complexes Exhibit Ultra-Boosted Catalytic Rate for Acetylcholine Synthesis-Mechanistic Insights for Development of Acetylcholine-Enhancing Micellar Nanotherapeutics.

Choline-acetyltransferase (ChAT) is the key cholinergic enzyme responsible for the biosynthesis of acetylcholine (ACh), a crucial signaling molecule with both canonical neurotransmitter function and auto- and paracrine signaling activity in non-neuronal cells, such as lymphocytes and astroglia. Cholinergic dysfunction is linked to both neurodegenerative and inflammatory diseases. In this study, we investigated a serendipitous observation, namely that the catalytic rate of human recombinant ChAT (rhChAT) protein greatly differed in buffered solution in the presence and absence of Triton X-100 (TX100). At a single concentration of 0.05% (v/v), TX100 boosted the specific activity of rhChAT by 4-fold. Dose-response analysis within a TX100 concentration range of 0.8% to 0.008% (accounting for 13.7 mM to 0.013 mM) resulted in an S-shaped response curve, indicative of an over 10-fold boost in the catalytic rate of rhChAT. This dramatic boost was unlikely due to a mere structural stabilization since it remained even after the addition of 1.0 mg/mL gelatin to the ChAT solution as a protein stabilizer. Furthermore, we found that the catalytic function of the ACh-degrading enzyme, AChE, was unaffected by TX100, underscoring the specificity of the effect for ChAT. Examination of the dose-response curve in relation to the critical micelle concentration (CMC) of TX100 revealed that a boost in ChAT activity occurred when the TX100 concentration passed its CMC, indicating that formation of micelle-ChAT complexes was crucial. We challenged this hypothesis by repeating the experiment on Tween 20 (TW20), another non-ionic surfactant with ~3-fold lower CMC compared to TX100 (0.06 vs. 0.2 mM). The analysis confirmed that micelle formation is crucial for ultra-boosting the activity of ChAT. In silico molecular dynamic simulation supported the notion of ChAT-micelle complex formation. We hypothesize that TX100 or TW20 micelles, by mimicking cell-membrane microenvironments, facilitate ChAT in accessing its full catalytic potential by fine-tuning its structural stabilization and/or enhancing its substrate accessibility. These insights are expected to facilitate research toward the development of new cholinergic-enhancing therapeutics through the formulation of micelle-embedded ChAT nanoparticles.

Association between birth weight and chronic obstructive pulmonary disease in the UK Biobank: a prospective cohort study

BackgroundBirth weight has been reported to be associated with chronic obstructive pulmonary disease (COPD) in adulthood, but the results have not yet been determined. This study aims to analyse the...

Boronic Acid-Containing 3H- pyrazolo[4,3-f]quinoline Compounds as Dual CLK/ROCK Inhibitors with Anticancer Properties.

Background: The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as anticancer agents. Compounds with polypharmacology are desired, especially in oncology, due to the potential for high efficacy as well as addressing resistance issues. In this report, we have identified and characterized novel, boron-containing dual CLK/ROCK inhibitors with promising anticancer properties. Methods: A library of boronic acid-based CLK/ROCKi was synthesized via Povarov/Doebner-type multicomponent reactions. Kinase inhibition screening and cancer cell viability assays were performed to identify the hit compounds. To gain insights into the probable binding modes of the compounds to the kinases, docking studies were performed. Cell cycle analysis, qPCR and immunoblotting were carried out to further characterize the mode(s) of action of the lead candidates. Results: At 25 nM, the top compounds HSD1400 and HSD1791 inhibited CLK1 and 2 and ROCK2 at greater than 70%. While HSD1400 also inhibited CLK4, the C1 methylated analog HSD1791 did not inhibit CLK4. Antitumor effects of the top compounds were evaluated and dose-response analysis indicated potent inhibition of renal cancer and leukemia cell growth. Immunoblotting results indicated that the top compounds induce DNA damage via upregulation of p-H2AX. Moreover, flow cytometry results demonstrated that the top compounds promote cell cycle arrest in the renal cancer cell line, Caki-1. qPCR and immunoblotting analysis upon HSD1791 dosing indicated suppression of cyclin D/Rb oncogenic pathway upon compound treatment. Conclusions: Novel boronic acid-containing pyrazolo[4,3-f]quinoline-based dual CLK/ROCK inhibitors were identified. The so-called "magic methylation" design approach was used to tune CLK selectivity. Additionally, the findings demonstrate potent in vitro anticancer activity of the lead candidates against renal cancer and leukemia. This adds to the growing list of boron-containing compounds that display biological activities.