U-shaped Dose-response Research Articles

Dose‒response effects of resistance exercise on ameliorating cravings and executive functions in individuals with methamphetamine use disorders

PurposeResistance exercise (RE) can acutely benefit symptoms in individuals with methamphetamine use disorder (MUD), though the optimal dose has not yet been established. We aimed to determine the dose response relationship between RE intensity and cue-elicited cravings and executive functions in individuals with MUD. MethodsA total of 128 male participants with MUD (34.73 ± 5.65) were randomly assigned to the low-intensity (30%–35%1-RM) RE group (LREG), moderate-intensity (55%–60%1-RM) RE group (MREG), high-intensity (75%–80%1-RM) RE group (HREG), or control group (CONG). Cravings based on the cue-reactivity paradigm were measured before, immediately after, and 40 min after acute RE, and inhibitory control, working memory, and cognitive flexibility were measured before and after acute RE. ResultsImmediately after and 40 min after RE, the Δcue-elicited cravings of the MREG from baseline was significantly more negative than that of the LREG and CONG. Trend analyses revealed a U-shaped dose‒response curve for RE intensity and Δcue-elicited cravings, indicating that moderate-intensity RE had the greatest ameliorating effect on cue-elicited cravings. Δinhibitory control and Δworking memory scores increased only in the MREG, and Δcognitive flexibility scores significantly increased in all RE groups. Trend analyses revealed a cubic curvilinear relationship between RE intensity and inhibitory control and a quadratic curvilinear relationship with working memory and cognitive flexibility. ConclusionRE proved effective in diminishing cue-elicited cravings and enhancing executive functions. A significant dose‒response relationship existed among RE intensity, cue-elicited cravings and executive function, and moderate-intensity RE had a more pronounced ameliorative effect on individuals with MUD.

Associations between urine glyphosate levels and metabolic health risks: insights from a large cross-sectional population-based study

BackgroundThe prevalence of metabolic syndrome (MetS) in American adults increased from 37.6% in the 2011–12 period to 41.8% in 2017–2018. Environmental exposure, particularly to common compounds such as glyphosate, has drawn increasing attention as a potential risk factor.MethodsWe employed three cycles of data (2013–2018) from the National Health and Nutrition Examination Survey (NHANES) in a cross-sectional study to examine potential associations between urine glyphosate measurements and MetS incidence. We first created a MetS score using exploratory factor analysis (EFA) of the International Diabetes Federation (IDF) criteria for MetS, with data drawn from the 2013–2018 NHANES cycles, and validated this score independently on an additional associated metric, the albumin-to-creatinine (ACR) ratio. The score was validated via a machine learning approach in predicting the ACR score via binary classification and then used in multivariable regression to test the association between quartile-categorized glyphosate exposure and the MetS score.ResultsIn adjusted multivariable regressions, regressions between quartile-categorized glyphosate exposure and MetS score showed a significant inverted U-shaped or saturating dose‒response profile, often with the largest effect for exposures in quartile 3. Exploration of potential effect modification by sex, race, and age category revealed significant differences by race and age, with older people (aged > 65 years) and non-Hispanic African American participants showing larger effect sizes for all exposure quartiles.ConclusionsWe found that urinary glyphosate concentration is significantly associated with a statistical score designed to predict MetS status and that dose–response coefficient is nonlinear, with advanced age and non-Hispanic African American, Mexican American and other Hispanic participants exhibiting greater effect sizes.

5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice.

The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2A receptor (5-HT2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear. The primary objective of this study is to investigate the modulation of 5-HT2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM. In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice. The 5-HT2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615-10mg/kg, i.p.) in C57BL/6J mice. M100907 (50µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10mg/kg) in C57BL/6J mice. The 5-HT2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1mg/kg, i.p.) reduced the HTR induced by a dose of 2.5mg/kg DOM, but did not affect the response to other doses. SB242084 (1mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615-10mg/kg, i.p.) in mice. The 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gαi/o inhibitor PTX (0.25µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice. Receptor subtypes 5-HT2C and 5-HT1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.

Potentiation of the muscarinic acetylcholine receptor 1 modulates neurophysiological features in a mouse model of Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X chromosome-linked gene Methyl-CpG Binding Protein 2 (MECP2). Restoring MeCP2 expression after disease onset in a mouse model of RTT reverses phenotypes, providing hope for development of treatments for RTT. Translatable biomarkers of improvement and treatment responses have the potential to accelerate both preclinical and clinical evaluation of targeted therapies in RTT. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials, that correlate with disease severity, suggesting that they could be useful as biomarkers of disease improvement or early treatment response. We recently demonstrated that treatment of RTT mice with a positive allosteric modulator (PAM) of muscarinic acetylcholine subtype 1 receptor (M1) improved phenotypes, suggesting that modulation of M1 activity is a potential therapy in RTT. To evaluate whether neurophysiological features could be useful biomarkers to assess the effects of M1 PAM treatment, we acutely administered the M1 PAM VU0486846 (VU846) at doses of 1, 3, 10 and 30 ​mg/kg in wildtype and RTT mice. This resulted in an inverted U-shaped dose response with maximal improvement of AEP features at 3 ​mg/kg but with no marked effect on basal EEG power or epileptiform discharges in RTT mice and no significant changes in wildtype mice. These findings suggest that M1 potentiation can improve neural circuit synchrony to auditory stimuli in RTT mice and that neurophysiological features have potential as pharmacodynamic or treatment-responsive biomarkers for preclinical and clinical evaluation of putative therapies in RTT.

Associations between static and dynamic changes of platelet counts and in-hospital mortality in critical patients with acute heart failure

To investigate the predictive value of baseline platelet count and its short-term dynamic changes in the prognosis of patients with acute heart failure (AHF) in the intensive care unit. Patients diagnosed with AHF in the medical information mart for intensive care III and their clinical data were retrospectively filtered. Patients were divided into survivor and non-survivor groups based on their prognosis during hospitalization, and differences in baseline data between groups were compared. Logistic regression models and restricted cubic spline (RCS) plots were performed to evaluate the relationship between baseline platelet counts and in-hospital mortality. Changes and trends in platelet counts were compared between the survivor and non-survivor groups after adjusting for confounders with the generalized additive mixing model (GAMM). A total of 2930 critical patients with acute heart failure were included, of which 2720 were survivors and 210 were non-survivors. Multiple logistic regression models revealed that baseline platelet count was an independent factor in hospital mortality (OR 0.997, 95% CI 0.994–0.999, P-value = 0.018). The RCS plot demonstrated a U-shaped dose–response relationship between baseline platelet count and in-hospital mortality. GAMM analysis suggested that the platelet counts decreased and then increased in the survivor group and gradually decreased in the non-survivor group, with a gradual increase of difference between two groups. After adjusting for confounders, the mean daily increase was −6.014 (95% CI −7.076–4.953, P-value < 0.001). Baseline platelet demonstrated a U-shaped dose–response relationship with adverse outcomes in critical patients with AHF. Early elevation of platelet was correlated with higher in-hospital mortality, indicating that tracking early changes in platelet might help determine the short-term prognosis of critical patients with AHF.

Gedunin induces apoptosis and inhibits HMBG1/PI3K/AKT signaling pathways in a rat model of gastric carcinogenesis induced by methylnitronitrosoguanidine.

This study aimed to evaluate the anti-cancer effects of gedunin, a natural compound, in a rat model of gastric carcinogenesis induced by MNNG. Fifty-four rats were randomly assigned to six groups for a 60-day study on the effects of MNNG and gedunin. Groups 1-4 received 200 mg/kg MNNG (1, 10, or 100 mg/kg), and group 5 had only 100 mg/kg gedunin. Gedunin at low doses exhibited anti-cancer and protective properties against MNNG-induced damage, including reduced inflammation, and apoptosis. Gedunin demonstrates a U-shaped dose-response, with low doses offering protection and high doses promoting tumor growth.

Evaluating the progression to abnormal thyrotropin in euthyroid preconception women: a population-based study

Background Abnormal preconception thyrotropin levels were associated with fecundability and adverse fetomaternal outcomes, however, little is known regarding the natural change of serum thyrotropin in euthyroid preconception women. Thus, we performed a population-based study to evaluate the progression to abnormal thyrotropin in euthyroid preconception women.Methods This retrospective cohort study used data from the National Free Prepregnancy Checkups Project (NFPCP) collected between 2010 and 2020. Female Han Chinese participants aged 20–49 years who had two repeated NFPCP participations with a time interval of 1.5–3.0 years, confirmed non-pregnant status within this duration, and normal thyrotropin levels during their first participation were included for the analysis of thyrotropin abnormalities during the second NFPCP examination. Data were analyzed between June 1 and October 1, 2023.ResultsThis study included 186,095 euthyroid women of reproductive age (mean ± SD, 26.72 ± 4.70 years) whose preconception thyrotropin levels were between 0.37 and 4.87 mIU/L. The median follow-up time was 2.13 (IQR, 1.85–2.54) years. A total of 8,497 (4.57%) women developed abnormal thyrotropin, including 4,118 (2.21%) subnormal thyrotropin and 4,379 (2.35%) supranormal thyrotropin. Compared with the reference group (thyrotropin 1.01–2.00 mIU/L), the lower baseline thyrotropin group had greater risk of developing subnormal thyrotropin, and the higher baseline thyrotropin group had greater risk of developing supranormal thyrotropin. Moreover, the restricted cubic spline analysis revealed a U-shaped dose–response association of baseline thyrotropin levels or thyrotropin multiples of the median (MOM) levels against risk of subnormal thyrotropin in the follow-up, and a J-shaped dose–response association against risk of supranormal thyrotropin levels in the follow-up. We further found that baseline thyrotropin outside of 1.43–1.93 mIU/L or baseline thyrotropin MOM outside 0.59–1.36 would hava a higher risk of developing of abnormal thyrotropin.ConclusionsBoth low and high baseline thyrotropin were associated with a significantly increased risk of developing abnormal thyrotropin outcomes. The optimal preconception baseline thyrotropin levels may be between 1.43 mIU/L and 1.93 mIU/L or baseline thyrotropin MoM between 0.59 and 1.36 to minimize progression toward abnormal thyrotropin after 1.5–3.0 years. These findings may help with counseling of preconception thyroid function monitoring.

Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose–response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = −0.05, −0.10 to 0.003, P = 0.067; IL-9: −0.01, −0.02 to −0.003, P = 0.005; MIP-1b: −0.02, −0.04 to −0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed.Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Biphasic effects of cannabis and cannabinoid therapy on pain severity, anxiety, and sleep disturbance: a scoping review.

Cannabinoids are being used by patients to help with chronic pain management and to address the 2 primary chronic pain comorbidities of anxiety and sleep disturbance. It is necessary to understand the biphasic effects of cannabinoids to improve treatment of this symptom triad. A scoping review was conducted to identify whether biphasic effects of cannabinoids on pain severity, anxiolysis, and sleep disturbance have been reported. The search included the Embase, Biosis, and Medline databases of clinical literature published between 1970 and 2021. The inclusion criteria were (1) adults more than 18 years of age, (2) data or discussion of dose effects associated with U-shaped or linear dose responses, and (3) measurements of pain and/or anxiety and/or sleep disturbance. Data were extracted by 2 independent reviewers (with a third reviewer used as a tiebreaker) and subjected to a thematic analysis. After the database search and study eligibility assessment, 44 publications met the final criteria for review. Eighteen publications that specifically provided information on dose response were included in the final synthesis: 9 related to pain outcomes, 7 measuring anxiety, and 2 reporting sleep effects. This scoping review reports on biphasic effects of cannabinoids related to pain, sleep, and anxiety. Dose-response relationships are present, but we found gaps in the current literature with regard to biphasic effects of cannabinoids in humans. There is a lack of prospective research in humans exploring this specific relationship.

Garlic consumption and colorectal cancer risk in US adults: a large prospective cohort study.

To clarify the inconsistent findings of epidemiological studies on the association between dietary garlic consumption and colorectal cancer (CRC) incidence, by prospectively assessing the association in a large US population. Data of 58,508 participants (aged 55-74) from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were analyzed. Dietary data were collected using a validated questionnaire. Multivariable Cox regression analysis determined hazard ratio (HR) and 95% confidence interval (CI). Restricted cubic spline regression was used to investigate the non-linear relationship, and subgroup analysis was conducted to examine potential effect modifiers. During a median follow-up of 12.05 years, 782 CRC cases were documented, including 456 proximal colon cancer cases, 322 distal CRC cases, and 4 CRC cases with an unknown site. Moderate dietary garlic consumption was significantly associated with a reduced risk of overall CRC (HRquintile 3vs. 1: 0.70, 95% CI: 0.54 to 0.91, p = 0.007, P for trend: 0.434), exhibiting a U-shaped dose-response pattern, and also with overall CRC in males in the stratified Cox regression model (Model 2: HRquintile 3vs. 1: 0.57, 95% CI: 0.40 to 0.81, p = 0.002), but not in females. The protective association was more pronounced in men, Caucasian, and those with lower alcohol consumption. Notably, these protective effects were observed for overall distal CRC (HRquintile 3vs. 1: 0.62, 95% CI: 0.42 to 0.93, p = 0.021; and HRquintile 4vs. 1: 0.63, 95% CI: 0.43 to 0.92, p = 0.018, P for trend: 0.208); and for distal CRC in males (HRquintile 3vs. 1: 0.40, 95% CI: 0.22 to 0.71, p = 0.002, P for trend: 0.696), but not for proximal CRC. Moderate consumption of dietary garlic is associated with a decreased CRC risk in the US population, with variations based on CRC anatomic subsites. Further in-depth prospective studies are needed to validate these findings in different populations and to explore subsites-specific associations.

The dopamine D1 receptor positive allosteric modulator, DETQ, improves cognition and social interaction in aged mice and enhances cortical and hippocampal acetylcholine efflux

Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response curve. DETQ, [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one] is highly selective for the human D1Rs as shown in humanized D1R knock-in (hD1Ki) mice. Here, we have ascertained the efficacy of DETQ in aged [13–23-month-old (mo)] hD1Ki mice and their corresponding age-matched wild-type (WT; C57BL/6NTac) controls. We found that in aged mice, DETQ, given acutely, subchronically, and chronically, rescued both novel object recognition memory and social behaviors, using novel object recognition (NOR) and social interaction (SI) tasks, respectively without any adverse effect on body weight or mortality. We have also shown, using in vivo microdialysis, a significant decrease in basal DA and norepinephrine, increase in glutamate (Glu) and gamma-amino butyric acid (GABA) efflux with no significant changes in acetylcholine (ACh) levels in aged vs young mice. In young and aged hD1Ki mice, DETQ, acutely and subchronically increased ACh in the medial prefrontal cortex and hippocampal regions in aged hD1Ki mice without affecting Glu. These results suggest that the D1PAM mechanism is of interest as potential treatment for cognitive and social behavioral deficits in neuropsychiatric disorders including but not restricted to neurodegenerative disorders, such as Parkinson’s disease.

Impact of Removal of Lymph Nodes on Survival in Stage I-III Gastric Signet-Ring Cell Cancer: The More, the Better?

There is an ongoing debate over the prognostic value of the number of examined lymph nodes (ELNs) in cases of gastric signet-ring cell cancer (GSRCC). In this study, we sought to evaluate the correlation between the number of ELNs and the prognosis of GSRCC and identify the optimal number of ELNs. A total of 1020 patients diagnosed with GSRCC between 2011 and 2018 in the National Cancer Center database were identified. Clinicopathological characteristics were retrospectively collected, and optimal cutoff values of ELNs were calculated by using X-tile. The impact of different ELNs on overall survival (OS) was compared by using Kaplan-Meier curves. We used univariate and multivariate Cox and subgroup analyses to explore the relationship between ELNs and OS. Furthermore, nonlinear correlations were investigated by using restricted cubic splines (RCSs). X-tile showed that the optimal cutoff value of ELNs was 22. The 5-year OS was higher for patients with ELNs > 22 (vs. ELNs ≤ 22, 66.9% vs. 74.9%, P = 0.026). Multivariate Cox analyses showed that high ELNs were associated with superior OS (hazard ratio = 0.56, 95% confidence interval 0.43-0.74, P < 0.001). In subgroup analyses, the significant association between tumor size > 4cm, and TNM III stage was still observed. The RCS regression model showed a U-shaped dose-response nonlinear relationship between ELNs and OS; the inflection point, as well as the lowest risk points, corresponded to 44-52 ELNs. A U-shaped, nonlinear correlation with inflection points of 44-52 ELNs between ELNs and prognosis in GSRCC was identified.

Effects of prenatal single and mixed bisphenol exposure on bone mineral density in preschool children: A population-based prospective cohort study

Exposure to bisphenols can affect bone mineral density (BMD) in animals and humans. However, the effects of maternal exposure to bisphenols during pregnancy on bone health in preschool children remain unknown. We aimed to assess the effects of prenatal exposure to single and multiple bisphenols on bone health in preschool children. A total of 230 mother–child pairs were included in this study. Generalized linear regression, restricted cubic spline (RCS), principal component analysis (PCA), and Bayesian kernel machine regression (BKMR) were utilized to assess the relationship between bisphenol levels and bone health in preschool children. Each natural log (Ln) unit increase in tetrabromobisphenol A was related to a 0.007 m/s (95 % CI: –0.015, 0.000) decrease in Ln-transformed speed of sound (SOS) among girls. Decreased BMD Z scores in preschool children were found only in the high bisphenol S exposure group (β = -0.568; 95 % CI: –1.087, –0.050) in boys. The risk of low BMD (BMDL) was significantly higher in the middle-exposure group (OR = 4.695; 95 % CI: 1.143, 24.381) and high-exposure group of BPS (OR = 6.165, 95 % CI: 1.445, 33.789) compared with the low-exposure group in boys. In girls, the risk of BMDL decreased with increasing bisphenol A concentration (OR = 0.413, 95 % CI: 0.215, 0.721). RCS analysis revealed a U-shaped nonlinear correlation between BPB concentration and BMDL in girls (P-overall = 0.011, P-nonlinear = 0.009). In PCA, a U-shaped dose–response relationship was found between PC2 and the risk of BMDL (P-overall = 0.048, P-nonlinear = 0.032), and a significant association was only noted in girls when stratified by sex. The BKMR model revealed a horizontal S-shaped curve relationship between bisphenol mixtures and BMDL in girls. The results indicated that prenatal exposure to single and mixed bisphenols can affect BMD in preschool children, exerting nonmonotonic and child sex-specific effects.

Persistent free radicals generated from a range of biochars and their physiological effects on wheat seedlings

Biochar is a promising soil conditioner and environmental remediation material. However, the amount, type, and environmental effect and risk of persistent free radicals (PFRs) associated with biochar need to be better understood. Thus, this study characterized PFRs in a range of biochar types and their effects on the growth and oxidative stress of wheat seedlings. Among the biochars prepared by pyrolysis of different types of biomass at 500 °C, the concentrations of PFRs in cow dung and egg shell biochar were the highest and the lowest, respectively. They both increased with artificial weathering treatment but decreased with aging. The dominant types of biochar PFRs were transformed from carbon-centered to oxygen and carbon/oxygen-centered free radicals with weathering. The amount and type of biochar PFRs in mixtures of biochar and soil varied with soil type and biochar dose. After 30 d incubation in different soil-biochar mixtures, measures of wheat plant germination and growth and antioxidant enzyme activity showed increases at lower biochar doses but decreases at higher doses. Catalase activity was 38.1 % greater at 20 g·kg−1 biochar dosage and 25.2 % less at 80 g·kg−1 dosage, on average. In contrast, leaf malondialdehyde content and staining by Evans Blue, both indicators of plant cell membrane damage, generally increased with increasing biochar dosages. Finally, soil hydrolase enzyme activity also displayed an inverted U-shaped dose response. The toxicity indicators showed an increasing trend with higher PFR concentrations in the soil-biochar combinations. While these findings provide evidence for significant potential agricultural and ecological risks associated with the application of biochar due to PFRs damage, it also points to ways that these risks could be mediated such as through biochar dosage restrictions and pre-aging. This study provides new insights into the potential toxicological mechanism and ecological risks associated with the application of biochar in agricultural and environmental settings.

Anxiogenic doses of rapamycin prevent URB597-induced anti-stress effects in socially defeated mice

Repeated exposure to psychosocial stress modulates the endocannabinoid system, particularly anandamide (AEA) signaling in brain regions associated with emotional distress. The mTOR protein regulates various neuroplastic processes in the brain disrupted by stress, including adult hippocampal neurogenesis. This kinase has been implicated in multiple effects of cannabinoid drugs and the anti-stress behavioral effects of psychoactive drugs. Therefore, our hypothesis is that enhancing AEA signaling via pharmacological inhibition of the fatty acid amide hydrolase (FAAH) enzyme induces an anti-stress behavioral effect through an mTOR-dependent mechanism. To test this hypothesis, male C57Bl6 mice were exposed to social defeat stress (SDS) for 7 days and received daily treatment with either vehicle or different doses of the FAAH inhibitor, URB597 (0.1; 0.3; 1 mg/Kg), alone or combined with rapamycin. The results suggested that URB597 induced an inverted U-shaped dose–response curve in mice subjected to SDS (with the intermediate dose of 0.3 mg/kg being anxiolytic, and the higher tested dose of 1 mg/Kg being anxiogenic). In a second independent experiment, rapamycin treatment induced an anxiogenic-like response in control mice. However, in the presence of rapamycin, the anxiolytic dose of URB597 treatment failed to reduce stress-induced anxiety behaviors in mice. SDS exposure altered the hippocampal expression of the mTOR scaffold protein Raptor. Furthermore, the anxiogenic dose of URB597 decreased the absolute number of migrating doublecortin (DCX)-positive cells in the dentate gyrus, suggesting an anti-anxiety effect independent of newly generated/immature neurons. Therefore, our results indicate that in mice exposed to repeated psychosocial stress, URB597 fails to counteract the anxiogenic-like response induced by the pharmacological dampening of mTOR signaling.

Breast cancer progression and kynurenine pathway enzymes are induced by hexachlorobenzene exposure in a Her2-positive model.

Breast cancer is one of the leading cancers among women worldwide. Given the evidence that pesticides play an important role in breast cancer, interest has grown in pesticide impact on disease progression. Hexachlorobenzene (HCB), an aryl hydrocarbon receptor (AhR) ligand, promotes triple-negative breast cancer cell migration and invasion. Estrogen receptor β (ERβ) inhibits cancer motility, while G protein-coupled ER (GPER) modulates the neoplastic transformation. Tryptophan is metabolized through the kynurenine pathway by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO), with kynurenine signaling activation often predicting worse prognosis in cancer. In this context, we examined the HCB (0.005; 0.05; 0.5 and 5μM) effect on LM3 cells, a human epidermal growth factor receptor 2 (HER2)-positive breast cancer model. Results show that HCB increases IDO and TDO mRNA levels and promotes cell viability, proliferation and migration through the AhR pathway. Moreover, HCB boosts mammosphere formation, vascular endothelial growth factor and cyclooxygenase-2 expression and reduces IL-10 levels. For some parameters, U-shaped or inverted U-shaped dose-response curves are shown. HCB alters ER levels, reducing ERβ while increasing GPER. These results demonstrate that exposure to environmentally relevant concentrations of HCB up-regulates the kynurenine pathway and dysregulates ERβ and GPER levels, collaborating in HER2-positive breast cancer progression.

Standardized Centella asiatica (ECa 233) extract decreased pain hypersensitivity development in a male mouse model of chronic inflammatory temporomandibular disorder

Chronic inflammatory temporomandibular disorder (TMD) pain has a high prevalence, and available nonspecific treatments have adverse side effects. ECa 233, a standardized Centella asiatica extract, is highly anti-inflammatory and safe. We investigated its therapeutic effects by injecting complete Freund’s adjuvant (CFA) into right temporomandibular joint of mice and administering either ibuprofen or ECa 233 (30, 100, and 300 mg/kg) for 28 days. Inflammatory and nociceptive markers, bone density, and pain hypersensitivity were examined. CFA decreased ipsilateral bone density, suggesting inflammation localization, which ipsilaterally caused immediate calcitonin gene-related peptide elevation in the trigeminal ganglia (TG) and trigeminal subnucleus caudalis (TNC), followed by late increase of NaV1.7 in TG and of p-CREB and activation of microglia in TNC. Contralaterally, only p-CREB and activated microglia in TNC showed delayed increase. Pain hypersensitivity, which developed early ipsilaterally, but late contralaterally, was reduced by ibuprofen and ECa 233 (30 or 100 mg/kg). However, ibuprofen and only 100-mg/kg ECa 233 effectively mitigated marker elevation. This suggests 30-mg/kg ECa 233 was antinociceptive, whereas 100-mg/kg ECa 233 was both anti-inflammatory and antinociceptive. ECa 233 may be alternatively and safely used for treating chronic inflammatory TMD pain, showing an inverted U-shaped dose–response relationship with maximal effect at 100 mg/kg.

Association between blood metal exposures and hyperuricemia in the U.S. general adult: A subgroup analysis from NHANES

BackgroundThe relationship between metal exposure and hyperuricemia is still controversial, especially in certain population groups. MethodsThis cross-sectional study included adults from NHANES 2011–2016. Seven metals, including Pb, Cd, Hg, Mn, Se, Cu, and Zn, were detected in blood by ICP‒MS. Multivariable logistic regression, LASSO, and BKMR models were used to assess the effects of single and mixed metal exposures and hyperuricemia. Moreover, this association was analyzed by sex, BMI, and age. ResultsA total of 4074 individuals were included in our final analysis, and 825 (20.3%) people were classified as having hyperuricemia. In logistic regression, Pb (Q4: OR [95% CI]: 1.50 [1.00, 2.24]) was associated with hyperuricemia after adjusting for all covariates. LASSO penalized regression analysis further indicated positive associations of lead and zinc with hyperuricemia. In BKMR analysis, U-shaped dose‒response curves were generated for Se, Mn, Cu, and Zn when fixing the other metals in the 50th percentile. A significant positive trend was found between mixed metal exposure and hyperuricemia, in which blood Se, Zn, and Cd had the highest PIP (PIP = 0.651, 0.549, and 0.530, respectively). In weighted logistic regression, subgroup analyses revealed a significant association between Pb and hyperuricemia among the non-overweight group. Significant positive trends between mixed metals and hyperuricemia were found in the male and non-overweight groups in the BKMR models. ConclusionOur study suggests that a higher concentration of mixed metal might increase the risk of hyperuricemia in U.S. adults. Males and people with a BMI under 25 are more likely to be affected.

Too much is too little: Estimating the optimal physical activity level for a healthy mental state.

Although physical activity and exercise are generally thought to have favorable effects on mental health, excessive physical activity may have unfavorable effects. In this study, the associations between physical activity and the states of mental health with U-shaped dose-response curves were hypothesized, and the ranges of physical activity resulting in optimal effects on mental health were investigated. A cross-sectional survey was conducted on 1,237 adult volunteers in 2017 and 2018. Of these volunteers, 526 participants validly answered the self-administered questionnaires asking about physical activity, depression, anxiety, resilience, insomnia vulnerability, and life events. A comparison of mental health measures by physical activity levels and quadratic equation model regressions were performed. No significant linear associations between physical activity levels and mental health measurements were observed; however, the U-shaped, quadratic equation models indicated a significance. The following levels of physical activity per week optimized the mental health measurements values of the participants: 6,953 MET-minutes and 25.70 h for depression, 5,277 MET-minutes and 21.60 h for state anxiety, 5,678 MET-minutes and 22.58 h for trait anxiety, 25.41 h for resilience, and 9,152 MET-minutes and 31.17 h for insomnia vulnerability. Physical activities in the optimal range were associated with more favorable mental health measurements. Physical activities that were too much or too long and outside of the optimal range were associated with less favorable mental health measurements.

NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine.

Ketamine is a well-characterized NMDA receptor (NMDAR) antagonist, although the relevance of this pharmacology to its rapid (within hours of administration) antidepressant actions, which depend on mechanisms convergent with strengthening of excitatory synapses, is unclear. Activation of synaptic NMDARs is necessary for the induction of canonical long-term potentiation (LTP) leading to a sustained expression of increased synaptic strength. We tested the hypothesis that induction of rapid antidepressant effects requires NMDAR activation, by using behavioral pharmacology, western blot quantification of hippocampal synaptoneurosomal protein levels, and ex vivo hippocampal slice electrophysiology in male mice. We found that ketamine exerts an inverted U-shaped dose-response in antidepressant-sensitive behavioral tests, suggesting that an excessive NMDAR inhibition can prevent ketamine's antidepressant effects. Ketamine's actions to induce antidepressant-like behavioral effects, up-regulation of hippocampal AMPAR subunits GluA1 and GluA2, as well as metaplasticity measured ex vivo using electrically-stimulated LTP, were abolished by pretreatment with other non-antidepressant NMDAR antagonists, including MK-801 and CPP. Similarly, the antidepressant-like actions of other putative rapid-acting antidepressant drugs (2R,6R)-hydroxynorketamine (ketamine metabolite), MRK-016 (GABAAα5 negative allosteric modulator), and LY341495 (mGlu2/3 receptor antagonist) were blocked by NMDAR inhibition. Ketamine acted synergistically with an NMDAR positive allosteric modulator to exert antidepressant-like behavioral effects and activation of the NMDAR subunit GluN2A was necessary and sufficient for such relevant effects. We conclude rapid-acting antidepressant compounds share a common downstream NMDAR-activation dependent effector mechanism, despite variation in initial pharmacological targets. Promoting NMDAR signaling or other approaches that enhance NMDAR-dependent LTP-like synaptic potentiation may be an effective antidepressant strategy.SIGNIFICANCE STATEMENT The anesthetic and antidepressant drug ketamine is well-characterized as an NMDA receptor (NMDAR) antagonist; though, the relevance and full impact of this pharmacology to its antidepressant actions is unclear. We found that NMDAR activation, which occurs downstream of their initial actions, is necessary for the beneficial effects of ketamine and several other putative antidepressant compounds. As such, promoting NMDAR signaling, or other approaches that enhance NMDAR-dependent long-term potentiation (LTP)-like synaptic potentiation in vivo may be an effective antidepressant strategy directly, or acting synergistically with other drug or interventional treatments.