Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an μ-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of Trpv4 knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.

During the hyperacute phase of intracerebral hemorrhage (ICH), the mass effect and blood components mechanically lead to brain damage and neurotoxicity. Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake, culminating in ferroptosis in neurons. M6A (N6-methyladenosine) modification, the most prevalent mRNA modification, plays a critical role in various cell death pathways. The Fto (fat mass and obesity-associated protein) demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels. Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis. Applying nanopore direct RNA sequencing, we identified voltage-dependent anion channel 3 (Vdac3) as a potential target associated with ferroptosis. Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA. These findings elucidate the intricate interplay between Fto, Vdac3, m6A methylation, and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
Ferroptosis/physiology* ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Animals ; Neurons/metabolism* ; Transferrin/pharmacology* ; Mice ; Methylation ; Mice, Inbred C57BL ; Adenosine/metabolism* ; RNA, Messenger/metabolism* ; Male ; Oxidative Stress/physiology*

Objective To analyze the disease burden of early-onset colorectal cancer (EOCRC) at the global, regional, and national levels from 1990 to 2021, and to predict the disease burden trend from 2022 to 2026. Methods Based on the Global Burden of Disease (GBD) database, the incidence, mortality, and disability-adjusted life year (DALY) rate of EOCRC across 204 countries and regions from 1990 to 2021 were obtained. The time trends of these indicators were assessed by calculating the estimated annual percentage change (EAPC), and the contributions of ten risk factors to the EOCRC burden were analyzed. The autoregressive integrated moving average (ARIMA) model was used to predict the disease burden from 2022 to 2026. Results From 1990 to 2021, the number of new global EOCRC cases increased from 107 310 to 211 890, with the incidence rising from 3.96 to 5.37 per 100 000 people. In 2021, global EOCRC incidence, mortality, and DALY rate increased with age; males had higher rates than females in terms of incidence, mortality, and DALY rate in all age groups. In 2021, East Asia had the highest number of new cases, deaths, and DALY. From 1990 to 2021, the global EAPC for incidence rate was 0.96%, and death rate was –0.38%. ARIMA model indicated that from 2022 to 2026, the global incidence of EOCRC would continue to rise, while mortality and DALY rate would be expected to decline. Conclusions The disease burden of EOCRC has significantly increased globally from 1990 to 2021, with notable regional, age, and sex differences. By 2026, the mortality and DALY rate of EOCRC will decline, while the incidence is expected to further increase, highlighting the urgency of taking active measures to address the growing trend of EOCRC.

Objective:To analyze early improvements in clinical indicators among patients with pre-diabetes (pre-DM), type 2 diabetes mellitus (T2DM), and hypertension (HT) participating in the Chronic Disease Co-Care (CDCC) Pilot Scheme in the Hong Kong Special Administrative Region of the People′s Republic of China (HKSAR). Methods:This longitudinal study enrolled participants with pre-DM, T2DM, and HT who participated in the CDCC Pilot Scheme between November 2023 and May 2024. Baseline clinical data was collected. All participants were managed followed standardized protocols: family doctors issued prescriptions in accordance with the Hong Kong Reference Framework by the Health Bureau of the Government of the HKSAR, District Health Centre (DHC) and DHC Express provided health education, and personalized counseling by allied health professionals (nurses, optometrists, and dietitians). During the screening phase, screening costs, including consultations and related laboratory investigations, were fully covered by the Government of the HKSAR, while partial subsidies were available during the treatment phase. Participants were followed for 6 months. Primary outcomes were glycated hemoglobin A1c (HbA1c) for pre-DM and T2DM, and blood pressure for HT. Secondary outcomes included body mass index (BMI), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and the Framingham model-based 10-year cardiovascular risk score. Changes in clinical indicators from baseline to 6 months were analyzed using a linear mixed model, with subgroup analyses by age, sex, and baseline Framingham 10-year cardiovascular disease risk score. Results:A total of 3 910 participants were included in the study, comprising 903 (23.1%) with pre-DM, 478 (12.2%) with T2DM, and 2 529 (64.7%) with HT. Pre-DM participants had an age of (61.4±7.0) years with 641 (71.0%) females; T2DM participants had an age of (60.4±7.4) years with 247 (51.7%) females; HT participants had an age of (60.8±7.9) years with 1 237 (48.9%) females. At 6 months, HbA1c levels declined in the pre-DM and T2DM groups by -0.09% (95% CI:-0.10%--0.07%) and -1.06% (95% CI:-1.21%--0.91%), respectively. In the HT group, systolic blood pressure decreased by 15.3 mmHg (1 mmHg=0.133 kPa) (95% CI:-16.0--14.6 mmHg) and diastolic blood pressure by 8.6 mmHg (95% CI:-9.0--8.1 mmHg). BMI decreased in the three groups, with the largest reduction in the T2DM group (-1.04 kg/m 2, 95% CI:-1.22--0.86 kg/m 2). TC, TG, and LDL-C levels decreased in the three groups (all P<0.05). Subgroup analysis revealed that among HT participants, individuals with a baseline Framingham 10-year cardiovascular disease risk of ≥20% experienced greater reductions in blood pressure compared to those with a risk <20% ( P<0.05). Additionally, male participants demonstrated significantly lower diastolic blood pressure than female participants ( P<0.05). Among participants with T2DM, males exhibited greater reductions in HbA1c levels than females, and participants aged 45-64 years showed significantly lower HbA1c levels compared to those aged 65 years and older (both P<0.05). Conclusions:In the early phase of the CDCC Pilot Scheme, glycemic, blood pressure, lipid, and BMI indicators improved among patients with pre-DM, T2DM, and HT. These effects were particularly pronounced in males and in individuals younger than 65 years of age.

Objective:To analyze early improvements in clinical indicators among patients with pre-diabetes (pre-DM), type 2 diabetes mellitus (T2DM), and hypertension (HT) participating in the Chronic Disease Co-Care (CDCC) Pilot Scheme in the Hong Kong Special Administrative Region of the People′s Republic of China (HKSAR). Methods:This longitudinal study enrolled participants with pre-DM, T2DM, and HT who participated in the CDCC Pilot Scheme between November 2023 and May 2024. Baseline clinical data was collected. All participants were managed followed standardized protocols: family doctors issued prescriptions in accordance with the Hong Kong Reference Framework by the Health Bureau of the Government of the HKSAR, District Health Centre (DHC) and DHC Express provided health education, and personalized counseling by allied health professionals (nurses, optometrists, and dietitians). During the screening phase, screening costs, including consultations and related laboratory investigations, were fully covered by the Government of the HKSAR, while partial subsidies were available during the treatment phase. Participants were followed for 6 months. Primary outcomes were glycated hemoglobin A1c (HbA1c) for pre-DM and T2DM, and blood pressure for HT. Secondary outcomes included body mass index (BMI), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and the Framingham model-based 10-year cardiovascular risk score. Changes in clinical indicators from baseline to 6 months were analyzed using a linear mixed model, with subgroup analyses by age, sex, and baseline Framingham 10-year cardiovascular disease risk score. Results:A total of 3 910 participants were included in the study, comprising 903 (23.1%) with pre-DM, 478 (12.2%) with T2DM, and 2 529 (64.7%) with HT. Pre-DM participants had an age of (61.4±7.0) years with 641 (71.0%) females; T2DM participants had an age of (60.4±7.4) years with 247 (51.7%) females; HT participants had an age of (60.8±7.9) years with 1 237 (48.9%) females. At 6 months, HbA1c levels declined in the pre-DM and T2DM groups by -0.09% (95% CI:-0.10%--0.07%) and -1.06% (95% CI:-1.21%--0.91%), respectively. In the HT group, systolic blood pressure decreased by 15.3 mmHg (1 mmHg=0.133 kPa) (95% CI:-16.0--14.6 mmHg) and diastolic blood pressure by 8.6 mmHg (95% CI:-9.0--8.1 mmHg). BMI decreased in the three groups, with the largest reduction in the T2DM group (-1.04 kg/m 2, 95% CI:-1.22--0.86 kg/m 2). TC, TG, and LDL-C levels decreased in the three groups (all P<0.05). Subgroup analysis revealed that among HT participants, individuals with a baseline Framingham 10-year cardiovascular disease risk of ≥20% experienced greater reductions in blood pressure compared to those with a risk <20% ( P<0.05). Additionally, male participants demonstrated significantly lower diastolic blood pressure than female participants ( P<0.05). Among participants with T2DM, males exhibited greater reductions in HbA1c levels than females, and participants aged 45-64 years showed significantly lower HbA1c levels compared to those aged 65 years and older (both P<0.05). Conclusions:In the early phase of the CDCC Pilot Scheme, glycemic, blood pressure, lipid, and BMI indicators improved among patients with pre-DM, T2DM, and HT. These effects were particularly pronounced in males and in individuals younger than 65 years of age.

Efferocytosis refers to the process that phagocytes recognize and remove the apoptotic cells, which is essential for maintaining tissue homeostasis both in physiological and pathological conditions. Numerous studies have demonstrated that efferocytosis can prevent secondary necrosis and proinflammatory factor release, leading to the resolution of inflammation and tissue immunological tolerance in numerous diseases such as stroke. Stroke is a leading cause of death and morbidity for adults worldwide. Persistent inflammation triggered by the dead cells or cell debris is a major contributor to post-stroke brain damage. Effective efferocytosis might be an efficient strategy to minimize inflammation and restore brain homeostasis for neuronal regeneration and function recovery. In this review, we will discuss the phagocytes in the brain, the molecular mechanisms underlying efferocytosis, the role of efferocytosis in inflammation resolution, and the potential therapeutic applications targeting efferocytosis in stroke.
Humans ; Stroke ; Phagocytosis/physiology* ; Inflammation ; Apoptosis/physiology* ; Animals ; Phagocytes/physiology* ; Brain/metabolism* ; Efferocytosis

SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.

Background: and Purpose Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. Conclusions During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

Lingguizhugan Decoction (LGZG) has been investigated in basic studies, with satisfactory effects on insulin resistance in non-alcoholic fatty liver disease (NAFLD). This translational approach aimed to explore the effect and underlying mechanism of LGZG in clinical setting. A randomized, double-blinded, placebo-controlled trial was performed. A total of 243 eligible participants with NAFLD were equally allocated to receive LGZG (two groups: standard dose and low dose) or placebo for 12 weeks on the basis of lifestyle modifications. The primary efficacy variable was homeostasis model assessment of insulin resistance (HOMA-IR). Analyses were performed in two populations in accordance with body mass index (BMI; overweight/obese, BMI ⩾ 24 kg/m²; lean, BMI < 24 kg/m²). For overweight/obese participants, low-dose LGZG significantly decreased their HOMA-IR level compared with placebo (-0.19 (1.47) versus 0.08 (1.99), P = 0.038). For lean subjects, neither dose of LGZG showed a superior effect compared with placebo. Methylated DNA immunoprecipitation sequencing and real-time qPCR found that the DNA N6-methyladenine modification levels of protein phosphatase 1 regulatory subunit 3A (PPP1R3A) and autophagy related 3 (ATG3) significantly increased after LGZG intervention in overweight/obese population. Low-dose LGZG effectively improved insulin resistance in overweight/obese subjects with NAFLD. The underlying mechanism may be related to the regulation of DNA N6-methyladenine modification of PPP1R3A and ATG3. Lean subjects may not be a targeted population for LGZG.
Humans ; Non-alcoholic Fatty Liver Disease/drug therapy* ; Overweight/drug therapy* ; Insulin Resistance ; Obesity/drug therapy* ; China ; DNA/therapeutic use*