A natural heme deficiency exists in biology that allows nitric oxide to control heme protein functions by regulating cellular heme distribution.

A natural heme deficiency that exists in cells outside of the circulation broadly compromises the heme contents and functions of heme proteins in cells and tissues. Recently, we found that the signaling molecule, nitric oxide (NO), can trigger or repress the deployment of intracellular heme in a concentration-dependent hormetic manner. This uncovers a new role for NO and sets the stage for it to shape numerous biological processes by controlling heme deployment and consequent heme protein functions in biology.

NO rapidly mobilizes cellular heme to trigger assembly of its own receptor.

Nitric oxide (NO) signaling in biology relies on its activating cyclic guanosine monophosphate (cGMP) production by the NO receptor soluble guanylyl cyclase (sGC). sGC must obtain heme and form a heterodimer to become functional, but paradoxically often exists as an immature heme-free form in cells and tissues. Based on our previous finding that NO can drive sGC maturation, we investigated its basis by utilizing a fluorescent sGC construct whose heme level can be monitored in living cells. We found that NO generated at physiologic levels quickly triggered cells to mobilize heme to immature sGC. This occurred when NO was generated within cells or by neighboring cells, began within seconds of NO exposure, and led cells to construct sGC heterodimers and thus increase their active sGC level by several-fold. The NO-triggered heme deployment involved cellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-heme complexes and required the chaperone hsp90, and the newly formed sGC heterodimers remained functional long after NO generation had ceased. We conclude that NO at physiologic levels triggers assembly of its own receptor by causing a rapid deployment of cellular heme. Redirecting cellular heme in response to NO is a way for cells and tissues to modulate their cGMP signaling and to more generally tune their hemeprotein activities wherever NO biosynthesis takes place.

Celastrol inhibits platelet function and thrombus formation.

INTRODUCTION: Celastrol is an active pentacyclic triterpenoid extracted from Tripterygium wilfordii and has anti-inflammatory and anti-tumor properties. Whether Celastrol modulates platelet function remains unknown. Our study investigated its role in platelet function and thrombosis. METHODS: Human platelets were isolated and incubated with Celastrol (0, 1, 3 and 5 µM) at 37 °C for 1 h to measure platelet aggregation, granules release, spreading, thrombin-induced clot retraction and intracellular calcium mobilization. Additionally, Celastrol (2 mg/kg) was intraperitoneally administrated into mice to evaluate hemostasis and thrombosis in vivo. RESULTS: Celastrol treatment significantly decreased platelet aggregation and secretion of dense or alpha granules induced by collagen-related peptide (CRP) or thrombin in a dose-dependent manner. Additionally, Celastrol-treated platelets showed a dramatically reduced spreading activity and decreased clot retraction. Moreover, Celastrol administration prolonged tail bleeding time and inhibited formation of arterial/venous thrombosis. Furthermore, Celastrol significantly reduced calcium mobilization. CONCLUSION: Celastrol inhibits platelet function and venous/arterial thrombosis, implying that it might be utilized for treating thrombotic diseases.

Broadband lens and graphene/silicon photodiode for wide spectral imaging.

We designed a broadband lens along with a graphene/silicon photodiode for wide spectral imaging ranging from ultraviolet to near-infrared wavelengths. By using five spherical glass lenses, the broadband lens, with the modulation transfer function of 0.38 at 100 lp/mm, corrects aberrations ranging from 340 to 1700 nm. Our design also includes a broadband graphene/silicon Schottky photodiode with the highest responsivity of 0.63 A/W ranging from ultraviolet to near-infrared. By using the proposed broadband lens and the broadband graphene/silicon photodiode, several single-pixel imaging designs in ultraviolet, visible, and near-infrared wavelengths are demonstrated. Experimental results show the advantages of integrating the lens with the photodiode and the potential to realize broadband imaging with a single set of lens and a detector.

The effects of telerehabilitation on physiological function and disease symptom for patients with chronic respiratory disease: a systematic review and meta-analysis.

OBJECTIVE: To compare the impact of telerehabilitation versus conventional rehabilitation on the recovery outcomes of patients with chronic respiratory disease (CRD). METHODS: The Cochrane Library, MEDLINE, Web of Science and Embase were searched to collect randomized controlled trials (RCTs) on telerehabilitation for the rehabilitation of patients with chronic respiratory system diseases since the establishment of the database to November 14, 2023. Two researchers independently screened the literature and extracted valid data according to the inclusion criteria. The quality assessment of included studies was conducted individually by using the RoB 2(Risk of Bias 2) tool, followed by meta-analysis using RevMan5.3 software. RESULTS: Based on inclusion and exclusion criteria, 21 RCTs were included, comprising 3030 participants, with 1509 in the telerehabilitation group and 1521 in the conventional rehabilitation group. Meta-analysis results indicated that compared to conventional rehabilitation, video conference-based telerehabilitation demonstrated significant improvements in short-term (≤ 6 months) outcomes, including 6-min walk distance (6MWD) (MD = 7.52, 95% CI: 2.09, 12.94), modified Medical Research Council Dyspnea Scale (mMRC) (MD = -0.29, 95% CI: -0.41, -0.18), COPD assessment test (CAT) (MD = -1.77, 95% CI: -3.52, -0.02), HADS (MD = -0.44, 95% CI: -0.86, -0.03), and St. George's Respiratory Questionnaire (SGRQ's) activity, impact, and symptom scores. In the long term (> 6 months), although improvements persisted in 6WMD [MD = 12.89, 95% CI (-0.37, 26.14)], mMRC [MD = -0.38, 95% CI (-0.56, -0.21)], CAT [MD = -1.39, 95% CI (-3.83, 1.05)], Hospital anxiety and depression scale (HADS) [MD = -0.34, 95% CI (-0.66, -0.03)], and SGRQ's Activity, Impact, and Symptom scores between intervention and control groups, statistically significant differences were observed only for mMRC and HADS. Without considering time factors, the intervention group exhibited some improvement in FEV1% predicted and the forced expiratory volume in the first one second (FEV1)/ forced vital capacity (FVC) (%) without statistical significance compared to the control group. CONCLUSION: Telerehabilitation therapy demonstrates short-term benefits in enhancing patients' daily activity capacity, improving respiratory function, and enhancing mental health status, thereby improving patients' quality of life. However, further high-quality, large-sample RCTs are required to ascertain its long-term effectiveness conclusively. TRIAL REGISTRATION: This study protocol was approved and registered in PROSPERO: CRD 42024509154.

Sex differences and dietary patterns in the association of air pollutants and hypertension.

BACKGROUND: Hypertension is one of the major public health problems in China. Limited evidence exists regarding sex differences in the association between hypertension and air pollutants, as well as the impact of dietary factors on the relationship between air pollutants and hypertension. The aim of this study was to investigate the sex-specific effects of dietary patterns on the association between fine particulate matter (PM2.5), ozone(O3) and hypertension in adults residing in Jiangsu Province of China. METHODS: A total of 3189 adults from the 2015 China Adult Chronic Disease and Nutrition Surveillance in Jiangsu Province were included in this study. PM2.5 and O3 concentrations were estimated using satellite space-time models and assigned to each participant. Dietary patterns were determined by reduced rank regression (RRR), and multivariate logistic regression was used to assess the associations of the obtained dietary patterns with air pollutants and hypertension risk. RESULTS: After adjusting for confounding variables, we found that males were more sensitive to long-term exposure to PM2.5 (Odds ratio (OR) = 1.42 95%CI:1.08,1.87), and females were more sensitive to long-term exposure to O3 (OR = 1.61 95%CI:1.15,2.23). Traditional southern pattern identified through RRR exhibited a protective effect against hypertension in males (OR = 0.73 95%CI: 0.56,1.00). The results of the interaction between dietary pattern score and PM2.5 revealed that adherence to traditional southern pattern was significantly associated with a decreased risk of hypertension in males (P < 0.05), while no significant association was observed among females. CONCLUSIONS: Our findings suggested that sex differences existed in the association between dietary patterns, air pollutants and hypertension. Furthermore, we found that adherence to traditional southern pattern may mitigate the risk of long-term PM2.5 exposure-induced hypertension in males.

BAY58-2667 Activates Different Soluble Guanylyl Cyclase Species by Distinct Mechanisms that Indicate Its Principal Target in Cells is the Heme-Free Soluble Guanylyl Cyclase-Heat Shock Protein 90 Complex.

Nitric oxide (NO)-unresponsive forms of soluble guanylyl cyclase (sGC) exist naturally and in disease can disable NO-sGC-cGMP signaling. Agonists like BAY58-2667 (BAY58) target these sGC forms, but their mechanisms of action in living cells are unclear. We studied rat lung fibroblast-6 cells and human airway smooth muscle cells that naturally express sGC and HEK293 cells that we transfected to express sGC and variants. Cells were cultured to build up different forms of sGC, and we used fluorescence and FRET-based measures to monitor BAY58-driven cGMP production and any protein partner exchange or heme loss events that may occur for each sGC species. We found that: (i) BAY58 activated cGMP production by the apo-sGCß-Hsp90 species after a 5-8 minute delay that was associated with apo-sGCß exchanging its Hsp90 partner with an sGCα subunit. (ii) In cells containing an artificially constructed heme-free sGC heterodimer, BAY58 initiated an immediate and three times faster cGMP production. However, this behavior was not observed in cells expressing native sGC under any condition. (iii) BAY58 activated cGMP production by ferric heme sGC only after a 30-minute delay, coincident with it initiating a delayed, slow ferric heme loss from sGCß We conclude that the kinetics favor BAY58 activation of the apo-sGCß-Hsp90 species over the ferric heme sGC species in living cells. The protein partner exchange events driven by BAY58 account for the initial delay in cGMP production and also limit the speed of subsequent cGMP production in the cells. Our findings clarify how agonists like BAY58 may activate sGC in health and disease. SIGNIFICANCE STATEMENT: A class of agonists can activate cyclic guanosine monophosphate (cGMP) synthesis by forms of soluble guanylyl cyclase (sGC) that do not respond to NO and accumulate in disease, but the mechanisms of action are unclear. This study clarifies what forms of sGC exist in living cells, which of these can be activated by the agonists, and the mechanisms and kinetics by which each form is activated. This information may help to hasten deployment of these agonists for pharmaceutical intervention and clinical therapy.

AhR activation promotes Treg cell generation by enhancing Lkb1-mediated fatty acid oxidation via the Skp2/K63-ubiquitination pathway.

Several aryl hydrocarbon receptor (AhR) agonists have been reported to promote the generation of regulatory T cells (Treg cells), and the action mechanisms need to be identified. In this study, we addressed the underlying mechanism of AhR activation to induce the generation of Treg cells in the view of cellular metabolism. Naïve CD4+ T cells were purified with mouse CD4+ CD62L+ T Cells Isolation Kits. The proportions of Treg cells were detected by flow cytometry. The value of oxygen consumption rate (OCR) of CD4+ T cells was detected by the Seahorse XFe 96 analyzer. The activation of fatty acid oxidation (FAO)-related metabolic pathways was detected by Western blotting. Intracellular localization of Lkb1 was detected by immunofluorescence. The Strad-Mo25-Lkb1 complex formation and K63 chain ubiquitination modification of Lkb1 were detected by co-immunoprecipitation. The binding of AhR to the Skp2 promoter was detected by constructing luciferase reporter gene. AhR or carnitine palmitoyltransferases 1 was knockdown in dextran sulphate sodium (DSS)-induced colitis or collagen-induced arthritis (CIA) mice by infecting mice with adeno-associated virus via the tail vein injection. Compared to the control group, exogenous and endogenous AhR agonists 3,3'-diindolylmethane (DIM) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) were shown to preferentially upregulate the mRNA expression of FAO-related enzymes and the value of OCR. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of DIM and ITE on the differentiation of Treg cells. DIM and ITE functioned mainly through activating the liver kinase B1 (Lkb1)-AMPK pathway via promotion of Lkb1-Strad-Mo25 complex formation and Lkb1 K63 ubiquitination. DIM and ITE were also shown to upregulate the mRNA expression of Skp2, a ubiquitination-related enzyme, and facilitate the binding of AhR to the xenobiotic responsive element of Skp2 promoter region by luciferase reporter gene assay. Furthermore, the contribution of Skp2/K63 ubiquitination/Lkb1/FAO axis was verified in (DSS)-induced colitis or CIA mice. In summary, these findings indicate that AhR activation promotes Treg cell generation by enhancing Lkb1-mediated FAO via the Skp2/K63-ubiquitination pathway, and AhR agonists may be used as inducers of Treg cells to prevent and treat autoimmune diseases.

Direct-detected spectroscopy based on a plasmonic Schottky photodetector and a deep neural network.

Computational algorithms have facilitated the miniaturization of spectrometers, which is essential for on-chip and portable applications. A plasmonic Schottky photodetector provides a filter-free and CMOS-compatible scheme for spectral measurement. In this study, we report on a direct-detected spectral analysis based on an integrated vertically coupled plasmonic nanostructure Schottky photodetector. We demonstrate that the plasmonic Schottky photodetector has a fast response with a -3 dB bandwidth of 600 kHz and a high peak detectivity of 8.65 × 1010 Jones. By designing a deep neural network (DNN), we demonstrate the reconstruction of the unknown spectrum with a mean square error (MSE) of 1.57 × 10-4 at a broad operating wave band of 450-950 nm, using only 20 distinct devices. Moreover, the spectral resolution of the 20 devices can reach to 7 nm. These findings provide a promising route for the development of chip-integrated spectrometers with high spectral accuracy and optical performance.

Norisoboldine induces the development of Treg cells by promoting fatty acid oxidation-mediated H3K27 acetylation of Foxp3.

Norisoboldine (NOR), an alkaloid isolated from Radix Lindera, was previously reported to promote the differentiation of regulatory T cells (Treg cells), an important subtype of lymphocytes capable of controlling autoimmune diseases. The present study was performed to explore the mechanism of NOR in the view of cellular metabolism. A global metabolomic analysis indicated that NOR preferentially altered the fatty acid oxidation (FAO) pathway and elevated the content of related metabolites during Treg cell differentiation. The detection of oxygen consumption rate (OCR) and mRNA expression of FAO-related enzymes demonstrated that NOR promoted FAO in the early stage of Treg cell differentiation. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of NOR on Treg cell differentiation. Furthermore, NOR was shown to elevate the level of acetyl-CoA derived from FAO and acetylation of lysine 27 on histone 3 (H3K27) at the Foxp3 promoter and CNS2 regions. A knockdown of CPT1, the rate-limiting enzyme of FAO, weakened the promotion of NOR on the development, acetyl-CoA level, and acetylation of H3K27 of Treg cells in vitro and in the mice with collagen-induced arthritis, and attenuated the anti-arthritic effect of NOR. These findings demonstrate that NOR induces the development of Treg cells through promoting FAO, therefore, facilitating gene transcription of Foxp3 via acetyl-CoA-mediated H3K27 acetylation modification, and FAO might serve as a novel target to induce Treg cell development.

Corrosion Inhibition Mechanism of Water-Soluble Imidazoline on A572 Gr.65 Steel in 3.5 wt % NaCl Solution.

To optimize the economic advantages and corrosion-resisting property of A572 Gr.65 steels, the inhibition effect of water-soluble imidazoline on the sample surface with rare earth was explored in a 3.5 wt % NaCl solution. In this paper, the mechanism of corrosion and the adsorptive behavior of water-soluble imidazoline inhibitors on A572 Gr.65 steels with 47 ppm of rare earth in saltwater solution were discussed, along with the establishment of the adsorption model. Achievements proposed that the inhibition efficiency of water-soluble imidazoline was as high as 95.73% at 80 mg L-1 dosage following an anodic-dominated mixed-type inhibition mechanism. Besides, the scanning electron microscopy and X-ray diffraction analysis revealed that the corrosion inhibitor resulted in a smoother and more stable rust layer with a significant reduction of the γ-FeOOH. Theoretical calculations confirmed that imidazoline formed a unimolecular layer adsorption film on the steel surface, exhibiting adherence to both Langmuir and Frumkin adsorption isotherms, involving physical and chemical adsorption.

Potential impact of time trend of whole grain intake on burden of major cancers in China.

Numerous studies have revealed associations between high intake of whole grains and reduced risk of various cancers. Yet, in recent decades, the traditional Chinese diets have been challenged by reduction in whole grains and increase in refined grains. To assess the impact of this dietary transition on cancer prevention, we analyzed the time trend of whole grain intake using nationally representative sampling data of over 15 thousand individuals from the China Health and Nutrition Survey. We applied the comparative risk assessment method to estimate the population attributable fraction of cancers due to insufficient whole grain intake from 1997 to 2011 and projected the trend of whole grain intake and the associated burden of cancers to 2035. We found a significant decrease of approximately 59% of whole grain intake in the Chinese population from 1997 to 2011. Compared with 1997, insufficient intake of whole grains was responsible for 9940 more cases of breast cancer, 12,903 more cases of colorectal cancer and 434 more cases of pancreatic cancer in 2011. Our projections suggest that if every Chinese would consume 125 g whole grain per day as recommended by the latest Chinese Dietary Guidelines, 0.63% bladder cancer, 8.98% breast cancer, 15.85% colorectal cancer, 3.86% esophageal cancer, 2.52% liver cancer and 2.22% pancreatic cancer (totaling 186,659 incident cases) could theoretically be averted by 2035. Even if everyone maintained the 2011 whole grain intake level, an estimated 8.38% of cancer events could still be prevented by 2035.

Morin, the PPARγ agonist, inhibits Th17 differentiation by limiting fatty acid synthesis in collagen-induced arthritis.

T helper (Th) 17 cells highly contribute to the immunopathology of rheumatoid arthritis. Morin, a natural flavonoid, owns well anti-arthritic action but unclear effect on Th17 differentiation. This study tried to solve this issue and explore the mechanisms in view of cellular metabolism. Naïve CD4+ T cells were treated with anti-CD3/CD28 along with Th17-inducing cytokines. Morin was shown to block Th17 differentiation without affecting cell viability even when Foxp3 was dampened. The mechanisms were ascribed to the limited fatty acid synthesis by restricting FASN transcription, as indicated by metabolomics analysis, nile red staining, detection of triglycerides, FASN overexpression, and addition of palmitic acid. Moreover, morin had slight effect on cell apoptosis and protein palmitoylation during Th17 differentiation, but blocked the binding of RORγt to promoter and CNS2 region of Il17a gene. Oleic acid rescued the inhibition of morin on RORγt function, and Th17-inducing cytokines could not induce RORγt function in SCD1-defficient cells, suggesting that oleic acid but not palmitic acid was the direct effector in the action of morin. Then, PPARγ was identified as the target of morin, and GW9662 or PPARγ CRISPR/Cas9 KO plasmid weakened its above-mentioned effects. The transrepression of FASN by morin was owing to physical interaction between PPARγ and Sp1, and the importance of Sp1 in Th17 differentiation was confirmed by siSp1. Finally, the effects and mechanisms for morin-dampened Th17 responses were confirmed in collagen-induced arthritis (CIA) mice. Collectively, morin inhibited Th17 differentiation and alleviated CIA by limiting fatty acid synthesis subsequent to PPARγ activation.

Explaining the intention and behaviours of interinstitutional collaboration in chronic disease management among health care personnel: a cross-sectional study from Fujian Province, China.

BACKGROUND: The increasing number of chronic diseases consumes a large amount of health resources and puts a huge burden on health service system. The integrated management of chronic diseases in Sanming City aims to improve the efficiency and quality of chronic disease management through the collaboration between different levels of medical institutions. AIM: The aim of the present study was to use the theory of planned behaviour (TPB) to examine the intention and behaviours of interinstitutional collaboration in chronic disease management (ICCDM) among healthcare personnel. METHODS: A cross-sectional study of 274 health care personnel was conducted in medical institutions in Fujian Province, China, from March 2022 to April 2022. A self-administered questionnaire based on TPB theory was applied to measure the participants' ICCDM behaviours. RESULTS: The proposed TPB model revealed that attitude was significantly and positively associated with behaviour intention, and behaviour intention and perceived behavioural control were significant predictors of ICCDM behaviour. CONCLUSION: TPB provides insights into ICCDM behaviour. Due to the fact that attitude, perceived behavioural control, and behavioural intention towards ICCDM behaviour were demonstrated to be significant predictors of ICCDM behaviour, these factors may be a promising focus of ICCDM interventions in the integrated management of chronic diseases in China.

Ultrathin Supratrochlear Artery Cutaneous Branch Flaps for Large Defects Around Eyebrows.

BACKGROUND: The key point of repairing large defects around eyebrows is to keep the eyebrow undistorted. The limited skin elevates the application difficulty of conventional methods such as direct suture or local flap. Forehead pedicle flaps do well in tension control. However, most of them are too thick for defects because the frontalis muscle must be included. Recently, 1 stable supratrochlear artery cutaneous branch was found, which provides an opportunity to make an ultrathin forehead flap with a good blood supply. This study aims to investigate whether the supratrochlear artery cutaneous branch flap could perform good esthetic reconstruction for defects around the eyebrow. METHODS: The authors retrospectively included 15 patients whose defect around the eyebrows was repaired by the supratrochlear artery cutaneous branch flap from June 2017 to June 2020. The authors followed up about their flap color and texture, scar, abnormal sensation, any complication, recurrence, and patient satisfaction for at least 6 months online or face-to-face. RESULTS: All of the flaps survived, without distortion of the eyebrows or inner canthi. Similar flap color, texture, and thickness with the nearby skin were obtained, except 2 patients reported pigmentation. Donor and receptor scars were acceptable. There was no recurrence or other complications. All of the patients were satisfied with the surgery effect. CONCLUSIONS: The supratrochlear artery cutaneous branch flap is a valuable alternative method to repair large defects around the eyebrows. It can avoid facial distortion and achieve good esthetic outcomes in single-stage surgery.

[Vitamin A and vitamin D nutritional status among children and adolescents aged 6-17 years in Jiangsu Province during 2016-2017].

OBJECTIVE: This study aimed to investigate vitamin A and vitamin D conditions and related factors among children and adolescents aged 6-17 years in Jiangsu Province of China. METHODS: All the data were derived from China Nutrition and Health Surveillance of Children and Lactating Mothers in 2016-2017. By applying multiple stage stratified cluster random sampling method, 3244 children aged 6-17 years were selected from 12 survey sites in Jiangsu Province. Face to face interview, physical measurements and 6 mL blood sample were used to collect the general information, anthropometric information and blood nutritional indexes of the participants. Multivariate Logistic analysis was used for vitamin A and vitamin D conditions to test related factors. RESULTS: The prevalence of vitamin A deficiency and marginal deficiency was 0.8% and 15.8%, respectively.23.2% of the participants had vitamin D deficiency, 54.2% had vitamin D insufficiency and 4.8% had vitamin A insufficiency combined with vitamin D deficiency. Age group, weight levels, screen time and mother's education levels are the relevant factors of vitamin A insufficiency in children and adolescents. The related factors of vitamin D deficiency among children and adolescents are gender, age group, residence, physical activity level, screen time and mother's education levels. Gender, residence, weight levels, screen time and mother's education levels are the related factors of vitamin A insufficiency combined with vitamin D deficiency. CONCLUSION: Vitamin A insufficiency and vitamin D deficiency are at high epidemic levels among children and adolescents in Jiangsu Province in 2016-2017.

[Cardiovascular complications in malaria: a review].

Malaria, one of the major global public health events, is a leading cause of mortality and morbidity among children and adults in tropical and subtropical regions(mainly in sub-Saharan Africa), threatening human health. It is well known that malaria can cause various complications including anemia, blackwater fever, cerebral malaria, and kidney damage. Conventionally, cardiac involvement has not been listed as a common reason affecting morbidity and mortality of malaria, which may be related to ignored cases or insufficient diagnosis. However, the serious clinical consequences such as acute coronary syndrome, heart failure, and malignant arrhythmia caused by malaria have aroused great concern. At present, antimalarials are commonly used for treating malaria in clinical practice. However, inappropriate medication can increase the risk of cardiovascular diseases and cause severe consequences. This review summarized the research advances in the cardiovascular complications including acute myocardial infarction, arrhythmia, hypertension, heart failure, and myocarditis in malaria. The possible mechanisms of cardiovascular diseases caused by malaria were systematically expounded from the hypotheses of cell adhesion, inflammation and cytokines, myocardial apoptosis induced by plasmodium toxin, cardiac injury secondary to acute renal failure, and thrombosis. Furthermore, the effects of quinolines, nucleoprotein synthesis inhibitors, and artemisinin and its derivatives on cardiac structure and function were summarized. Compared with the cardiac toxicity of quinolines in antimalarial therapy, the adverse effects of artemisinin-derived drugs on heart have not been reported in clinical studies. More importantly, the artemisinin-derived drugs demonstrate favorable application prospects in the prevention and treatment of cardiovascular diseases, and are expected to play a role in the treatment of malaria patients with cardiovascular diseases. This review provides reference for the prevention and treatment of malaria-related cardiovascular complications as well as the safe application of antimalarials.

Chronic exercise increases excitability of lamina X neurons through enhancement of persistent inward currents and dendritic development in mice.

Chronic exercise has been shown to enhance excitability of spinal interneurons in rodents. However, the mechanisms underlying this enhancement remain unclear. In this study we investigated adaptability of lamina X neurons with 3-week treadmill exercise in mice of P21-P24. Whole-cell patch-clamp recording was performed on the interneurons from slices of T12-L4. The experimental results included the following. (1) Treadmill exercise reduced rheobase by 7.4 ± 2.2 pA (control: 11.3 ± 6.1 pA, n = 12; exercise: 3.8 ± 4.6 pA, n = 13; P = 0.002) and hyperpolarized voltage threshold by 7.1 ± 1.5 mV (control: -36.6 ± 4.6 mV, exercise: -43.7 ± 2.7 mV; P = 0.001). (2) Exercise enhanced persistent inward currents (PICs) with increase of amplitude (control: 140.6 ± 56.3 pA, n = 25; exercise: 225.9 ± 62.5 pA, n = 17; P = 0.001) and hyperpolarization of onset voltage (control: -50.3 ± 3.6 mV, exercise: -56.5 ± 5.5 mV; P = 0.001). (3) PICs consisted of dihydropyridine-sensitive calcium (Ca-PIC) and tetrodotoxin-sensitive sodium (Na-PIC) components. Exercise increased amplitude of both components but hyperpolarized onset voltage of Na-PIC only. (4) Exercise reduced derecruitment current of repetitive firing evoked by a current bi-ramp and prolonged firing in the falling phase of the bi-ramp. The derecruitment reduction was eliminated by bath application of 3 µM riluzole or 25 µM nimodipine, suggesting that both Na-PIC and Ca-PIC contributed to the exercise-prolonged hysteresis of firing. (5) Exercise facilitated dendritic development with significant increase in dendritic length by 285.1 ± 113 µm (control: 457.8 ± 171.8 µm, n = 12; exercise: 742.9 ± 357 µm, n = 14; P = 0.019). We concluded that 3-week treadmill exercise increased excitability of lamina X interneurons through enhancement of PICs and increase of dendritic length. This study provided insight into cellular and channel mechanisms underlying adaptation of the spinal motor system in exercise. KEY POINTS: Chronic exercise alters adaptability of the spinal motor system in rodents; multiple mechanisms are responsible for the adaptation, including regulation of neuronal excitability and change in dendritic morphology. Spinal interneurons in lamina X are a cluster of heterogeneous neurons playing multifunctional roles in the spinal cord; chronic exercise in juvenile mice increased excitability of these interneurons and facilitated dendritic development. Lamina X neurons expressed persistent inward currents (PICs) with calcium (Ca-PIC) and sodium (Na-PIC) components; the exercise-increased excitability of lamina X neurons was mediated by enhancing the Ca-PIC and Na-PIC components and increasing dendritic length. This study unveiled novel morphological and ionic mechanisms underlying adaptation of lamina X neurons in rodents during chronic exercise.

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase.

Soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand nitric oxide (NO); sGC thereby acts as an amplifier in NO-driven biological signaling cascades. Because sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production, boosting sGC activity and preventing or reversing sGC inactivation are important therapeutic and pharmacologic goals. Work over the last two decades is uncovering the processes by which sGC matures to become functional, how sGC is inactivated, and how sGC is rescued from damage. A diverse group of small molecules and proteins have been implicated in these processes, including NO itself, reactive oxygen species, cellular heme, cell chaperone Hsp90, and various redox enzymes as well as pharmacologic sGC agonists. This review highlights their participation and provides an update on the processes that enable sGC maturation, drive its inactivation, or assist in its recovery in various settings within the cell, in hopes of reaching a better understanding of how sGC function is regulated in health and disease.

Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation.

Our previous studies have demonstrated that tetrandrine can induce the generation of regulatory T (Treg) cells in vitro and in vivo. But, the underlying mechanism of tetrandrine remains obscure. Naïve CD4+ T cells are isolated from the mesenteric lymph nodes of mice for the differentiation of Treg cells. Flow cytometry is used to detect the frequencies of Treg cells. Non-targeted metabolomics analysis based on UHPLC-QTOF/MS is performed to assess the intracellular metabolic profiles. ChIP-PCR analysis is conducted to detect the level of H3K27ac at Foxp3 promoter and CNS regions. Tetrandrine treatment alters the metabolic profile of Treg cells, and pathway enrichment of differential metabolites mainly involves fatty acid oxidation (FAO). Tetrandrine promotes the mRNA expression of carnitine palmitoyl transferase-1, and increases the level of acetyl coenzyme A (acetyl-CoA) and the intracellular oxygen consumption rate. Either CPT1 inhibitor (etomoxir) or siRNA markedly diminishes the promotion of tetrandrine on Treg cell differentiation. Furthermore, tetrandrine enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl-CoA derived from FAO. In the mice with collagen-induced arthritis, tetrandrine also induces Treg cell generation through FAO pathway. In addition, tetrandrine enhances the immunosuppressive function of Treg cells both in vitro and in vivo. The findings indicate that tetrandrine promotes Treg cell differentiation by enhancing FAO-mediated Foxp3 acetylation, and the CPT1-mediated FAO can serve as the target for the discovery of novel inducers of Treg cell generation.