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Cardiovascular disease is the leading cause of mortality worldwide. Excessive oxidative stress and inflammation play an important role in the development and progression of cardiovascular disease. Molecular hydrogen, a small colorless and odorless molecule, is considered harmless in daily life when its concentration is below 4% at room temperature. Owing to the small size of the hydrogen molecule, it can easily penetrate the cell membrane and can be metabolized without residue. Molecular hydrogen can be administered through inhalation, the drinking of hydrogen-rich water, injection with hydrogen-rich-saline, and bathing of an organ in a preservative solution. The utilization of molecular hydrogen has shown many benefits and can be effective for a wide range of purposes, from prevention to the treatment of diseases. It has been demonstrated that molecular hydrogen exerts antioxidant, anti-inflammatory, and antiapoptotic effects, leading to cardioprotective benefits. Nevertheless, the exact intracellular mechanisms of its action are still unclear. In this review, evidence of the potential benefits of hydrogen molecules obtained from in vitro, in vivo, and clinical investigations are comprehensively summarized and discussed with a focus on the cardiovascular aspects. The potential mechanisms involved in the protective effects of molecular hydrogen are also presented. These findings suggest that molecular hydrogen could be used as a novel treatment in various cardiovascular pathologies, including ischemic-reperfusion injury, cardiac injury from radiation, atherosclerosis, chemotherapy-induced cardiotoxicity, and cardiac hypertrophy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aberrant activation of NLRP3 inflammasome causes the progression of various inflammation-related diseases, but the small-molecule inhibitors of NLRP3 are not currently available for clinical use. Tabersonine (Tab) is a natural product derived from a traditional Chinese herb Catharanthus roseus that is usually used as an anti-tumor agent. In this study we investigated the anti-inflammatory effects and molecular targets of Tab. We first screened 151 in-house natural compounds for their inhibitory activity against IL-1β production in BMDMs. We found that Tab potently inhibited NLRP3-mediated IL-1β production with an IC 50 value of 0.71 μM. Furthermore, we demonstrated that Tab suppressed the assembly of NLRP3 inflammasome, especially the interaction between NLRP3 and ASC. Interestingly, we found that Tab directly bound to NLRP3 NACHT domain, thereby reducing the self-oligomerization of NLRP3. In addition, we showed that administration of Tab significantly ameliorated NLRP3-driven diseases, such as peritonitis, acute lung injury, and sepsis in mouse models. The preventive effects of Tab were not observed in the models of NLRP3 knockout mouse. In conclusion, we have identified Tab as a natural NLRP3 inhibitor and a lead compound for the design and discovery of novel NLRP3 inhibitors., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca 2+ uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCU fl/fl ) and conditional MCU knockout (MCU fl/fl-MCM ) mice. LV function was reduced by chronic iron loading in MCU fl/fl mice, but not in MCU fl/fl-MCM mice. The level of mitochondrial iron and reactive oxygen species were increased and mitochondrial membrane potential and spare respiratory capacity (SRC) were reduced in MCU fl/fl cardiomyocytes, but not in MCU fl/fl-MCM cardiomyocytes. After iron loading, lipid oxidation levels were increased in MCU fl/fl , but not in MCU fl/fl-MCM hearts. Ferrostatin-1, a selective ferroptosis inhibitor, reduced lipid peroxidation and maintained LV function in vivo after chronic iron treatment in MCU fl/fl hearts. Isolated cardiomyocytes from MCU fl/fl mice demonstrated ferroptosis after acute iron treatment. Moreover, Ca 2+ transient amplitude and cell contractility were both significantly reduced in isolated cardiomyocytes from chronically Fe treated MCU fl/fl hearts. However, ferroptosis was not induced in cardiomyocytes from MCU fl/fl-MCM hearts nor was there a reduction in Ca 2+ transient amplitude or cardiomyocyte contractility. We conclude that mitochondrial iron uptake is dependent on MCU, which plays an essential role in causing mitochondrial dysfunction and ferroptosis under iron overload conditions in the heart. Cardiac-specific deficiency of MCU prevents the development of ferroptosis and iron overload-induced cardiac dysfunction., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Inflammation and oxidative stress are mechanisms which potentially underlie the brain damage that can occur after cardiac ischemic and reperfusion (I/R) injury. 2i-10 is a new anti-inflammatory agent, acting via direct inhibition of myeloid differentiation factor 2 (MD2). However, the effects of 2i-10 and the antioxidant N-acetylcysteine (NAC) on pathologic brain in cardiac I/R injury are unknown. We hypothesized that 2i-10 and NAC offer similar neuroprotection levels against dendritic spine reduction through attenuation of brain inflammation, loss of tight junction integrity, mitochondrial dysfunction, reactive gliosis, and suppression of AD protein expression in rats with cardiac I/R injury. Male rats were allocated to either sham or acute cardiac I/R group (30 min of cardiac ischemia and 120 min of reperfusion). Rats in cardiac I/R group were given one of following treatments intravenously at the onset of reperfusion: vehicle, 2i-10 (20 or 40 mg/kg), and NAC (75 or 150 mg/kg). The brain was then used to determine biochemical parameters. Cardiac I/R led to cardiac dysfunction with dendritic spine loss, loss of tight junction integrity, brain inflammation, and mitochondrial dysfunction. Treatment with 2i-10 (both doses) effectively reduced cardiac dysfunction, tau hyperphosphorylation, brain inflammation, mitochondrial dysfunction, dendritic spine loss, and improved tight junction integrity. Although both doses of NAC effectively reduced brain mitochondrial dysfunction, treatment using a high dose of NAC reduced cardiac dysfunction, brain inflammation, and dendritic spine loss. In conclusion, treatment with 2i-10 and a high dose of NAC at the onset of reperfusion alleviated brain inflammation and mitochondrial dysfunction, consequently reducing dendritic spine loss in rats with cardiac I/R injury., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Doxorubicin (DOX) has been recognized as one of the most effective chemotherapies and extensively used in the clinical settings of human cancer. However, DOX-mediated cardiotoxicity is known to compromise the clinical effectiveness of chemotherapy, resulting in cardiomyopathy and heart failure. Recently, accumulation of dysfunctional mitochondria via alteration of the mitochondrial fission/fusion dynamic processes has been identified as a potential mechanism underlying DOX cardiotoxicity. DOX-induced excessive fission in conjunction with impaired fusion could severely promote mitochondrial fragmentation and cardiomyocyte death, while modulation of mitochondrial dynamic proteins using either fission inhibitors (e.g., Mdivi-1) or fusion promoters (e.g., M1) can provide cardioprotection against DOX-induced cardiotoxicity. In this review, we focus particularly on the roles of mitochondrial dynamic pathways and the current advanced therapies in mitochondrial dynamics-targeted anti-cardiotoxicity of DOX. This review summarizes all the novel insights into the development of anti-cardiotoxic effects of DOX via the targeting of mitochondrial dynamic pathways, thereby encouraging and guiding future clinical investigations to focus on the potential application of mitochondrial dynamic modulators in the setting of DOX-induced cardiotoxicity.

Acute lung injury (ALI) is an inflammation-mediated respiratory disease that is associated with a high mortality rate. In this study, a series of novel O-benzylcinnamic acid derivatives were designed and synthesized using cinnamic acid as the lead compound. We tested the preliminary anti-inflammatory activity of the compounds by evaluating their effect on inhibiting the activity of alkaline phosphatase (ALP) in Hek-Blue-TLR4 cells, in which compound L26 showed the best activity and 7-fold more active than CIN. ELISA, immunoprecipitation, and molecular docking indicated that L26 targeted MD-2 protein and competed with LPS to bind to MD-2, which resulted in the inhibition of inflammation. In the LPS-induced mouse model of ALI, L26 was found to decrease ALP activity and inflammatory cytokine TNF-α release to reduce lung injury by inhibiting the NF-κB signaling pathway. Acute toxicity experiments showed that high doses of L26 did not cause adverse reactions in mice, and it was safe in vivo. Also, the preliminary pharmacokinetic parameters of L26 were investigated in SD rats (T 1/2  = 4.246 h). In summary, L26 exhibited optimal pharmacodynamic and pharmacokinetic characteristics, which suggested that L26 could serve as a potential agent for the development of ALI treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Environmental pollution, which contains ambient particulate matter, has been shown to have a significant impact on human health and longevity over the past 30 years. Recent studies clearly showed that exposure to particulate matter directly caused adverse effects on the respiratory system via various mechanisms including the accumulation of free radical peroxidation, the imbalance of intercellular calcium regulation, and inflammation, resulting in respiratory diseases. Recent evidence showed the importance of the role of the respiratory microbiome on lung immunity and lung development. In addition, previous studies have confirmed that several chronic respiratory diseases were associated with an alteration in the respiratory microbiome. However, there is still a lack of knowledge with regard to the changes in the respiratory microbiome with regard to the role of particulate matter exposure in respiratory diseases. Therefore, this review aims to summarize and discuss all the in vivo to clinical evidence which investigated the effect of particulate matter exposure on the respiratory microbiome and respiratory diseases. Any contradictory findings are incorporated and discussed. A summary of all these pieces of evidence may offer an insight into a therapeutic approach for the respiratory diseases related to particulate matter exposure and respiratory microbiome., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery., Experimental Approach: A compound library containing 160 natural products was used to screen potential anti-inflammatory compounds. Mice with LPS-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds., Key Results: Licochalcone A was discovered from the anti-inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation-regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro-inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo, licochalcone A treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction., Conclusion and Implications: In summary, our study identified MD2 as a direct target of licochalcone A for its anti-inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy., (© 2022 British Pharmacological Society.)

Regardless of the progress made in the pathogenesis of ischemic stroke, it remains a leading cause of adult disability and death. To date, the most effective treatment for ischemic stroke is the timely recanalization of the occluded artery. However, the short time window and reperfusion injury have greatly limited its application and efficacy. Mitochondrial dysfunction and ATP depletion have become regarded as being hallmarks of neuropathophysiology following ischemic stroke. Mitochondrial transplantation is a novel potential therapeutic intervention for ischemic stroke that has sparked widespread concern during the past few years. This review summarizes and discusses the effects of mitochondrial transplantation in in vitro and in vivo ischemic stroke models. In addition, pharmacological interventions promoting mitochondrial transplantation are reviewed and discussed. We also discuss the potential challenges to the clinical application of mitochondrial transplantation in the treatment of ischemic stroke., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute lung injury (ALI) and sepsis, characterized by systemic inflammatory response syndrome, remain the major causes of death in severe patients. Inhibiting the release of proinflammatory cytokines is considered to be a promising method for the treatment of inflammation-related diseases. In this study, a total of 28 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivatives were designed and synthesized and their anti-inflammatory activities in J774A.1 were evaluated. Among them, derivative 13a was found to significantly inhibit lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) on J774A.1, THP-1 and LX-2 cells, and inhibited the activation of the NF-κB pathway. Furthermore, administration of 13ain vivo significantly improved the symptoms in LPS-induced ALI mice, including alleviation of pathological changes in the lung tissue, reduction of pulmonary edema, and inhibition of macrophage infiltration. Moreover, the administration of 13ain vivo significantly promoted survival in LPS-induced sepsis mice. 13a demonstrated favorable pharmacokinetic properties with T 1/2 value of 11.8 h and F value of 36.3%. Therefore, this study has identified a novel 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivative, 13a, which is an effective anti-inflammatory agent. The findings have laid a foundation for the further development of agents to treat ALI and sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Mitochondrial dysfunction is a factor potentially contributing to the Aging process. However, evidence surrounding changes in mitochondrial function and aging is still limited; therefore, this study aimed to investigate further the association between them. Possible confounding factors were included in the statistical analysis to explore the possibility of any independent associations. One thousand seven hundred and sixty-nine participants (619 middle-aged adults [age < 65] and 1,150 older adults [age ≥ 65]) from the Electricity Generating Authority of Thailand were enrolled in the study. The clinical characteristics and medical history were collected. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood and used for analysis of mitochondrial function. Several parameters pertinent to mitochondrial respiration including non-mitochondrial respiration, basal respiration, maximal respiration, proton leak, and spare respiratory capacity were found to be two to three times lower in the mitochondria isolated from the cells of older adults. Interestingly, the mitochondrial ATP production was only slightly reduced, and the percentage of coupling efficiency of PBMC mitochondria was significantly higher in the older adult group. The mitochondrial mass and oxidative stress were significantly reduced in older adult participants; however, the ratio of oxidative stress to mass was significantly increased. The association of these parameters with age was still shown to be the same from the outcome of the multivariate analyses. The mitochondrial functions and mitochondrial mass in PBMCs were shown to decline in association with age. However, the upregulation of mitochondrial oxidative stress production and mitochondrial coupling efficiency might indicate a compensatory response in mitochondria during aging., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Mitochondrial dynamics play a pivotal role in maintaining the homeostasis of the dental pulp. Inflammation and oxidative stress can trigger changes in mitochondrial dynamics, leading to cell death in the dental pulp. This study aimed to investigate inflammation, oxidative stress, mitochondrial dynamic alterations, and cell death in inflamed pulpal tissues compared to healthy pulp tissues., Methods: Pulpal tissues were collected (n=15 per group) from: 1) healthy people as the control and 2) people with clinically diagnosed irreversible pulpitis. Proteins indicating inflammation, oxidative stress, mitochondrial dynamics, and cell death markers were investigated by western blot analysis. A Student's t-test was used to analyse differences between the healthy and irreversible pulpitis groups. A probability of 0.05 was used to indicate statistical significance (p<0.05)., Results: The expression of the proteins, tumour necrosis factor-alpha (TNF-α) and nuclear factor kappa-lightchain-enhancer, by activated B cells (NF-κB) from inflamed pulp tissues were significantly higher than those of control. Compared to controls, 4 hydroxynonenal (4HNE) and dynamin-related protein 1 (Drp1) were significantly higher, while mitofusin 2 (MFN2) and optic atrophy type 1 (OPA1) were significantly lower in inflamed pulp tissues. Bcl-2-associated X protein (Bax), cleaved caspase-3, and cytochrome c were significantly higher in inflamed pulpal tissues compared to controls. In inflamed pulpal tissues, we found a significant increase in the expression of receptor-interacting serine or threonine-protein kinase 1 (RIPK1) but not receptor-interacting serine or threonine-protein kinase 3 (RIPK3)., Conclusion: Irreversible pulpitis is associated with inflammation, oxidative stress, alterations in mitochondrial dynamics, and apoptosis in pulpal tissues. (EEJ-2022-01-014).

Doxorubicin is a potent chemotherapeutic drug; however, its clinical application has been limited due to its cardiotoxicity. One of the major mechanisms of doxorubicin-induced cardiotoxicity is the induction of oxidative stress. Evidence from in vitro and in vivo studies demonstrates that melatonin attenuated the increase in ROS production and lipid peroxidation from doxorubicin. Melatonin has been shown to exert protective effects on mitochondria damaged by doxorubicin via attenuating the depolarization of the mitochondrial membrane, restoring ATP production, and maintaining mitochondrial biogenesis. Doxorubicin increased mitochondrial fragmentation which impaired mitochondrial function; however, these adverse effects were reversed by melatonin. Melatonin also modulated cell death pathways by suppressing apoptotic and ferroptotic cell death caused by doxorubicin. These beneficial effects of melatonin could be responsible for the attenuation of changes in ECG, left ventricular dysfunction, and hemodynamic deterioration caused by doxorubicin. Despite these potential benefits, clinical evidence regarding the impact of melatonin in reducing cardiotoxicity induced by doxorubicin is still limited. Further clinical studies are justified to evaluate the efficacy of melatonin in protecting against doxorubicin-induced cardiotoxicity. This valuable information can be used to warrant the use of melatonin in a clinical setting under this condition.

The fate of osteoprogenitor cells along with the progression of type 2 diabetes (T2DM) and factors determining the fate of those cells remains to be elucidated. This cross-sectional study included 18 normoglycemic, 27 prediabetic, and 73 T2DM to determine osteogenic differentiation across the continuum of dysglycemia and to construct a model to predict the fate of osteoprogenitor cells. This study demonstrated a preserved osteogenic differentiation ability of peripheral blood-derived mononuclear cells (PBMC) isolated from normoglycemic and prediabetic but a progressive decline in their osteogenic differentiation during the progression of T2DM. The rate of osteogenic differentiation rapidly declined by 4-7% annually during the first 10 years of diabetes and then slowed down. A predictive model composed of three independent risk factors, including age, duration of diabetes, and glomerular filtration rate, demonstrated an AuROC of 0.834. With a proposed cut-off of 21.25, this model had 72.0% sensitivity, 87.5% specificity, and 78.9% accuracy in predicting the fate of osteoprogenitor cells. In conclusion, this study provided a perspective on the osteogenic differentiation ability of the osteoprogenitor cells across a continuum of dysglycemia and a predictive model with good diagnostic performance for the prediction of the fate of osteoprogenitor cells in patients with T2DM., (© 2023. The Author(s).)

Purpose: There is an increasing body of evidence to show that impairment in mitochondrial dynamics including excessive fission and insufficient fusion has been observed in the pre-diabetic condition. In pre-diabetic rats with cardiac ischemia-reperfusion (I/R) injury, acute treatment with a mitochondria fission inhibitor (Mdivi-1) and a fusion promoter (M1) showed cardioprotection. However, the potential preventive effects of chronic Mdivi-1 and M1 treatment in a pre-diabetic model of cardiac I/R have never been elucidated., Methods: Male Wistar rats (n = 40) were fed with a high-fat diet (HFD) for 12 weeks to induce prediabetes. Then, all pre-diabetic rats received the following treatments daily via intraperitoneal injection for 2 weeks: (1) HFDV (Vehicle, 0.1% DMSO); (2) HFMdivi1 (Mdivi-1 1.2 mg/kg); (3) HFM1 (M1 2 mg/kg); and (4) HFCom (Mdivi-1 + M1). At the end of treatment protocols, all rats underwent 30 min of coronary artery ligation followed by reperfusion for 120 min., Results: Chronic Mdivi-1, M1, and the combined treatment showed markedly improved cardiac mitochondrial function and dynamic control, leading to a decrease in cardiac arrhythmias, myocardial cell death, and infarct size (49%, 42%, and 51% reduction for HFMdivi1, HFM1, and HFCom, respectively vs HFDV). All of these treatments improved cardiac function following cardiac I/R injury in pre-diabetic rats., Conclusion: Chronic inhibition of mitochondrial fission and promotion of fusion exerted cardioprevention in prediabetes with cardiac I/R injury through the relief of cardiac mitochondrial dysfunction and dynamic alterations, and reduction in myocardial infarction, thus improving cardiac function., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To determine the effects of lipopolysaccharides (LPS), hydrogen peroxide (H 2 O 2 ), and both combined on cell proliferation/differentiation, inflammation, mitochondrial dynamics as indicated by mitochondrial fission/fusion, antioxidants as indicated by superoxide dismutase 2 (SOD2), and apoptosis of human dental pulpal cells (HDPCs)., Methodology: Pulpal tissues from eight healthy subjects (n = 8) were collected from Faculty of Dentistry, Chiang Mai University. Isolated HDPCs from healthy donors were divided into four experimental groups: vehicle, 20 μg/ml LPS, 400 μM H 2 O 2 , and the two combined. All experimental groups were investigated to assess cell proliferation, mineralization, differentiation, inflammation, mitochondrial dynamics, antioxidants, and apoptosis., Results: H 2 O 2 and combined agents decreased cell proliferation of HDPCs equally. LPS, H 2 O 2, and both combined decreased mineralization and differentiation with an increase in tumour necrosis factor-alpha (TNF-α) levels. Surprisingly, LPS and combined agents increased SOD2 expression and caused an imbalance in mitochondrial dynamics. A significant increase in apoptosis was observed in the case of H 2 O 2 and combined agents., Conclusions: These findings suggest that LPS induced inflammation, imbalanced mitochondrial dynamics, and reduced cell differentiation without altering apoptosis and cell proliferation. However, H 2 O 2 decreased cell proliferation, and differentiation, and increased inflammation, and apoptosis without interfering with mitochondrial dynamics. Based on our findings, combining LPS and H 2 O 2 could be potentially used as the inducers in in vitro study to mimic the clinical pulpitis., (© 2022 British Endodontic Society. Published by John Wiley & Sons Ltd.)

Trastuzumab has an impressive level of efficacy as regards antineoplasticity, however it can cause serious cardiotoxic side effects manifested by impaired cardiac contractile function. Although several pharmacological interventions, including melatonin and metformin, have been reported to protect against various cardiovascular diseases, their potential roles in trastuzumab-induced cardiotoxicity remain elusive. We hypothesized that either melatonin or metformin co-treatment effectively attenuates trastuzumab-mediated cardiotoxicity through attenuating the impaired mitochondrial function and mitochondrial dynamics. Male Wistar rats were divided into control (normal saline, n = 8) and trastuzumab group (4 mg/kg/day for 7 days, n = 24). Rats in the trastuzumab group were subdivided into 3 interventional groups (n = 8/group), and normal saline, or melatonin (10 mg/kg/day), or metformin (250 mg/kg/day) were orally administered for 7 consecutive days. Cardiac parameters were determined, and biochemical investigations were carried out on blood and heart tissues. Trastuzumab induced left ventricular (LV) dysfunction by increasing oxidative stress, inflammation, and apoptosis. It also impaired cardiac mitochondrial function, dynamics, and autophagy. Treatment with either melatonin or metformin equally attenuated trastuzumab-induced cardiac injury, indicated by a marked reduction in inflammation, oxidative damage, cardiac mitochondrial injury, mitochondrial dynamic imbalance, autophagy dysregulation, and apoptosis, leading to improved LV function, as demonstrated by increased LV ejection fraction. Melatonin and metformin conferred equal levels of cardioprotection against trastuzumab-induced cardiotoxicity, which may provide novel and promising approaches for management of cardiotoxicity induced by trastuzumab., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The blockade of the overexpression of pro-inflammatory cytokines by anti-inflammatory natural products has been proven therapeutically beneficial in the treatment of acute lung injury (ALI). Given the fact that cinnamic acid has been proven to have significant anti-inflammatory activity, we selected it as a promising lead compound to develop more effective analogs in treating ALI. Learning from the symmetric structure of curcumin, 32 new symmetric cinnamic derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Among them, 6h not only displayed a remarkable inhibitory activity in vitro (85.9% and 65.7% for  IL-6 and TNF-α, respectively) without cytotoxicity but also possessed chemical structure stability. Furthermore, an in vivo study in mice revealed that the administration of 6h significantly attenuated lipopolysaccharide-induced ALI, providing new lead structures for the development of anti-inflammatory drugs for the treatment of ALI., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

This study aimed to identify the alterations of blood metabolome levels and their association with cardiac dysfunction and cardiac injury following treatment with doxorubicin and trastuzumab. Eight-week-old male Wistar rats were divided into four groups (n = 6 per group) to receive intraperitoneal injection with either: (1) 1 mL of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin); (2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group); (3) 1 mL of NSS at days 0-6 (control group for trastuzumab); or (4) 4 mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was determined. The rats were then euthanized to collect venous blood and the heart for the quantification of 107 serum and 100 cardiac metabolomes using mass spectrometry-based targeted metabolomics. We observed strong relationships between 72 cardiac versus 61 serum metabolomes in doxorubicin and trastuzumab groups. Moreover, significant correlations between cardiac function and the cardiac injury biomarker versus 28 and 58 serum metabolomes were revealed in doxorubicin and trastuzumab-treated rats, respectively. Interestingly, the patterns of both serum and cardiac metabolome alterations differed between doxorubicin and trastuzumab groups. Our findings emphasize the potential role of the constituents of the blood metabolome as non-invasive biomarkers to assess severity and prognosis of heart failure induced by doxorubicin and trastuzumab. These findings may contribute to the development of metabolic-targeted therapy specific for cardioprotection during different phases of cancer treatment., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: The present study was aimed to investigate the effects of cell death inhibitors including ferroptosis inhibitor, ferrostatin-1 (FER-1) and a pan-caspase inhibitor, z-VAD-FMK on brain parameters and cognitive function in iron-overloaded rats., Main Methods: Male Wistar rats (n = 30) were divided into 2 groups to receive an intraperitoneal injection with either 10 % dextrose in normal saline solution (NSS) (control group, n = 6) or 100 mg/kg iron dextran (Fe group, n = 24) for 6 weeks. After 4 weeks of injection, Fe-injected rats were subdivided into 4 subgroups (n = 6/subgroup) to subcutaneously receive with 1) vehicle (10 % DMSO in NSS), 2) deferoxamine (25 mg/kg), 3) FER-1 (2 mg/kg), or 4) z-VAD-FMK (1 mg/kg). Control group was received vehicle. All subgroups were received each treatment for 2 weeks. Behavioral tests including the Morris water maze test and novel object recognition test, were performed at the end of treatment. Then, circulating iron levels and brain parameters including blood-brain barrier proteins, iron level, synaptic proteins, and ferroptosis/apoptosis were determined., Key Findings: All treatment attenuated iron-overloaded condition, brain pathologies, and the cognitive impairment. FER-1 and z-VAD-FMK provided superior effects than deferoxamine by attenuating loss of synaptic proteins and restoring cognitive function in both hippocampal-dependent and hippocampal-independent manners., Significance: These findings suggest that cell death inhibitors act as the novel therapeutic targets for neuroprotection in iron-overloaded condition., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Acute lung injury (ALI) is a devastating disease with a high mortality rate of 30%-40%. There is an unmet clinical need owing to limited treatment strategies and little clinical benefit. The pathology of ALI indicates that reducing the inflammatory response could be a highly desirable strategy to treat ALI. In this study, we designed and synthesized 36 novel 1-(4-(benzylsulfonyl)-2-nitrophenyl) derivatives and evaluated their anti-inflammatory activities by measuring the release of cytokines in lipopolysaccharide (LPS)-challenged J774A.1 cells. Compounds 19, 20, and 39 potently reduced the release of IL-6 and TNF-α in J774A.1 cells. Additionally, 39 improved LPS-induced ALI in vivo and inhibited cytokine production in lung tissues. Furthermore, 39 reduced inflammatory infiltration and downregulated p-p65 levels in lung tissues. Thus, compound 39 could serve as a new lead structure for the development of anti-inflammatory drugs to treat ALI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Myocardial infarction (MI) has recently accounted for more than one-third of global mortality. Multiple molecular pathological pathways, such as oxidative stress, inflammation, and mitochondrial dysfunction, have been recognized as possible mechanisms in the development of MI. Furthermore, different phases of ischemic injury following the progression of MI were also associated with multiple types of programmed cell death (PCDs), including apoptosis, necroptosis, ferroptosis, and pyroptosis. However, it remains unknown whether which types of PCDs play the most dominant role in post-myocardial infarction (post-MI)., Method: In this study, we used a preclinical rat model of MI induced by permanent left anterior descending coronary artery (LAD) ligation (n = 6) or a sham operated rat model (n = 6). After a 5-week experiment, cardiac function and morphology, mitochondrial studies, and molecular signaling analysis of PCDs were determined., Results: Herein, we demonstrated that post-MI rats had considerably impaired cardiac geometry, increased oxidative stress, myocardial injuries, and subsequently contractile dysfunction. They also exhibited worsened cardiac mitochondrial function and dynamic imbalance. More importantly, we found that post-MI mediated abundant myocardial cell death through multiple PCDs, including apoptosis, necroptosis, and pyroptosis, but not ferroptosis., Conclusion: In this study, we provide the first insights into the mechanism of PCDs by pyroptosis, which is leveraged as the most dominant mode of cell death after MI., (© 2023. The Author(s).)

Objective: To compare the levels of Non-transferrin bound iron (NTBI) in fetuses with anemia, using Hb Bart's disease as a study model, and those in unaffected fetuses and to determine the association between fetal cardiac function and the levels of NTBI., Patients and Methods: A prospective study was conducted on pregnancies at risk of fetal Hb Bart's disease. All fetuses underwent standard ultrasound examination at 18-22 weeks of gestation for fetal biometry, anomaly screening and fetal cardiac function. After that, 2 ml of fetal blood was taken by cordocentesis to measure NTBI by Labile Plasma Iron (LPI), serum iron, hemoglobin and hematocrit. The NTBI levels of both groups were compared and the correlation between NTBI and fetal cardiac function was determined., Results: A total of 50 fetuses, including 20 fetuses with Hb Bart's disease and 30 unaffected fetuses were recruited. There was a significant increase in the level of serum iron in the affected group (median: 22.7 vs. 9.7; p -value: 0.013) and also a significant increase in NTBI when compared with those of the unaffected fetuses (median 0.11 vs. 0.07; p -value: 0.046). In comparisons of fetal cardiac function, myocardial performance (Tei) index of both sides was significantly increased in the affected group (left Tei: p = 0.001, Right Tei: p = 0.008). Also, isovolumetric contraction time (ICT) was also significantly prolonged (left ICT: p = 0.00, right ICT: p = 0.000). Fetal LPI levels were significantly correlated inversely with fetal hemoglobin levels ( p = 0.030) but not significantly correlated with the fetal serum iron levels ( p = 0.138). Fetal LPI levels were also significantly correlated positively with myocardial performance index (Tei) of both sides (right Tei: R = 0.000, left Tei: R = 0.000) and right ICT ( R = 0.013), but not significantly correlated with left ICT ( R = 0.554)., Conclusion: Anemia caused by fetal Hb Bart's disease in pre-hydropic stage is significantly associated with fetal cardiac dysfunction and increased fetal serum NTBI levels which are significantly correlated with worsening cardiac dysfunction. Nevertheless, based on the limitations of the present study, further studies including long-term data are required to support a role of fetal anemia as well as increased fetal serum NTBI levels in development of subsequent heart failure or cardiac compromise among the survivors, possibly predisposing to cardiovascular disease in adult life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jatavan, Sekararithi, Jaiwongkam, Kumfu, Chattipakorn and Tongsong.)

Cardiomyocyte death is one of the major mechanisms contributing to the development of myocardial infarction (MI) and myocardial ischemia/reperfusion (MI/R) injury. Due to the limited regenerative ability of cardiomyocytes, understanding the mechanisms of cardiomyocyte death is necessary. Pyroptosis, one of the regulated programmed cell death pathways, has recently been shown to play important roles in MI and MI/R injury. Pyroptosis is activated by damage-associated molecular patterns (DAMPs) that are released from damaged myocardial cells and activate the formation of an apoptosis-associated speck-like protein containing a CARD (ASC) interacting with NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), resulting in caspase-1 cleavage which promotes the activation of Gasdermin D (GSDMD). This pathway is known as the canonical pathway. GSDMD has also been shown to be activated in a non-canonical pathway during MI and MI/R injury via caspase-4/5/11. Suppression of GSDMD has been shown to provide cardioprotection against MI and MI/R injury. Although the effects of MI or MI/R injury on pyroptosis have previously been discussed, knowledge concerning the roles of GSDMD in these settings remains limited. In this review, the evidence from in vitro , in vivo , and clinical studies focusing on cardiac GSDMD activation during MI and MI/R injury is comprehensively summarized and discussed. Implications from this review will help pave the way for a new therapeutic target in ischemic heart disease., Competing Interests: The authors declare no conflicts of interest., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Obstructive sleep apnea is the most common sleep-related breathing disorder. Repetitive episodes of the obstructive respiratory events lead to arousal, sleep fragmentation, and excessive daytime sleepiness. Orexin, also known as hypocretin, is one of the most important neurotransmitters responsible for sleep and arousal regulation. Deficiency of orexin has been shown to be involved in the pathogenesis of narcolepsy, which shares cardinal symptoms of sleep apnea and excessive daytime sleep with obstructive sleep apnea. However, the relationship between orexin and obstructive sleep apnea is not well defined. In this review, we summarize the current evidence, from in vitro, in vivo, and clinical data, regarding the association between orexin and obstructive sleep apnea. The effects of orexin on sleep apnea, as well as how the consequences of obstructive sleep apnea affect the orexin system function are also discussed. Additionally, the contrary findings are also included and discussed., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Chronic and persistent obesity can lead to various complications, including obesity cardiomyopathy. Inhibition of the inflammatory response is an effective measure for the intervention of obesity cardiomyopathy. Numerous studies indicate that costunolide (Cos) can reduce inflammation. However, the role of Cos in obesity cardiomyopathy and its molecular targets remains unknown., Hypothesis/purpose: We aimed to clarify potential cardioprotective effects and mechanism of Cos against obesity cardiomyopathy., Methods: The model of obesity cardiomyopathy was established by feeding mice with a high-fat diet for 24 weeks. Cos at 10 and 20 mg/kg or vehicle (1% CMCNa solution) was administered once every two days via oral gavage from the 17th to 24th week. Body weight, heart weight/tibia length, cardiac function, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers, inflammatory factors were assessed. The targets of Cos were predicted through molecular docking. Pull-down assay and biolayer interferometry were used to confirm the target of Cos., Results: Cos effectively reduces obesity-induced cardiomyocyte inflammation, cardiac hypertrophy and fibrosis, thereby improving cardiac function. We confirmed that Cos can interact with TAK1 and inhibit downstream NF-κB pathway activation by blocking the formation of the TAK1/TAB2 complex, thus inhibiting inflammatory cytokine release in cardiomyocytes., Conclusion: Our results demonstrated that Cos significantly improved myocardial remodeling and cardiac dysfunction against obesity cardiomyopathy by reducing myocardial inflammation. Therefore, Cos may serve as a promising therapeutic agent in obesity cardiomyopathy., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Melatonin (Mel) and metformin (Met) show beneficial effects in various brain pathologies. However, the effects of Mel and Met on doxorubicin (DOX)-induced chemobrain remain in need of elucidation. We aimed to investigate whether Mel and Met provide neuroprotective effects on glial dysmorphologies, brain inflammation, oxidative stress, brain mitochondrial dysfunction, apoptosis, necroptosis, neurogenesis, hippocampal dysplasticity, and cognitive dysfunction in rats with DOX-induced chemobrain. Thirty-two male Wistar rats were divided into 2 groups and received normal saline (NSS, as control, n = 8) or DOX (3 mg/kg/day; n = 24) by intraperitoneal (i.p.) injection on days 0, 4, 8, 15, 22, and 29. The DOX-treated group was divided into 3 subgroups receiving either vehicle (NSS; n = 8), Mel (10 mg/kg/day; n = 8), or Met (250 mg/kg/day; n = 8) by gavage for 30 consecutive days. Following this, cognitive function was assessed in all rats. The number of glial cells and their fluorescence intensity had decreased, while the glial morphology in DOX-treated rats showed a lower process complexity. Brain mitochondrial dysfunction, an increase in brain inflammation, oxidative stress, apoptosis and necroptosis, a decrease in the number of hippocampal dendritic spines and neurogenesis, and cognitive decline were also observed in DOX-treated rats. Mel and Met equally improved those brain pathologies, resulting in cognitive improvement in DOX-treated rats. In conclusion, concomitant treatment with either Mel or Met counteract DOX-induced chemobrain by preservation of glial morphology, brain inflammation, brain oxidative stress, brain mitochondrial function, hippocampal plasticity, and brain apoptosis. This study highlighted the role of the glia as key mediators in DOX-induced chemobrain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Fibroblast growth factor 21 (FGF21) is closely associated with metabolic syndrome (MetS). An alteration of FGF21 is possibly affected by periodontitis. The present study aimed to investigate the levels of serum FGF21 in MetS patients with generalized periodontitis and its association with periodontal and metabolic parameters., Methods: One hundred forty-six MetS patients were recruited from the CORE (Cohort Of patients at a high Risk for Cardiovascular Events) Thailand registry. All participants received general data interviewing, periodontal examination and blood collection for measurement of FGF21 levels and biochemistry parameters. Periodontitis was defined according to the new classification and divided into two groups of localized periodontitis and generalized periodontitis., Results: FGF21 was significantly higher in generalized periodontitis group when compared with localized periodontitis group (p <  0.05). The significant correlation was observed between FGF21 and variables including number of remaining teeth, mean clinical attachment loss, hypertriglyceridemia and low high-density lipoprotein cholesterol. The elevation of serum FGF21 was associated with presence of generalized periodontitis after adjusting of covariate factors (OR = 27.12, p = 0.012)., Conclusions: The elevation of serum FGF21 might be a potential biomarker for MetS patients who have risk of generalized periodontitis., (© 2022. The Author(s).)

Study Design: A cross-sectional study., Objective: To investigate the correlations between gut microbiota and metabolic parameters in people with different levels of chronic spinal cord injury (SCI)., Setting: An SCI-specialized rehabilitation facility in a university hospital., Methods: Forty-three participants with chronic SCI were recruited. Blood samples of each participant were collected for analysis of metabolic parameters. Feces were collected after the bowel opening method the patient routinely uses to evaluate fecal bacterial microbiota using quantitative RT-PCR. Body composition was examined using dual-energy x-ray absorptiometry (DEXA). Data were analyzed to evaluate the correlations between gut microbiota and other parameters., Results: Of the 43 participants, 31 people (72.1%) were paraplegic and 12 people (27.9%) tetraplegic. Thirty-two people (74.4%) were diagnosed with obesity using the percentage of body fat (% body fat) criteria. The mean (SD) ratio of Firmicutes:Bacteroides (F/B), which represents the degree of gut dysbiosis, was 18.3 (2.45). Using stepwise multivariable linear regression analysis, both having tetraplegia and being diagnosed with obesity from % body fat evaluated by DEXA were independent positively-correlating factors of F/B (p < 0.001 and p = 0.001, respectively), indicating more severe gut dysbiosis in people with tetraplegia than paraplegia., Conclusion: In people with chronic SCI, having tetraplegia and being diagnosed with obesity from % body fat evaluated by DEXA are independent positive-correlating factors of gut dysbiosis. These results indicate a significant association between gut microbiota and the characteristics of SCI as well as metabolic parameters., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Hyperglycemia-associated inflammation contributes to diabetic cardiomyopathy. Myeloid differentiation primary-response protein 88 (MyD88) is an adapter protein of many Toll-like receptors (TLRs) and is recruited to TLRs to initiate inflammatory response in endotoxin-activated innate immunity. However, the role of MyD88 in diabetic cardiomyopathy is unknown. We examined the role and mechanism of MyD88 in inflammatory heart injuries in diabetes and identified MyD88 as a potential target for the treatment of diabetic cardiomyopathy. In this study, we first found that MyD88 expression was increased in cardiomyocytes of diabetic mouse hearts. In cultured cardiomyocytes, MyD88 inhibition either by siRNA or by small-molecular inhibitor LM8 markedly blocked TLR4-MyD88 complex formation, reduced pro-inflammatory mitogen-activated protein kinases/nuclear factor-κB (MAPKs/NF-κB) cascade activation and decreased pro-inflammatory cytokine expression under high glucose condition. Moreover, pharmacologic inhibition of MyD88 by LM8 showed significantly anti-inflammatory, anti-hypertrophic and anti-fibrotic effects in the hearts of both type 1 and type 2 diabetic mice. These beneficial effects of MyD88 inhibition were correlated to the reduced activation of TLR4-MyD88-MAPKs/NF-κB signaling pathways in the hearts. Taken together, MyD88 in cardiomyocytes mediates diabetes-induced cardiac inflammatory injuries and pharmacological inhibition of MyD88 shows significantly cardioprotective effects, indicating MyD88 as a potential therapeutic target for diabetic cardiomyopathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Neurodegeneration, as indicated by brain dysfunction and cognitive decline, is one of the complications associated with obesity and estrogen deprivation. Calorie restriction and exercise regimes improved brain function in neurodegenerative diseases. However, the comparative effects of a combination of calorie restriction with exercise, calorie restriction, and an exercise regime alone on brain/cognitive function in obesity with or without estrogen deprivation have not been investigated. Sixty female rats were fed a normal diet (ND) or a high-fat diet (HFD) for 27 weeks. At week 13, the ND-fed rats underwent a sham operation with sedentary lifestyle, HFD-fed rats were divided into two groups: each having either a sham operation (HFS) or ovariectomy (HFO). At week 20, HFD-fed rats in each group were divided into four subgroups undergoing either a sedentary lifestyle, calorie restriction, exercise regime or a combination of calorie restriction and exercise for 7 weeks. Insulin resistance, cognitive decline and hippocampal pathologies were found in both HFS and HFO rats. HFO rats had higher levels of insulin resistance and hippocampal reactive oxygen species levels than HFS rats. Calorie restriction decreased metabolic disturbance and hippocampal oxidative stress but failed to attenuate cognitive decline in HFS and HFO rats. Exercise attenuated metabolic/hippocampal dysfunctions, resulting in improved cognition only in HFS rats. Combined therapies restored brain function, and cognitive function in HFS and HFO rats. Therefore, a combination of calorie restriction with exercise is probably the greatest lifestyle modification to diminish the brain pathologies and cognitive decline in obesity with or without estrogen deprivation., (Copyright © 2022. Published by Elsevier Inc.)

Chronic kidney disease-mineral and bone disorders (CKD-MBD) is a common complication of CKD Stages 3-5. Hyperphosphatemia is one of the major metabolic components of CKD-MBD, frequently resulting in vascular calcification (VC) in advanced-stage patients. Also, a long duration of renal replacement therapy can cause the worsening of VC, leading to increased cardiovascular morbidity and mortality. Vascular smooth muscle cells play an important role in the development of VC through osteochondrogenic transformation and the apoptotic process. It has been shown that mitochondrial dysfunction is involved with CKD progression, and excessive oxidative stress can aggravate osteoblastic transformation and VC. Currently, novel interventions targeting mitochondrial function and dynamics, in addition to mitochondrial antioxidants, have been studied with the aim of attenuating VC. This review aims to comprehensively summarize and discuss the experimental and clinical reports concerning mitochondrial studies, along with the purpose of interventions that can improve the outcomes of VC among CKD patients., (© 2022 Wiley Periodicals LLC.)

Objectives: At the time of diagnosis, the blood glucose of women with gestational diabetes mellitus (GDM) who require subsequent insulin treatment does not differ from that of women with adequate diet control. Hence, in this study, we aimed to determine the role of maternal gut microbiota as a marker of insulin necessity in GDM and to identify the effect of insulin therapy on gut microbiota composition in mothers with GDM and their newborns., Methods: Seventy-one pregnant women were enrolled into the study, including 38 GDM and 33 non-GDM participants. During the follow-up period, 8 of the 38 GDM subjects required insulin therapy (GDM-I group), whereas 30 of the 38 GDM cases with sufficient glycemic control by diet alone (GDM-D group). Maternal blood and feces were obtained at the time of GDM diagnosis (pretreatment; 24 to 28 weeks of gestation) and before delivery (posttreatment; ≥37 weeks of gestation). Meconium and first feces of the newborns were also collected., Results: Pretreatment, the glycemic profile did not differ between the GDM-D and GDM-I groups. However, the proportions of Clostridiales, Lactobacillus and Bacteroidetes were higher in the GDM-I group than in the non-GDM and GDM-D groups. After treatment, gut microbiota composition showed no difference between non-GDM and GDM-I groups. Interestingly, a higher Firmicutes/Bacteroidetes (F/B) ratio was displayed in GDM-D mothers at posttreatment, and this was also observed in both meconium and first feces of GDM-D newborns., Conclusion: Insulin therapy changed maternal gut microbiota composition, which could be transferable to the mothers' newborns., (Copyright © 2022 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Chemotherapy-induced neurotoxicity is one of the most prevalent side effects in cancer patients and survivors. Cognitive decline and peripheral neuropathy are the most common chemotherapy-induced neurotoxic symptoms. These symptoms lead not only to the limiting of the dose of chemotherapy given to cancer patients, but also have an impact on the quality of life of cancer survivors. Although the exact mechanisms involved in chemotherapy-induced neurotoxicity are still unclear, neuroinflammation is widely regarded as being one of the major causes involved in chemotherapy-induced neurotoxicity. It is known that Toll-like receptor 4 (TLR4) plays a critical role in the inflammatory process, and it has been recently reported that it is associated with chemotherapy-induced neurotoxicity. In this review, we summarize and discuss all available evidence regarding the activation of the TLR4 signaling pathway in various models of chemotherapy-induced neurotoxicity. This review also emphasizes the evidence pertinent to TLR4 inhibition on chemotherapy-induced neurotoxicity in rodent studies. Understanding the role of the TLR4 signaling pathway behind chemotherapy-induced neurotoxicity is crucial for improving treatments and ensuring the long-term survival of cancer patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Interruptins A and B exhibited anti-diabetic, anti-inflammatory, and anti-oxidative effects. This study aimed to investigate the therapeutic ability of extract enriched by interruptins A and B (EEI) from an edible fern Cyclosorus terminans on insulin resistance and non-alcoholic fatty liver disease (NAFLD) in a high-fat diet (HFD)-induced obese rats and elucidate their possible mechanisms. HFD-induced obese rats were treated with EEI for 2 weeks. Real-time polymerase chain reaction (PCR) was used to examine the molecular basis. We found that EEI supplementation significantly attenuated body and liver weight gain, glucose intolerance, and insulin resistance. Concurrently, EEI increased liver and soleus muscle glycogen storage and serum high-density lipoprotein (HDL) levels. EEI also attenuated NAFLD, as indicated by improving liver function. These effects were associated with enhanced expression of insulin signaling genes ( Slc2a2, Slc2a4, Irs1 and Irs2 ) along with diminished expression of inflammatory genes ( Il6 and Tnf ). Furthermore, EEI led to the suppression of lipogenesis genes, Srebf1 and Fasn , together with an increase in fatty acid oxidation genes, Ppara and Cpt2 , in the liver. These findings suggest that EEI could ameliorate HFD-induced insulin resistance and NAFLD via improving insulin signaling pathways, inflammatory response, lipogenesis, and fatty acid oxidation.

Doxorubicin (DOXO)-induced cardiomyopathy (DIC) is a lethal complication in cancer patients. Major mechanisms of DIC involve oxidative stress in cardiomyocytes and hyperactivated immune response. Extracellular vesicles (EVs) mediate cell-cell communication during oxidative stress. However, functions of circulating EVs released after chronic DOXO exposure on cardiomyocytes and immune cells are still obscured. Herein, we developed a DIC in vivo model using male Wistar rats injected with 3 mg/kg DOXO for 6 doses within 30 days (18 mg/kg cumulative dose). One month after the last injection, the rats developed cardiotoxicity evidenced by increased BCL2-associated X protein and cleaved caspase-3 in heart tissues, along with N-terminal pro B-type natriuretic peptide in sera. Serum EVs were isolated by size exclusion chromatography. EV functions on H9c2 cardiomyocytes and NR8383 macrophages were evaluated. EVs from DOXO-treated rats (DOXO&#95;EVs) attenuated ROS production via increased glutathione peroxidase-1 and catalase gene expression, and reduced hydrogen peroxide-induced cell death in cardiomyocytes. In contrast, DOXO&#95;EVs induced ROS production, interleukin-6, and tumor necrosis factor-alpha, while suppressing arginase-1 gene expression in macrophages. These results suggested the pleiotropic roles of EVs against DIC, which highlight the potential role of EV-based therapy for DIC with a concern of its adverse effect on immune response.

Inflammatory bowel disease (IBD) comprises a group of intestinal disorders, including ulcerative colitis and Crohn's disease. Currently, the incidence and prevalence of IBD are increasing globally. Although both biologic agents and small molecule drugs have been available for treatment of IBD patients, approximately one third of treated patients do not respond to these treatments. Therefore, novel therapy or repurposing of drugs have been extensively studied to obtain an effective therapy for IBD patients. Among these drugs, metformin has been reported to exert beneficial effects in many organs via its anti-inflammatory effect. Additionally, evidence from cellular to clinical models of IBD demonstrated significant positive effects of metformin on inflammatory pathways, oxidative stress, gut barrier integrity, and gut microbiota. In this review, the beneficial effects of metformin on IBD are comprehensively summarized and discussed using the results of in vitro, in vivo, and clinical studies. Increased understanding of these protective effects and the underlying mechanisms may pave the way for effective use of metformin in IBD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Air pollution remains the major environmental problem globally. There is extensive evidence showing that the variety of air pollutants from environmental and occupational exposures cause adverse effects to our health. The clinical symptoms of those effects may present at a late stage, so surveillance is difficult to manage. Several biomarkers have been used for the early detection of health issues following exposure to air pollution, including the use of telomere length which indicates cellular senescence in response to oxidative stress. Oxidative stress is one of the most plausible mechanisms associated with exposure to air pollutants. Some specific contexts including age groups, gender, ethnicity, occupations, and health conditions, showed significant alterations in telomere length after exposure to air pollutants. Several reports demonstrated both negative and positive associations between telomere length and air pollution, the studies using different concentrations and exposure times to air pollution on the study of telomere lengths. Surprisingly, some studies reported that low levels of exposure to air pollutants (lower than regulated levels) caused the alterations in telomere length. Those findings suggest that telomere length could be one of most practical biomarkers in air pollution surveillance. Therefore, this review aimed to summarize and discuss the relationship between telomere length and exposure to air pollution. The knowledge from this review will be beneficial for the planning of public health to reduce health problems in the general population, particularly in vulnerable people, who still live in areas with high air pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Orofacial clefts are among the most common craniofacial anomalies with multifactorial etiologies, including genetics and environments. DNA methylation, one of the most acknowledged mechanisms of epigenetics, is involved in the development of orofacial clefts. DNA methylation has been examined in patients with non-syndromic cleft lip with cleft palate (nsCL/P) from multiple specimens, including blood, saliva, lip, and palate, as well as experimental studies in mice. The results can be reported in two different trends: hypomethylation and hypermethylation. Both hypomethylation and hypermethylation can potentially increase the risk of nsCL/P depending on the types of specimens and the specific regions on each gene and chromosome. This is the most up-to-date review, intending to summarize evidence of the alterations of DNA methylation in association with the occurrence of orofacial clefts. To make things straightforward to understand, we have systematically categorized the data into four main groups: human blood, human tissues, animal models, and the factors associated with DNA methylation. With this review, we are moving closer to the core of DNA methylation associated with nsCL/P development; we hope this is the initial step to find a genetic tool for early detection and prevention of the occurrence of nsCL/P.

Aims: This study aimed to investigate the changes in gut microbiota in iron-overload thalassemia and the roles of an iron chelator on gut dysbiosis/inflammation, and metabolites, including short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO)., Main Methods: Adult male C57BL/6 mice both wild-type (WT: n = 15) and heterozygous β-thalassemia (BKO: n = 15) were fed on either a normal (ND: n = 5/group) or a high‑iron diet for four months (HFe: n = 10/group). HFe-treated WT and HFe-treated BKO groups were further subdivided into two subgroups and each subgroup given either vehicle (n = 5/subgroup) or deferiprone (n = 5/subgroup) during the last month. Gut microbiota profiles, gut barrier characteristics, levels of proinflammatory cytokines, and plasma SCFAs and TMAO were determined at the end of the study., Key Findings: HFe-fed WT mice showed distinct gut microbiota profiles from those of ND-fed WT mice, whereas HFe-fed BKO mice showed slightly different gut microbiota profiles from ND-fed BKO. Gut inflammation and barrier disruption were found only in HFe-fed BKO mice, however, an increase in plasma TMAO levels and decreased levels of SCFAs were observed in both WT and BKO mice with HFe-feeding. Treatment with deferiprone, gut dysbiosis and disturbance of metabolites were attenuated in HFe-fed WT mice, but not in HFe-fed BKO mice. Increased Verrucomicrobia and Ruminococcaceae were associated with the beneficial effects of deferiprone., Significance: Iron-overload leads to gut dysbiosis/inflammation and disturbance of metabolites, and deferiprone alleviates those conditions more effectively in WT than in those that are thalassemic., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Tourniquet-induced ischemia and reperfusion (I/R) has been related to postoperative muscle atrophy through mechanisms involving protein synthesis/breakdown, cellular metabolism, mitochondrial dysfunction, and apoptosis. Ischemic preconditioning (IPC) could protect skeletal muscle against I/R injury. This study aims to determine the underlying mechanisms of IPC and its effect on muscle strength after total knee arthroplasty (TKA)., Methods: Twenty-four TKA patients were randomized to receive either sham IPC or IPC (3 cycles of 5-min ischemia followed by 5-min reperfusion). Vastus medialis muscle biopsies were collected at 30 ​min after tourniquet (TQ) inflation and the onset of reperfusion. Western blot analysis was performed in muscle protein for 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1 ser616 , Drp1, Mfn1, Mfn2, Opa1, PGC-1ɑ, ETC complex I-V, cytochrome c , cleaved caspase-3, and caspase-3. Clinical outcomes including isokinetic muscle strength and quality of life were evaluated pre- and postoperatively., Results: IPC significantly increased Mfn2 (2.0 ​± ​0.2 vs 1.2 ​± ​0.1, p  ​= ​0.001) and Opa1 (2.9 ​± ​0.3 vs 1.9 ​± ​0.2, p  ​= ​0.005) proteins expression at the onset of reperfusion, compared to the ischemic phase. There were no differences in 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1 ser616 /Drp1, Mfn1, PGC-1ɑ, ETC complex I-V, cytochrome c , and cleaved caspase-3/caspase-3 expression between the ischemic and reperfusion periods, or between the groups. Clinically, postoperative peak torque for knee extension significantly reduced in the sham IPC group (-16.6 [-29.5, -3.6] N.m, p  ​= ​0.020), while that in the IPC group was preserved (-4.7 [-25.3, 16.0] N.m, p  ​= ​0.617)., Conclusion: In TKA with TQ application, IPC preserved postoperative quadriceps strength and prevented TQ-induced I/R injury partly by enhancing mitochondrial fusion proteins in the skeletal muscle., The Translational Potential of This Article: Mitochondrial fusion is a potential underlying mechanism of IPC in preventing skeletal muscle I/R injury. IPC applied before TQ-induced I/R preserved postoperative quadriceps muscle strength after TKA., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:P. Leurcharusmee receives a grant from the Faculty of Medicine Research Fund of Chiang Mai University [grant number 014/2562]. N. Chattipakorn receives grants from the National Science and Technology Development Agency of Thailand [contact grant number: NSTDA Research Chair Grant (NC)] and Chiang Mai University [contact grant number: Center of CMU Excellence Award (NC)]. S.C. Chattipakorn receives a grant from the National Research Council of Thailand [contact grant number: Senior Research Scholar Grant (SCC)]., (© 2022 The Authors.)

Trimethylamine- N -oxide (TMAO) has been shown to be associated with cardiovascular (CV) disease and cognitive impairment. The association between early stages of cognitive impairment and TMAO in a high CV risk population has not been previously investigated. This study aimed to investigate the association between the plasma TMAO level and cognitive function in a population with a high risk of CV disease. Participants at a high risk of CV were included. The cognition was evaluated using the Montreal Cognitive Assessment. A score lower than 25 out of 30 was used to indicate mild cognitive impairment (MCI). Blood samples of all participants ( n = 233) were collected to measure the plasma levels of TMAO and other metabolic parameters, including fasting blood sugar and lipid profiles. Logistic regression was used to evaluate the association between MCI and high plasma TMAO levels, adjusted for confounding factors. Of 233 patients, the mean age of patients in this study was 64 years old (SD 8.4). The median TMAO level was 4.31 μM (IQR 3.95). The high TMAO level was an independent risk factor of MCI (aOR 2.36, 95% CI 1.02 to 5.47; p 0.046), when adjusted for age, gender, health care service scheme, smoking history, metabolic syndrome, and history of established CV events. The high TMAO level was associated with MCI, after adjustment for potential confounding factors. These findings demonstrate that plasma TMAO levels can serve for target prediction as an independent risk factor for MCI in this population.

Insulin resistance is an underlying condition prior to the development of several diseases, including type 2 diabetes, cardiovascular diseases, cognitive impairment, and cerebrovascular complications. Organophosphates (OPs) are one of several factors thought to induce insulin resistance. Previous studies showed that the exposure to OPs pesticides induced insulin resistance through the impairment of hepatic glucose metabolism, pancreatic damage, and disruption of insulin signaling of both adipose tissues and skeletal muscles. Several studies reported possible mechanisms associated with OPs-induced insulin resistance in different models in in vivo studies including those in adult animals, obese animals, and offspring models, as well as in clinical studies. In addition, pharmacological interventions in OPs-induced insulin resistance have been previously investigated. This review aims to summarize and discuss all the evidence concerning OPs-induced insulin resistance in different models including in vitro, in vivo and clinical studies. The interventions of OPs-induced insulin resistance are also discussed. Any contradictory findings also considered. The information from this review will provide insight for possible therapeutic approaches to OPs-induced insulin resistance in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)