SIRT3-mediated OPA1 deacetylation protects against sepsis-induced acute lung injury by inhibiting alveolar macrophage pro-inflammatory polarization.

AIMS: Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on SIRT3-induced optic atrophy protein 1 (OPA1) deacetylation. RESULTS: The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3TYP-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI. INNOVATION: Our study revealed for the first time the regulation of mitochondrial dynamics and AMs polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease. CONCLUSIONS: Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI, and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury.

Sirtuin 5 alleviates excessive mitochondrial fission via desuccinylation of ATPase inhibitory factor 1 in sepsis-induced acute kidney injury.

ABSTRACT: Sepsis-induced acute kidney injury (SAKI) poses a significant clinical challenge with high morbidity and mortality. Excessive mitochondrial fission has been identified as the central pathogenesis of sepsis-associated organ damage, which is also implicated in the early stages of SAKI. Sirtuin 5 (SIRT5) has emerged as a central regulator of cellular mitochondrial function; however, its role in the regulation of sepsis-induced excessive mitochondrial fission in kidney and the underlying mechanism remains unclear.In this study, SAKI was modeled in mice through cecal ligation and puncture (CLP), and in human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide (LPS), to mimic the cell SAKI model. Our findings revealed that septic mice with a SIRT5 knockout (SIRT5 KO) exhibited shortened survival times and elevated levels of renal injury compared to wild-type (WT) mice, suggesting the significant involvement of SIRT5 in SAKI pathophysiology. Additionally, we observed that SIRT5 depletion led to increased renal mitochondrial fission, while the use of a mitochondrial fission inhibitor (Mdivi-1) reversed the detrimental effects caused by SIRT5 depletion, emphasizing the pivotal role of SIRT5 in preventing excessive mitochondrial fission. In vitro experiments demonstrated that the overexpression of SIRT5 effectively mitigated the adverse effects of LPS on HK-2 cells viability and mitochondrial fission. Conversely, downregulation of SIRT5 decreased HK-2 cells viability and exacerbated LPS-induced mitochondrial fission. Mechanistically, the protective function of SIRT5 may be in part, ascribed to its desuccinylating action on ATPase inhibitory factor 1 (ATPIF1).In conclusion, this study provides novel insights into the underlying mechanisms of SAKI, suggesting the possibility of identifying future drug targets in terms of improved mitochondrial dynamics by SIRT5.

Role of low-density lipoprotein electronegativity and sexual dimorphism in contributing early ventricular tachyarrhythmias following ST-elevation myocardial infarction.

Background: Early ventricular tachycardia/fibrillation (VT/VF) in patients with ST-elevation myocardial infarction (STEMI) has higher morbidity and mortality. This study examines gender-differentiated risk factors and underlying mechanisms for early onset VT/VF in STEMI. Methods: We analyzed data from 2,964 consecutive STEMI patients between January 1, 2008 and December 31, 2021. Early VT/VF was defined as occurrence of spontaneous VT/VF of ≥30 s or requirement of immediate cardioversion/defibrillation within the first 48 h after symptoms. An ex vivo ischemic-reperfusion experiments were conducted in 8-week-old ApoE-/- mice fed a high-fat diet to explore the underlying mechanisms of early VT/VF. Results: In 255 of out 2,964 STEMI patients who experienced early VT/VF, the age was younger (58.6 ± 13.8 vs. 61.0 ± 13.0 years old, P = 0.008) with a male predominance. The plasma levels of L5, the most electronegative subclass of low-density lipoprotein, was higher in early VT/VF patients compared to those without early VT/VF (n = 21, L5: 14.1 ± 22.6% vs. n = 46, L5: 4.3 ± 9.9%, P = 0.016). In the experimental setup, all male mice (n = 4) developed VT/VF post sham operation, whereas no such incidence was observed in the female mice (n = 3). Significantly, male mice exhibited considerably slower cardiac conduction velocity as compared to their female counterparts in whole heart preparations (25.01 ± 0.93 cm/s vs.42.32 ± 5.70 cm/s, P < 0.001), despite analogous action potential durations. Furthermore, isolated ventricular myocytes from male mice showed a distinctly lower sodium current density (-29.20 ± 3.04 pA/pF, n = 6) in comparison to female mice (-114.05 ± 6.41 pA/pF, n = 6, P < 0.001). This decreased sodium current density was paralleled by a reduced membrane expression of Nav1.5 protein (0.38 ± 0.06 vs. 0.89 ± 0.09 A.U., P < 0.001) and increased cytosolic Nav1.5 levels (0.59 ± 0.06 vs. 0.29 ± 0.04 A.U., P = 0.001) in male mice. Furthermore, it was observed that the overall expressions of sorting nexin 27 (SNX27) and vacuolar protein sorting 26 (VPS26) were significantly diminished in male mice as compared to female littermates (0.91 ± 0.15 vs. 1.70 ± 0.28, P = 0.02 and 0.74 ± 0.09 vs. 1.57 ± 0.13, P < 0.01, respectively). Conclusions: Our findings reveal that male STEMI patients with early VT/VF are associated with elevated L5 levels. The gender-based discrepancy in early VT/VF predisposition might be due to compromised sodium channel trafficking, possibly linked with increased LDL electronegativity.

Micro-biological degradation and transformation of dissolved organic matter following continuous cropping of tobacco.

In recent years, the problems associated with continuous cropping (CC) that cause soil degradation have become increasingly serious. As a key soil quality property, dissolved organic matter (DOM) affects the circulation of carbon and nutrients and the composition of bacterial communities in soil. However, research on the changes in the molecular composition of DOM after CC is limited. In this study, the soil chemical properties, DOM chemical diversity, bacterial community structure, and their interactions are explored in the soil samples from different CC years (CC1Y, CC3Y, CC5Y, and CC7Y) of tobacco. With increasing CC year of tobacco, most of the soil chemical properties, such as total carbon, total nitrogen and organic matter, decreased significantly, while dissolved organic carbon first decreased and then increased. Likewise, the trends of DOM composition differed with changing duration of CC, such as the tannin compounds decreased from 18.13 to 13.95%, aliphatic/proteins increased from 2.73 to 8.85%. After 7 years of CC, the soil preferentially produced compounds with either high H/C ratios (H/C > 1.5), including carbohydrates, lipids, and aliphatic/proteins, or low O/C ratios (O/C < 0.1), such as unsaturated hydrocarbons. Furthermore, core microorganisms, including Nocardioides, wb1-P19, Aquabacterium, Methylobacter, and Thiobacillus, were identified. Network analysis further indicated that in response to CC, Methylobacter and Thiobacillus were correlated with the microbial degradation and transformation of DOM. These findings will improve our understanding of the interactions between microbial community and DOM in continuous cropping soil.

Investigation of the Therapeutic Potential of Organic Nitrates in Mortality Reduction Following Acute Myocardial Infarction in Hyperlipidemia Patients: A Population-Based Cohort Study.

BACKGROUND: Dyslipidemia is a known risk factor for cardiac dysfunction, and lipid-lowering therapy with statins reduces symptoms and reduces hospitalization related to left ventricular heart failure. Acute myocardial infarction (AMI) is a cause of morbidity and mortality worldwide. In this study, we aimed to determine the real-world AMI treatment drug combination used in Taiwan by using the NHI database to understand the treatment outcomes of current clinical medications prescribed for hyperlipidemia patients with AMI. METHODS: Using the NHI Research Database (NHIRD), we conducted a retrospective cohort study that compared different treatments for AMI in hyperlipidemia patients in the period from 2016 to 2018. We compared the survival outcomes between those treated with and without organic nitrates in this cohort. RESULTS: We determined that most hyperlipidemia patients were aged 61-70 y (29.95-31.46% from 2016 to 2018), and the annual AMI risk in these patients was <1% (0.42-0.68% from 2016 to 2018). The majority of hyperlipidemia patients with AMI were women, and 25.64% were aged 61-70 y. Receiving organic nitrates was associated with lower all-cause mortality rates (HR, 95% CI, p-value = 0.714, 0.674-0.756, p < 0.0001). After multivariate analysis, the overall survival in four groups (beta-blockers, beta-blocker + diuretics, diuretics, and others) receiving an organic nitrate treatment was significantly higher than in the groups that were not treated with organic nitrates (beta-blockers HR = 0.536, beta-blocker + diuretics HR = 0.620, diuretics HR = 0.715, and others HR = 0.690). CONCLUSIONS: The survival benefit was significantly greater in patients treated with organic nitrates than in those treated without organic nitrates, especially when combined with diuretics. A combination of organic nitrates could be a better treatment option for hyperlipidemia patients with AMI.

Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation.

ABBREVIATIONS: AKI: acute kidney injury; ATP: adenosine triphosphate; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; eGFR: estimated glomerular filtration rate; H&E: hematoxylin and eosin staining; LCN2/NGAL: lipocalin 2; LPS: lipopolysaccharide; LTL: lotus tetragonolobus lectin; mKeima: mitochondria-targeted Keima; mtDNA: mitochondrial DNA; PAS: periodic acid - Schiff staining; RTECs: renal tubular epithelial cells; SAKI: sepsis-induced acute kidney injury; Scr: serum creatinine; SIRT3: sirtuin 3; TFAM: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine.

Fe-based double perovskite with Zn doping for enhanced electrochemical performance as intermediate-temperature solid oxide fuel cell cathode material.

This study aims to investigate the implications of transition-metal Zn doping at the B-site on the crystal structure, average thermal expansion coefficient (TEC), electrocatalytic activity, and electrochemical performance of LaBaFe2O5+δ by preparing LaBaFe2-xZnxO5+δ (x = 0, 0.05, 0.1, 0.15, 0.2, LBFZx). The X-ray diffraction (XRD) results show that Zn2+ doping does not change the crystal structure, the unit cell volume increases, and the lattice expands. The X-ray photoelectron spectroscopy (XPS) and mineral titration results show that the oxygen vacancy concentration and Fe4+ content gradually increase with the increase in doping amount. TEC decreases with the increase in Zn2+ doping amount, and the TEC of LBFZ0.2 is 11.4 × 10-6 K-1 at 30-750 °C. The conductivity has the best value of 103 S cm-1 at the doping amount of x = 0.1. The scanning electron microscopy (SEM) images demonstrate that the electrolyte CGO(Gd0.1Ce0.9O1.95) becomes denser after high-temperature calcination, and the cathode material is well attached to the electrolyte. The electrochemical impedance analysis shows that Zn2+ doping at the B-site can reduce the (Rp) polarization resistance, and the Rp value of the symmetric cell with LaBaFe1.8Zn0.2O5+δ as cathode at 800 °C is 0.014 Ω cm2. The peak power density (PPD) value of the anode-supported single cell is 453 mW cm-2, which shows excellent electrochemical performance.

Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism.

Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease. It plays a key role in iron homeostasis by suppressing the iron-regulatory hormone, hepcidin. Lack of functional MT2 results in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia. Mt2 cleaves multiple components of the hepcidin-induction pathway in vitro. It is inhibited by the membrane-anchored serine protease inhibitor, Hai-2. Earlier in vivo studies show that Mt2 can suppress hepcidin expression independently of its proteolytic activity. In this study, our data indicate that hepatic Mt2 was a limiting factor in suppressing hepcidin. Studies in Tmprss6-/- mice revealed that increases in dietary iron to ∼0.5% were sufficient to overcome the high hepcidin barrier and to correct iron-deficiency anemia. Interestingly, the increased iron in Tmprss6-/- mice was able to further upregulate hepcidin expression to a similar magnitude as in wild-type mice. These results suggest that a lack of Mt2 does not impact the iron induction of hepcidin. Additional studies of wild-type Mt2 and the proteolytic-dead form, fMt2S762A, indicated that the function of Mt2 is to lower the basal levels of hepcidin expression in a manner that primarily relies on its nonproteolytic role. This idea is supported by the studies in mice with the hepatocyte-specific ablation of Hai-2, which showed a marginal impact on iron homeostasis and no significant effects on iron regulation of hepcidin. Together, these observations suggest that the function of Mt2 is to set the basal levels of hepcidin expression and that this process is primarily accomplished through a nonproteolytic mechanism.

PROMOTING MITOCHONDRIAL DYNAMIC EQUILIBRIUM ATTENUATES SEPSIS-INDUCED ACUTE LUNG INJURY BY INHIBITING PROINFLAMMATORY POLARIZATION OF ALVEOLAR MACROPHAGES.

ABSTRACT: Sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by widespread pulmonary inflammation and immune response, in which proinflammatory polarization of alveolar macrophages (AMs) plays an important role. Mitochondria are the key intracellular signaling platforms regulating immune cell responses. Moreover, accumulating evidence suggests that the mitochondrial dynamics of macrophages are imbalanced in sepsis and severe ALI/ARDS. However, the functional significance of mitochondrial dynamics of AMs in septic ALI/ARDS remains largely unknown, and whether it regulates the polarized phenotype of AMs is also unclear. Here, we demonstrated that the mitochondrial dynamics of AMs are imbalanced, manifested by impaired mitochondrial fusion, increased fission and mitochondrial cristae remodeling, both in septic models and ARDS patients. However, suppressing excessive mitochondrial fission with Mdivi-1 or promoting mitochondrial fusion with PM1 to maintain mitochondrial dynamic equilibrium in AMs could inhibit the polarization of AMs into proinflammatory phenotype and attenuate sepsis-induced ALI. These data suggest that mitochondrial dynamic imbalance mediates altered polarization of AMs and exacerbates sepsis-induced ALI. This study provides new insights into the underlying mechanisms of sepsis-induced ALI, suggesting the possibility of identifying future drug targets from the perspective of mitochondrial dynamics in AMs.

Multimodal Assessment of Schizophrenia Symptom Severity From Linguistic, Acoustic and Visual Cues.

Assessing the condition of every schizophrenia patient correctly normally requires lengthy and frequent interviews with professionally trained doctors. To alleviate the time and manual burden on those mental health professionals, this paper proposes a multimodal assessment model that predicts the severity level of each symptom defined in Scale for the Assessment of Thought, Language, and Communication (TLC) and Positive and Negative Syndrome Scale (PANSS) based on the patient's linguistic, acoustic, and visual behavior. The proposed deep-learning model consists of a multimodal fusion framework and four unimodal transformer-based backbone networks. The second-stage pre-training is introduced to make each off-the-shelf pre-trained model learn the pattern of schizophrenia data more effectively. It learns to extract the desired features from the view of its modality. Next, the pre-trained parameters are frozen, and the light-weight trainable unimodal modules are inserted and fine-tuned to keep the number of parameters low while maintaining the superb performance simultaneously. Finally, the four adapted unimodal modules are fused into a final multimodal assessment model through the proposed multimodal fusion framework. For the purpose of validation, we train and evaluate the proposed model on schizophrenia patients recruited from National Taiwan University Hospital, whose performance achieves 0.534/0.685 in MAE/MSE, outperforming the related works in the literature. Through the experimental results and ablation studies, as well as the comparison with other related multimodal assessment works, our approach not only demonstrates the superiority of our performance but also the effectiveness of our approach to extract and integrate information from multiple modalities.

Effect of Esmolol on Clinical Outcomes in Critically Ill Patients: Data from the MIMIC-IV Database.

BACKGROUND AND AIMS: Esmolol is a common short-acting drug to control ventricular rate. This study aimed to evaluate the association between use of esmolol and mortality in critically ill patients. METHODS: This is a retrospective cohort study from MIMIC-IV database containing adult patients with a heart rate of over 100 beats/min during the intensive care unit (ICU) stay. Multivariable Cox proportional hazard models and logistic regression were used to explore the association between esmolol and mortality and adjust confounders. A 1:1 nearest neighbor propensity score matching (PSM) was performed to minimize potential cofounding bias. The comparison for secondary outcomes was performed at different points of time using an independent t-test. RESULTS: A total of 30,332 patients were reviewed and identified as critically ill. There was no significant difference in 28-day mortality between two groups before (HR = 0.90, 95% CI = 0.73-1.12, p = 0.343) and after PSM (HR = 0.84, 95% CI = 0.65-1.08, p = 0.167). Similar results were shown in 90-day mortality before (HR = 0.93, 95% CI = 0.75-1.14, p = 0.484) and after PSM (HR = 0.85, 95% CI = 0.67-1.09, p = 0.193). However, esmolol treatment was associated with higher requirement of vasopressor use before (HR = 2.89, 95% CI = 2.18-3.82, p < 0.001) and after PSM (HR = 2.66, 95% CI = 2.06-3.45, p < 0.001). Esmolol treatment statistically reduced diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (all p < 0.001) and increased fluid balance at 24 hours (p < 0.05) but did not significantly lower SBP (p = 0.721). Patients in esmolol group showed no significant difference in lactate levels and daily urine output when compared with those in non-esmolol group when adjusted for confounders (all p > 0.05). CONCLUSION: Esmolol treatment was associated with reduced heart rate and lowered DBP and MAP, which may increase vasopressor use and fluid balance at the timepoint of 24 hours in critically ill patients during ICU stay. However, after adjusting for confounders, esmolol treatment was not associated with 28-day and 90-day mortality.

PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation.

The increase of lactate is an independent risk factor for patients with sepsis-induced acute kidney injury (SAKI). However, whether elevated lactate directly promotes SAKI and its mechanism remain unclear. Here we revealed that downregulation of the deacetylase Sirtuin 3 (SIRT3) mediated the hyperacetylation and inactivation of pyruvate dehydrogenase E1 component subunit alpha (PDHA1), resulting in lactate overproduction in renal tubular epithelial cells. We then found that the incidence of SAKI and renal replacement therapy (RRT) in septic patients with blood lactate ≥ 4 mmol/L was increased significantly, compared with those in septic patients with blood lactate < 2 mmol/L. Further in vitro and in vivo experiments showed that additional lactate administration could directly promote SAKI. Mechanistically, lactate mediated the lactylation of mitochondrial fission 1 protein (Fis1) lysine 20 (Fis1 K20la). The increase in Fis1 K20la promoted excessive mitochondrial fission and subsequently induced ATP depletion, mitochondrial reactive oxygen species (mtROS) overproduction, and mitochondrial apoptosis. In contrast, PDHA1 activation with sodium dichloroacetate (DCA) or SIRT3 overexpression decreased lactate levels and Fis1 K20la, thereby alleviating SAKI. In conclusion, our results show that PDHA1 hyperacetylation and inactivation enhance lactate overproduction, which mediates Fis1 lactylation and exacerbates SAKI. Reducing lactate levels and Fis1 lactylation attenuate SAKI.

Value of clinical applications of differential pressure and relative pressure imaging in the left ventricle.

Regional pressure differences between sites within the left ventricular cavity have long been identified, and the potential clinical value of diastolic and systolic intraventricular pressure differences (IVPDs) is of increasing interest. This study concluded that the IVPD plays an important role in ventricular filling and emptying and is a reliable indicator of ventricular relaxation, elastic recoil, diastolic pumping, and effective left ventricular filling. Relative pressure imaging, as a novel and potentially clinically applicable measure of left IVPDs, enables early and more comprehensive identification of the temporal and spatial characteristics of IVPD. In the future, as research related to relative pressure imaging continues, this measurement method has the possibility to become more refined and serve as an additional clinical aid that can replace the gold standard cardiac catheterization technique for the diagnosis of diastolic dysfunction.

A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice.

Chronic heavy alcohol use is associated with lethal arrhythmias. Whether common East Asian-specific aldehyde dehydrogenase deficiency (ALDH2*2) contributes to arrhythmogenesis caused by low level alcohol use remains unclear. Here we show 59 habitual alcohol users carrying ALDH2 rs671 have longer QT interval (corrected) and higher ventricular tachyarrhythmia events compared with 137 ALDH2 wild-type (Wt) habitual alcohol users and 57 alcohol non-users. Notably, we observe QT prolongation and a higher risk of premature ventricular contractions among human ALDH2 variants showing habitual light-to-moderate alcohol consumption. We recapitulate a human electrophysiological QT prolongation phenotype using a mouse ALDH2*2 knock-in (KI) model treated with 4% ethanol, which shows markedly reduced total amount of connexin43 albeit increased lateralization accompanied by markedly downregulated sarcolemmal Nav1.5, Kv1.4 and Kv4.2 expressions compared to EtOH-treated Wt mice. Whole-cell patch-clamps reveal a more pronounced action potential prolongation in EtOH-treated ALDH2*2 KI mice. By programmed electrical stimulation, rotors are only provokable in EtOH-treated ALDH2*2 KI mice along with higher number and duration of ventricular arrhythmia episodes. The present research helps formulate safe alcohol drinking guideline for ALDH2 deficient population and develop novel protective agents for these subjects.

Different endodontic treatments induced root development of two nonvital immature teeth in the same patient: A case report.

BACKGROUND: Pulp revascularization is a novel way to treat immature teeth with periapical disease, and the technique has become increasingly well established in recent years. By puncturing the periapical tissue, bleeding is induced, and a blood clot is formed in the root canal. The blood clot acts as a natural bioscaffold onto which mesenchymal stem cells from periapical tissue can be seeded and restore pulp vascularity, thus promoting root development as well as apical closure. Although the effect of pulp revascularization is ideal, there are certain requirements for the apical condition of the teeth. The apical barrier technique and apexification are still indispensable for teeth that cannot achieve ideal blood clot formation. In addition, a meta-analysis of several clinical studies concluded that pulp revascularization has no significant advantages over other treatments. CASE SUMMARY: A 10-year-old girl complained of pain in the right upper and lower posterior teeth for 2 d. Clinical and radiological examinations revealed that both the right maxillary and mandibular second premolars were immature with periapical radiolucency. The right maxillary second premolar was treated by pulp revascularization, while the right mandibular second premolar was treated by conventional apical barrier surgery after revascularization failed. The purpose of this report is to compare the different root maturation processes induced by the pulp revascularization and apical barrier techniques in the same patient in homonymous teeth from different jaws. Twelve months of follow-up showed that the apical foramen of both teeth presented a clear tendency to close; however, the tooth treated with pulp revascularization showed a significant increase in root length as well as root canal wall thickness. CONCLUSION: For the treatment of nonvital immature teeth, pulp revascularization showed a superior therapeutic effect in comparison with the apical barrier technique.

Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson's disease and neuronal damage through inhibition of microglia.

Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson's disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson's disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson's disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1ß and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson's disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.

Gut bacterium promotes host fitness in special ecological niche by affecting sugar metabolism in Drosophila suzukii.

As an important fruit pest of global significance, Drosophila suzukii occupies a special ecological niche, with the characteristics of high sugar and low protein contents. This niche differs from those occupied by other fruit-damaging Drosophila species. Gut bacteria substantially impact the physiology and ecology of insects. However, the contribution of gut microbes to the fitness of D. suzukii in their special ecological niche remains unclear. In this study, the effect of Klebsiella oxytoca on the development of D. suzukii was examined at physiological and molecular levels. The results showed that, after the removal of gut microbiota, the survival rate and longevity of axenic D. suzukii decreased significantly. Reintroduction of K. oxytoca to the midgut of D. suzukii advanced the development level of D. suzukii. The differentially expressed genes and metabolites between axenic and K. oxytoca-reintroduced D. suzukii were enriched in the pathways of carbohydrate metabolism. This advancement was achieved through an increased glycolysis rate and the regulation of the transcript level of key genes in the glycolysis/gluconeogenesis pathway. Klebsiella oxytoca is likely to play an important role in increasing host fitness in their high-sugar ecological niche by stimulating the glycolysis/gluconeogenesis pathway. As a protein source, bacteria can also provide direct nutrition for D. suzukii, which depends on the quantity or biomass of K. oxytoca. This result may provide a new target for controlling D. suzukii by inhibiting sugar metabolism through eliminating the effect of K. oxytoca and thus disrupting the balance of gut microbial communities.

ADENOSINE MONOPHOSPHATE-ACTIVATED PROTEIN KINASE PHOSPHORYLATION MEDIATED BY SIRTUIN 5 ALLEVIATES SEPTIC ACUTE KIDNEY INJURY.

ABSTRACT: Background : Our previous studies have shown that ameliorating mitochondrial damage in renal tubular epithelial cells (RTECs) can alleviate septic acute kidney injury (SAKI). It is reported that AMPK phosphorylation (p-AMPK) could ameliorate mitochondrial damage in renal tissue and Sirtuin 5 (SIRT5) overexpression significantly enhanced the level of p-AMPK in bovine preadipocytes. However, the role of SIRT5-mediated phosphorylation of AMPK in SAKI needs to be clarified. Methods : WT/SIRT5 gene knockout mouse model of cecal ligation and puncture-induced SAKI and a human kidney 2 cell model of LPS-induced SAKI were constructed. An AMPK chemical activator and SIRT5 overexpression plasmid were used. Indexes of mitochondrial structure and function, level of p-AMPK, and expression of SIRT5 protein in renal tissue and RTECs were measured. Results : After sepsis stimulation, the p-AMPK level was decreased, mitochondrial structure was disrupted, and ATP content was decreased. Notably, an AMPK activator alleviated SAKI. Sirtuin 5 gene knockout significantly aggravated SAKI, while SIRT5 overexpression alleviated mitochondrial dysfunction after LPS stimulation, as manifested by the increase of p-AMPK level, the alleviation of mitochondrial structure damage, the restoration of ATP content, the decrease of proapoptotic protein expression, as well as the reduction of reactive oxygen species generation. Conclusions : Upregulation of SIRT5 expression can attenuate mitochondrial dysfunction in RTECs and alleviate SAKI by enhancing the phosphorylation of AMPK.

Discriminative Ability of Left Ventricular Strain in Mildly Reduced Ejection Fraction Heart Failure.

Background: Left ventricular (LV) systolic strain is presumably a more sensitive myocardial indicator than LV ejection fraction (LVEF). Data regarding the use of LV strain in clinical risk stratification and in identifying angiotensin receptor-neprilysin inhibitor (ARNi) responders remain scarce in heart failure with mildly reduced ejection fraction (HFmrEF). Objectives: The authors aimed to examine whether assessing LV strain may provide prognostic insight beyond LVEF and help discriminate the therapeutic efficacy of ARNi in HFmrEF patients. Methods: LVEF and LV strain were quantified among 1,075 first-time hospitalized HFmrEF patients (mean age: 68.1 ± 15.1 years, 40% female). The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) risk score and its components were calculated. A Cox proportional hazard model was constructed for time-to-event analysis. Restrictive cubic spline curves were used to model the therapeutic effects of ARNi against renin-angiotensin system inhibitor according to baseline LVEF or LV strain. Results: LV strain showed a statistically significant inverse association with MAGGIC cardiac risk (coefficient: -0.14, P < 0.001). LV strain was independently associated with clinical outcomes after accounting for LVEF. MAGGIC-LV strain strata outperformed MAGGIC-LVEF strata in overall survival (Harrell's C-index: 0.71 and 0.56, P for difference <0.001; category-free net reclassification index: 0.44, P < 0.001). Lower LV strain but not LVEF consistently showed the beneficial therapeutic effects of ARNi against renin-angiotensin system inhibitor by Cox models and restrictive cubic spline (all P interaction <0.05). Conclusions: Among HFmrEF patients, LV strain may serve as an attractive systolic marker and provide a better prognostic and therapeutic discriminative measure for ARNi treatment than conventional LVEF.

PD-L1 and AKT Overexpressing Adipose-Derived Mesenchymal Stem Cells Enhance Myocardial Protection by Upregulating CD25+ T Cells in Acute Myocardial Infarction Rat Model.

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure-volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure-volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25+ regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.