Pathogenic Factors Research Articles

Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant

BackgroundHypertrophic cardiomyopathy (HCM) is typically manifested as a hereditary disorder, with 30 %–60 % of cases linked to cardiac sarcomere gene mutations. Despite numerous identified TNNI3 mutations associated with HCM, their severity, prevalence, and disease progression vary. The link between TNNI3 variants and phenotypes remains largely unexplored. This study aims to elucidate the impact of the TNNI3 c.235C > T mutation on HCM through clinical research and cell experiments and to explore its mechanism in HCM development. MethodsWe screened an HCM family for pathogenic gene mutations using gene sequencing. The proband and family members were assessed through electrocardiography, echocardiography, and cardiac MRI, and a pedigree map was created for disease prediction analysis. Mutant plasmids were constructed with the TNNI3 c.235C > T mutation and transfected into the AC16 human cardiomyocyte cell line to investigate the mutation's effects. ResultsThe TNNI3 c.235C > T mutation was identified as the disease-causing variant in the family. This mutation led to the upregulation of hypertrophy-associated genes ANP, BNP, and MYH7, increased cardiomyocyte size, and activation of the ERK signaling pathway. Further investigations revealed that the TNNI3 c.235C > T mutation impaired mitochondrial function, disrupted cardiomyocyte metabolism, and increased cellular autophagy and apoptosis. ConclusionsThe TNNI3 c.235C > T gene mutation may be a pathogenic factor for HCM, showing heterogeneous features and clinical phenotypes. This mutation induces myocardial hypertrophy, activates the ERK signaling pathway, and exacerbates mitochondrial dysfunction, apoptosis, and autophagy in cardiomyocytes. These findings provide insights into the mechanism of HCM caused by gene mutations and may inform HCM treatment strategies.

Duodenal-Jejunal Bypass Surgery in Diet-Induced Obese Diabetic Mice.

The prevalence of obesity and type 2 diabetes is a serious global health concern. Obesity is a major pathogenic factor in type 2 diabetes, cardiovascular disease, and some cancers. Bariatric surgery offers a long-term and effective treatment option for both obesity and diabetes. Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are widely recognized as the most popular bariatric surgeries. Additionally, several exploratory bariatric surgeries have demonstrated promising therapeutic effects. Duodenal-jejunal bypass (DJB), specifically tailored for diabetics with low body mass index, has shown beneficial metabolic outcomes. However, its weight-independent metabolic benefits are not fully understood due to limited animal models. In this article, we describe the optimized care protocols and surgical techniques for performing DJB surgery in diet-induced obese (DIO) diabetic mice. Using a mouse model contributes to a better understanding of the nature of changes induced by DJB surgery while facilitating related clinical practice.

Comparison of central precocious puberty frequency before and during COVID-19: a systematic review and meta-analysis

ObjectiveThe current systematic review and meta-analysis assessed the prevalence of central precocious puberty (CPP) throughout the novel coronavirus disease 2019 (COVID-19) pandemic.DesignA systematic review and meta-analysis were carried out following the principles outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA, 2020).Data sourcesPubMed, Embase, Web of Science, and WANFANG databases were searched from January 1, 2019, to March 30, 2023.Eligibility criteria for selecting studies(1) children and adolescents ≤ 15 years; (2) studies with the outcome of frequency of central precocious puberty, measured prior to and throughout the COVID-19 pandemic; (3) a novel CPP diagnosis was created depending on all of the following criteria: girls with a chronological age < 8 years and boys with a chronological age < 9 years at the onset of symptoms, basal luteinizing hormone (LH) levels > 0.3 UI/L, and/or GnRH-stimulated peak LH levels > 5 IU/L.Data extraction and synthesisThe process of extracting data and evaluating the likelihood of bias was carried out by two independent reviewers. The data were pooled employing the generic inverse-variance method and presented as mean differences (MDs) with 95% CIs. The evaluation of heterogeneity was conducted employing the Cochran Q statistic, and the degree of heterogeneity was measured employing the I2 statistic.ResultsThis meta-analysis included 17 studies. In contrast to the same period prior to the COVID-19 pandemic, the occurrence of CPP elevated (OR = 2.57; 95% CI, 1.85–3.56). Moreover, body mass index standard deviation score (BMI SDS) differences between CPP patients prior to COVID-19 and throughout the pandemic follow-up was 0.12 (95% CI − 0.01 to 0.25 P = 0.06).ConclusionOverall, CPP frequency significantly elevated throughout the COVID-19 pandemic. Given the restricted number of cohort investigations in this meta-analysis, additional research may be conducted on larger groups of children in order to establish a correlation between the observed rise in precocious puberty and specific pathogenic factors.

Construction of vulnerable plaque prediction model based on multimodal vascular ultrasound parameters and clinical risk factors

The rupture of vulnerable plaque (VP) are significant pathogenic factors leading to cardiovascular and cerebrovascular diseases. This study aims to construct a vulnerable plaque prediction model (VPPM) by combining multimodal vascular ultrasound parameters and clinical risk factors, and to validate it. A total of 196 atherosclerotic patients who underwent carotid endarterectomy (CEA) from January 2017 to December 2023 were collected and divided into a modeling group (n = 137) and a validation group (n = 59). Clinical information including: hypertension, diabetes, smoking history, and body mass index (BMI) was included in the analysis. All patients underwent carotid ultrasound and contrast-enhanced ultrasound (CEUS) examination after admission, with main ultrasound parameters including thickness, echogenicity types, stenosis degree, and CEUS neovascularization grading of plaques. Independent risk factors for VP in CEA patients were screened through binary Logistic regression analysis, and a prediction model was established along with a nomogram. The calibration curve, receiver-operating characteristic curve (ROC), and decision curve analysis (DCA) were employed to assess the calibration, diagnostic efficacy, and clinical utility of the VPPM model. There were no significant statistical differences in multimodal vascular ultrasound parameters and clinical risk factors between the modeling and validation groups (P > 0.05). Binary Logistic regression analysis identified plaque thickness, echo type, CEUS neovascularization grading, BMI, and smoking history as 5 variables entering the prediction model. The VPPM model showed good diagnostic efficacy, with an area under the ROC curve of 0.959 (95% CI 0.915–0.999). Using the nomogram with a VPPM risk assessment score of 135.42 as the diagnostic cutoff value in the modeling group, the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and Youden index were 88.1%, 94.1%, 14.98, 0.126, and 82.2%, respectively. In the DCA curve, the VPPM model curve was significantly better than two extreme lines, indicating good clinical utility. The VPPM model constructed by integrating multimodal ultrasound parameters and clinical key risk factors has high diagnostic efficacy and is expected to be an auxiliary tool for clinical diagnosis of vulnerable plaques.

Comparison of Cardioprotective Potential of Cannabidiol and β-Adrenergic Stimulation against Hypoxia/Reoxygenation Injury in Rat Atria and Ventricular Papillary Muscles

Background: Hypoxia is one of the most significant pathogenic factors in cardiovascular diseases. Preclinical studies suggest that nonpsychoactive cannabidiol (CBD) and β-adrenoceptor stimulation might possess cardioprotective potential against ischemia-reperfusion injury. The current study evaluates the influence of hypoxia-reoxygenation (H/R) on the function of atria and ventricular papillary muscles in the presence of CBD and the nonselective β-adrenoceptor agonist isoprenaline (ISO). Methods: The concentration curves for ISO were constructed in the presence of CBD (1 µM) before or after H/R. In chronic experiments (CBD 10 mg/kg, 14 days), the left atria isolated from spontaneously hypertensive (SHR) and their normotensive control (WKY) rats were subjected to H/R following ISO administration. Results: Hypoxia decreased the rate and force of contractions in all compartments. The right atria were the most resistant to hypoxia regardless of prior β-adrenergic stimulation. Previous β-adrenergic stimulation improved recovery in isolated left atria and right (but not left) papillary muscles. Acute (but not chronic) CBD administration increased the effects of ISO in left atria and right (but not left) papillary muscles. Hypertension accelerates left atrial recovery during reoxygenation. Conclusion: H/R directly modifies the function of particular cardiac compartments in a manner dependent on cardiac region and β-adrenergic prestimulation. The moderate direct cardioprotective potential of CBD and β-adrenergic stimulation against H/R is dependent on the cardiac region, and it is less than in the whole heart with preserved coronary flow. In clinical terms, our research expands the existing knowledge about the impact of cannabidiol on cardiac ischemia, the world′s leading cause of death.

Regualtion of LAMTOR1 by Oxidative Stress in Retinal Pigment Epithelium: Implications for Age-Related Macular Degeneration Pathogenesis

Oxidative stress is a critical pathogenic factor for age-related macular degeneration (AMD). Autophagy serves as a mechanism to counteract oxidative stress. LAMTOR1 regulates mTORC1 activity by recruiting or disassembling it on the lysosome under the addition or deprivation of amino acids. This regulation inhibits or enhances autophagy. Our study investigates whether oxidative stress impacts LAMTOR1, thereby adapting to oxidative conditions. We employed oxidative stressors, menadione (VK3) and 4-hydroxynonenal (4-HNE), and observed a reduction of LAMTOR1 in both human and mouse retinal pigment epithelium (RPE) following short-term (1h) and prolonged exposures (24h). Nrf2 overexpression increased both lamtor1 mRNA and LAMTOR1 protein in the RPE. To determine if Nrf2 regulates lamtor1 transcription, we cloned the deletion mutants of the lamtor1 promoter into a luciferase reporter. Although the promoter contained antioxidant response elements, transcriptional activity depended on the interaction between Nrf2 and the constructs containing the transcriptional start site. Moreover, Nrf2-driven transcription was significantly reduced by an inhibitor of histone acetyltransferase, p300. Correspondingly, Nrf2 overexpression increased levels of acetylated histone3 and p300. The reduction in LAMTOR1 by 4-HNE was reversed by pepstatin A and NH4Cl which block lysosomal degradation. 4-HNE increased TFEB nuclear translocation which was reversed by LAMTOR1 overexpression. In vivo, LAMTOR1 levels decreased in the photoreceptor and RPE layers of NaIO3-injected mice, compared to PBS-injected controls. In conclusion, oxidative injury reduces LAMTOR1, predominantly through lysosomal degradation although Nrf2-mediated histone acetylation enhances lamtor1 transcription. This study reveals a previously unrecognized regulatory mechanism of lamtor1 by oxidative stress, suggesting a novel role for LAMTOR1 in the pathogenesis of AMD.

Uric Acid: A Biomarker and Pathogenic Factor of Affective Disorders and Neurodegenerative Diseases.

Uric acid (UA), the end-product of purine metabolism, has a complicated physiological role in the body, showing the combination of regulating inflammatory response, promoting oxidation/anti-oxidation, and modifying autophagy activity in vivo. Meanwhile, various research and theories support that inflammation, oxidative stress, and other risk factors promote the onset and progression of affective disorders and neurodegenerative diseases. Existing studies suggest that UA may be involved in the pathophysiological processes of affective disorders in various ways, and there has been a gradual advance in the understanding of the interplay between UA levels and affective disorders and neurodegenerative diseases. This review summarized the role of UA in the process of inflammation, oxidative stress, and autophagy. On this basis, we discussed the correlation between UA and affective disorders and several neurodegenerative diseases, and simultaneously analyzed the possible mechanism of its influence on affective disorders and neurodegenerative diseases, to provide a theoretical basis for UA as a biomarker or therapeutic target for the diagnosis of these diseases.

Update understanding on diagnosis and histopathological examination of atrophic gastritis: A review.

Chronic atrophic gastritis (CAG) is a complex syndrome in which long-term chronic inflammatory stimulation causes gland atrophy in the gastric mucosa, reducing the stomach's ability to secrete gastric juice and pepsin, and interfering with its normal physiological function. Multiple pathogenic factors contribute to CAG incidence, the most common being Helicobacter pylori infection and the immune reactions resulting from gastric autoimmunity. Furthermore, CAG has a broad spectrum of clinical manifestations, including gastroenterology and extra-intestinal symptoms and signs, such as hematology, neurology, and oncology. Therefore, the initial CAG evaluation should involve the examination of clinical and serological indicators, as well as diagnosis confirmation via gastroscopy and histopathology if necessary. Depending on the severity and scope of atrophy affecting the gastric mucosa, a histologic staging system (Operative Link for Gastritis Assessment or Operative Link on Gastritis intestinal metaplasia) could also be employed. Moreover, chronic gastritis has a higher risk of progressing to gastric cancer (GC). In this regard, early diagnosis, treatment, and regular testing could reduce the risk of GC in CAG patients. However, the optimal interval for endoscopic monitoring in CAG patients remains uncertain, and it should ideally be tailored based on individual risk evaluations and shared decision-making processes. Although there have been many reports on CAG, the precise etiology and histopathological features of the disease, as well as the diagnosis of CAG patients, are yet to be fully elucidated. Consequently, this review offers a detailed account of CAG, including its key clinical aspects, aiming to enhance the overall understanding of the disease.

Virulence-linked adhesin drives mutualist colonization of the bee gut via biofilm formation.

Bacterial biofilms are stable multicellular structures that can enable long term host association. Yet, the role of biofilms in supporting gut mutualism is still not fully understood. Here, we investigate Snodgrassella alvi , a beneficial bacterial symbiont of honey bees, and find that biofilm formation is required for its colonization of the bee gut. We constructed fifteen S. alvi mutants containing knockouts of genes known to promote colonization with putative roles in biofilm formation. Genes required for colonization included staA and staB , encoding trimeric autotransporter adhesins (TAAs) and mltA , encoding a lytic transglycosylase. Intriguingly, TAAs are considered virulence factors in pathogens but support mutualism by the symbiont S. alvi. In vitro , biofilm formation was reduced in Δ staB cells and abolished in the other two mutants. Loss of staA also reduced auto-aggregation and cell-cell connections. Based on structural predictions, StaA/B are massive (>300 nm) TAAs with many repeats in their stalk regions. Further, we find that StaA/B are conserved across Snodgrassella species, suggesting that StaA/B-dependent colonization is characteristic of this symbiont lineage. Finally, staA deletion increases sensitivity to bactericidal antimicrobials, suggesting that the biofilm indirectly buffers against antibiotic stress. In all, the inability of two biofilm-deficient strains (Δ staA and Δ mltA ) to effectively mono-colonize bees indicates that S. alvi biofilm formation is required for colonization of the bee gut. We envision the bee gut system as a genetically tractable model for studying the physical basis of biofilm-mutualist-gut interactions.

Molecular Insight into Obesity-Associated Nephropathy: Clinical Implications and Possible Strategies for its Management.

Obesity is a significant health concern due to its rapid increase worldwide. It has been linked to the pathogenic factors of renal diseases, cancer, cardiovascular diseases, hypertension, dyslipidemia, and type 2 diabetes. Notably, obesity raises the likelihood of developing chronic kidney disease (CKD), leading to higher adult mortality and morbidity rates. This study explores the molecular mechanisms that underlie obesity-associated nephropathy and its clinical implications. Obesity-Associated Nephropathy (OAN) develops and worsens due to insulin resistance and hyperinsulinemia, which promote renal sodium reabsorption, glomerular hyperfiltration, and hypertension, leading to progressive kidney damage. Renal damage is further aggravated by persistent inflammation and redox damage, mediated by adipokines and proinflammatory cytokines, such as TNF-α and IL-6. Furthermore, stimulation of the sympathetic nervous system and the renin-angiotensin- aldosterone system (RAAS) intensifies glomerular hypertension and fibrosis. These elements cause glomerular hyperfiltration, renal hypertrophy, and progressive kidney damage. Clinical manifestations of obesity-associated nephropathy include proteinuria, reduced glomerular filtration rate (GFR), and ultimately, CKD. Management strategies currently focus on lifestyle modifications, such as weight loss through diet and exercise, which have been effective in reducing proteinuria and improving GFR. Pharmacological treatments targeting metabolic pathways, including GLP-1 receptor agonists and SGLT2 inhibitors, have shown renoprotective properties. Additionally, traditional RAAS inhibitors offer therapeutic benefits. Early detection and comprehensive management of OAN are essential to prevent its progression and lessen the burden of CKD.

Superior cervical ganglionectomy attenuates vascular remodeling in spontaneously hypertensive rats.

Sympathetic hyperactivity contributes to the pathogenesis of hypertension. However, it is unclear whether the excessive sympathetic activity is an independent and crucial factor for vascular remodeling in hypertension. This study focused on the effect of local sympathetic denervation with superior cervical ganglionectomy (SCGx) on vascular remodeling. Surgical bilateral SCGx was performed in 9-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Control rats received sham-operation without SCGx. All measurements were made 4 weeks after the surgery. The effectiveness of SCGx was confirmed by the eye features of Horner syndrome, greatly reduced tyrosine hydroxylase (TH) contents in the superior cervical ganglion (SCG)-innervated arteries in the head. Although SCGx had no significant effects on blood pressure and heart rate in WKY and SHR, it attenuated vascular remodeling of facial artery and superficial temporal artery in SHR, two representative SCG-innervated extracranial arteries, without significant effects on non-SCG-innervated thoracic aorta and mesenteric artery. SCGx-treated SHR had more auricular blood flow and retina microvasculature than sham-operated SHR. However, SCGx had only a mild effect in attenuating the vascular remodeling of basilar artery and middle cerebral artery, two representative SCG-innervated intracranial arteries, in SHR. SCGx-treated SHR exhibited upregulation of α-smooth muscle actin, downregulation of proliferating cell nuclear antigen, and attenuation of oxidative stress and inflammation in facial artery and superficial temporal artery. Sympathetic denervation by SCGx in SHR attenuated local vascular remodeling, suggesting that sympathetic overactivity is a crucial pathogenic factor of vascular remodeling in SHR.

Role of Akkermansia muciniphila in insulin resistance.

Insulin resistance (IR) is a pathogenic factor in numerous metabolic diseases. The gut microbiota plays a crucial role in maintaining the function of the intestinal barrier and overall human health, thereby influencing IR. Dysbiosis of the gut microbiota can contribute to the development of IR. Therefore, it is essential to maintain a balanced and diverse gut microbiota for optimal health. Akkermansia muciniphila, a widely present microorganism in the human intestine, has been shown to regulate gastrointestinal mucosal barrier integrity, reduce endotoxin penetration, decrease systemic inflammation levels, and improve insulin sensitivity. Reduced abundance of A.muciniphila is associated with an increased risk of IR and other metabolic diseases, highlighting its correlation with IR. Understanding the role and regulatory mechanism of A.muciniphila is crucial for comprehending IR pathogenesis and developing novel strategies for preventing and treating related metabolic disorders. Individual variations may exist in both the gut microbiota composition and its impact on IR among different individuals. Further investigation into individual differences between A.muciniphila and IR will facilitate advancements in personalized medicine by promoting tailored interventions based on the gut microbiota composition, which is a potential future direction that would optimize insulin sensitivity while preventing metabolic disease occurrence. In this review, we describe the physiological characteristics of A.muciniphila, emphasize its roles in underlying mechanisms contributing to IR pathology, and summarize how alterations in its abundance affect IR development, thereby providing valuable insights for further research on A.muciniphila, as well as new drug development targeting diabetes.

Identification of oxylipins and lipid mediators in pulmonary embolism

BackgroundThis study aimed to investigate the role of oxylipins and lipid mediators in Pulmonary Embolism (PE), a serious cardiovascular condition associated with high morbidity and mortality rates.MethodsA total of 6,365 hospitalized patients with thrombosis and 200 healthy individuals were recruited as the control group from 2015 to 2023. Thrombus type, coagulation, and lipid-related parameters were statistically analysed. Additionally, lipidomic characteristics of serum samples from the PE and control groups were examined via LC-MS/MS for the first time.ResultsAmong the 6,365 hospitalized patients with thrombosis, 72.1% (4,587/6,365) had venous thromboembolism (VTE). Within the VTE group, the incidence of PE was 12.1% (555/4,587). In comparison to the healthy control (HC) group, the PE group exhibited significant elevations in coagulation-related parameters, such as factor VIII (F VIII) and von Willebrand factor (vWF) activities, while antithrombin III (AT III) and factor XII (F XII) activities were notably reduced. Lipid-related parameters, including serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (apoA), were significant reductions in PE patients (P < 0.0001), with areas under the curve (AUCs) exceeding 0.9. LC-MS/MS analysis of serum samples revealed 118 oxidized lipid metabolites. Compared to the HC group, the PE group exhibited 10 upregulated oxidized lipid metabolites, with the most significant difference observed in 20-hydroxyPGF2α derived from arachidonic acid (ARA). The study identified upregulated oxidized lipid metabolites primarily linked to the ARA metabolism signalling pathway.ConclusionThis research indicates a notable correlation between lipid metabolism and the occurrence and development of PE. Specifically, upregulation of the arachidonic acid metabolism signalling pathway may be an important pathogenic factor for PE, and 20-hydroxyPGF2α derived from ARA has potential as a biomarker for PE disease.

Comparative genomic analysis of pathogenic factors of Listeria spp. using whole-genome sequencing

Listeria monocytogenes is an important foodborne pathogen known for causing listeriosis. To gain insights into the pathogenicity, genetic characterization, and evolution of various Listeria species, in vitro cell adhesion and invasion ability assays and whole-genome sequencing were performed using four Listeria strains isolated from livestock and poultry slaughterhouses. The four Listeria strains exhibited adhesion and invasion abilities in Caco-2 and RAW264.7 cells. Pathogenic Liv1-1 and Lm2-20 had higher adhesion ability, but non-pathogenic Lin4-99 was more invasive than Lm2-20 (p < 0.05). Genetic characterization revealed the presence of a single chromosome without plasmid across four strains with similar whole-genome sizes and G + C% content. Analysis of key pathogenic genes underscored the presence of multiple virulence genes among the four Listeria strains. In contrast, non-pathogenic Listeria lacked LIPI-1, LIPI-2, and LIPI-3 genes, which could possibly be the cause of their non-pathogenicity despite their in vitro cell adhesion and invasion abilities. Thus, genetic determinants of Listeria do not necessarily predict cell adhesion and/or invasive ability in vitro. This study presents a comprehensive comparative genome-wide analysis of four Listeria strains, offering invaluable insights into the pathogenesis of the Listeria genus.

Antimicrobial resistance and genotypic attributes of virulence among Vibrio spp. isolated from Japanese retail seafood

Bacterial diseases caused by Vibrio spp. are a significant impediment to the aquaculture industry owing to difficult-to-treat infections and mortality in farmed animals, affecting socioeconomic development. This study aimed to evaluate the role of Japanese retail seafood in the production of antimicrobial-resistant Vibrio spp. and pathogenic factors. One hundred seafood samples purchased from various retail supermarkets in Hiroshima, Japan, were examined using microbiological, phenotypic, and molecular techniques. One hundred and twenty-eight Vibrio isolates belonging to more than 11 species were identified and characterized. Among the 100 samples, 26 (26 %) tested positive for Vibrio spp. with antimicrobial resistance, while 44 (44 %) were positive for those carrying virulence determinants. Out of 128 isolates, V. alginolyticus was predominant (38 %), followed by V. parahaemolyticus (29 %), V. neocaledonicus (7.0 %), V. cholerae (6.3 %), among others. For virulence gene assessment, only six of the 10 virulence attributes, tlh (34.4 %), VPI (29.7 %), ompW (7.0 %), toxR (5.5 %), hlyA (3.9 %), and ompU (3.1 %), were detected in the isolates. tcpA, ctxA, ctxB, and tdh are absent. Eight V. cholerae isolates of international origin were VPI-positive, seven of which harbored the toxR regulon and other virulence genes. The blaTEM resistance gene was identified in V. alginolyticus (22 isolates). All 46 antimicrobial resistance gene-harboring isolates were phenotypically susceptible to cephalosporins, aztreonam, meropenem, tetracycline, chloramphenicol, and ciprofloxacin. Ampicillin resistance was the highest (91.3 %), followed by colistin (30.4 %) and fosfomycin (15.2 %). The multiple-antibiotic resistance index ranged from 0.2 to 0.47, suggesting that some isolates originate from high-risk contamination sources. Our results shed light on the incidence of potentially pathogenic Vibrio spp. and highlighted the importance of continuous monitoring to improve food safety in the seafood supply chain. These findings will be useful for developing microbiological risk assessments for retail seafood management.

The Role of SIRT1 in Leukemia.

Leukemia is a type of hematological malignancy (HM) caused by uncontrolled proliferation, apoptosis, and differentiation of hematopoietic stem cells (HSCs). Leukemia cells proliferate greatly in the bone marrow (BM), infiltrate other tissues and organs, and affect the normal hematopoietic function. Although the emergence of new targeted agents and immune agents has improved the prognosis of patients, due to the complex pathogenic factors and heterogeneity of leukemia, there are still some patients with poor prognosis. Recent studies have shown that silent information regulator 1 (SIRT1) is involved in the proliferation, apoptosis, metabolism, and senescence of leukemia cells. As a double-edged sword in leukemia cells, SIRT1 can both promote and inhibit the growth of leukemia cells. Since its mechanism of action has not been elucidated, it is urgent to explore the regulatory mechanism of SIRT1 in leukemia. In this review, we discussed the mechanisms of SIRT1 in different aspects of leukemia, providing a theoretical basis for the treatment of patients with leukemia.

Proteomics fingerprinting reveals importance of iron and oxidative stress in Streptomyces scabies-Solanum tuberosum interactions.

The Gram-positive actinobacterium Streptomyces scabies is the major causal agent of potato common scab. The main pathogenicity factor is thaxtomin A, a phytotoxin that causes atypical cell death, although other secondary metabolites have been described to play a role in S. scabies virulence. Despite this, many aspects of the interaction between S. scabies and its primary host Solanum tuberosum L. remain to be elucidated. Intracellular proteins of S. scabies EF-35 grown in the presence of in vitro produced tubers (microtubers) of the Russet Burbank and Yukon Gold potato cultivars were extracted and analysed by electrospray mass spectrometry (ES MS/MS). Based on the results of proteomic analysis, iron quantification by ICP-MS and nitrite quantification using Griess reagent in growth media as well as RT-qPCR analysis of the siderophore pyochelin gene expression were performed in the presence and absence of microtubers. Hydrogen peroxide accumulation was also determined in the nutrient medium used for co-cultivation of bacteria and potato microtubers. Potato microtubers caused an increase in the content of bacterial proteins involved in stress and defense, secondary metabolism, and cell differentiation, as well as secreted proteins. Co-cultivation with potato microtubers induced the accumulation of S. scabies proteins implicated in siderophore pyochelin biosynthesis, nitrite production and oxidative stress perception and response. The increase in the abundance of proteins related to pyochelin biosynthesis was consistent with a significant decrease in the iron content in the culture medium, as well as with induction of expression of pyochelin biosynthesis genes. Elevated nitrite/sulfite reductase protein levels were associated with increased nitrite excretion by S. scabies cells in the presence of host microtubers. The increase in the levels of proteins associated with signaling and oxidative stress response could have been caused by the accumulation of ROS, in particular hydrogen peroxide, detected in the studied system. These findings show that interactions of S. scabies with living potato microtubers induce the production of secondary metabolites, defense responses, and protection from oxidative stress. This study suggests the importance of iron during host - S. scabies interactions, resulting in competition between pathogen and its host.

Application of a modified multifunctional short peptide in the treatment of periodontitis

Periodontitis is a chronic inflammatory disease involving plaque biofilm as a pathogenic factor. Potassium ion plays an important role in cellular homeostasis; a large outflow of potassium may lead to local inflammation progression. In this work, the multifunctional short peptide molecule BmKTX-33 was designed by modifying the BmKTX, a Kv1.3 potassium channel inhibitor. This was to explore its antibacterial properties, capability of maintaining cell ion homeostasis, and bone-forming capacity. The results showed that BmKTX-33 had inhibitory effects on S. gordonii, F. nucleatum, and P. gingivalis. Moreover, BmKTX-33 also inhibited excessive potassium outflow in inflammatory environments. Finally, BmKTX-33 promoted MC3T3-E1 early osteogenesis while suppressing the NLRP3 inflammasome's production. In conclusion, BmKTX-33 not only has antibacterial properties, but also can inhibit the expression of NLRP3 inflammasome and play an anti-inflammatory role.

The pro-inflammatory responses of innate immune cells to Leishmania RNA virus 2-infected L. major support the survival and proliferation of the parasites

Infection of Leishmania by Leishmania RNA virus (LRV) has been proposed as a pathogenic factor that induces pro-inflammatory responses through the TLR3/TLR4 signaling pathway. We investigated the effect of L. major infection by LRV2 on innate immune cell responses (human neutrophil (HL-60) and macrophage (THP-1) cell lines). The expression levels of pro- and anti-inflammatory cytokine and chemokine genes as well as genes involved in the amino acid metabolism of arginine were then investigated by RT-qPCR. Moreover, the expression of TLR genes and their downstream signaling pathways were compared in THP-1 cells infected with the two isolates. Apoptosis was also evaluated in infected THP-1 and HL-60 cells using the PI/Annexin V flow cytometry assay. In both cell lines, the expression of pro-inflammatory cytokines increased in response to LRV2+ L. major (Lm+), and the expression of chemokines shifted toward macrophage recruitment. In contrast to LRV2- L. major (Lm-), Lm+ infected THP-1 cells acquired the M2-like phenotype. The presence of LRV2 increased the gene expression of TLRs and their signaling pathways, especially TLR3 and TLR4, which was proportional to the increase in pro-inflammatory cytokines. In addition, Lm+ increased the expression of IL-10 and IFN-β, which contribute to the survival and growth of the parasite in the phagolysosome. Altogether, our results showed that Lm+ could stimulate pro-inflammatory responses that promote parasite replication and stabilization in the host.

Protein P5 of pear chlorotic leaf spot-associated virus is a pathogenic factor that suppresses RNA silencing and enhances virus movement.

Pear chlorotic leaf spot-associated virus (PCLSaV) is a newly described emaravirus that infects pear trees. The virus genome consists of at least five single-stranded, negative-sense RNAs. The P5 encoded by RNA5 is unique to PCLSaV. In this study, the RNA silencing suppression (RSS) activity of P5 and its subcellular localization were determined in Nicotiana benthamiana plants by Agrobacterium tumefaciens-mediated expression assays and green fluorescent protein RNA silencing induction. Protein P5 partially suppressed local RNA silencing, strongly suppressed systemic RNA silencing and triggered reactive oxygen species accumulation. The P5 self-interacted and showed subcellular locations in plasmodesmata, endoplasmic reticulum and nucleus. Furthermore, P5 rescued the cell-to-cell movement of a movement defective mutant PVXΔP25 of potato virus X (PVX) and enhanced the pathogenicity of PVX. The N-terminal 1-89 amino acids of the P5 were responsible for the self-interaction ability and RSS activity, for which the signal peptide at positions 1-19 was indispensable. This study demonstrated the function of an emaravirus protein as a pathogenic factor suppressing plant RNA silencing to enhance virus infection and as an enhancer of virus movement.