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Microorganisms Jun 2024Toxin-antitoxin (TA) systems are the major mechanism for persister formation in (). Previous studies found that HigBA2 (Rv2022c-Rv2021c), a predicted type II TA system...
Toxin-antitoxin (TA) systems are the major mechanism for persister formation in (). Previous studies found that HigBA2 (Rv2022c-Rv2021c), a predicted type II TA system of , could be activated for transcription in response to multiple stresses such as anti-tuberculosis drugs, nutrient starvation, endure hypoxia, acidic pH, etc. In this study, we determined the binding site of HigA2 (Rv2021c), which is located in the coding region of the upstream gene (), and the conserved recognition motif of HigA2 was characterized via oligonucleotide mutation. Eight binding sites of HigA2 were further found in the genome according to the conserved motif. RT-PCR showed that HigA2 can regulate the transcription level of all eight of these genes and three adjacent downstream genes. DNA pull-down experiments showed that twelve functional regulators sense external regulatory signals and may regulate the transcription of the HigBA2 system. Of these, Rv0903c, Rv0744c, Rv0474, Rv3124, Rv2603c, and Rv3583c may be involved in the regulation of external stress signals. In general, we identified the downstream target genes and possible upstream regulatory genes of HigA2, which paved the way for the illustration of the persistence establishment mechanism in .
PubMed: 38930627
DOI: 10.3390/microorganisms12061244 -
Journal of Clinical Medicine Jun 2024: () infections can progress to severe respiratory complications, necessitating intensive care treatment. Recent post COVID-19 pandemic surges underscore the need for...
: () infections can progress to severe respiratory complications, necessitating intensive care treatment. Recent post COVID-19 pandemic surges underscore the need for timely diagnosis, given potential diagnostic method limitations. A retrospective case series analysis was conducted on PCR-positive patients admitted to two Dutch secondary hospitals' ICUs between January 2023 and February 2024. Clinical presentations, treatments, outcomes, and mechanical ventilation data were assessed. : Seventeen ICU-admitted patients were identified, with a median age of 44 years, primarily due to hypoxia. Non-invasive ventilation was effective for most, while five required invasive mechanical ventilation. None of the patients required extracorporeal membrane oxygenation. No fatalities occurred. Post-PCR, treatment was adjusted to doxycycline or azithromycin; seven received steroid treatment. : Increased ICU admissions for infection were observed. Diverse clinical and radiological findings emphasize heightened clinical awareness. Early molecular diagnostics and tailored antibiotic regimens are crucial since beta-lactam antibiotics are ineffective. : This study highlights the escalating challenge of severe infections in ICUs, necessitating a multifaceted approach involving accurate diagnostics, vigilant monitoring, and adaptable treatment strategies for optimal patient outcomes.
PubMed: 38929972
DOI: 10.3390/jcm13123443 -
Journal of Personalized Medicine Jun 2024This study compared the therapeutic effects of engineered exosomes derived from RAW264.7 cells overexpressing hsa-let-7i-5p (engineered exosomes) to exosomes from human...
Therapeutic Effects of Engineered Exosomes from RAW264.7 Cells Overexpressing hsa-let-7i-5p against Sepsis in Mice-A Comparative Study with Human Placenta-Derived Mesenchymal Stem Cell Exosomes.
This study compared the therapeutic effects of engineered exosomes derived from RAW264.7 cells overexpressing hsa-let-7i-5p (engineered exosomes) to exosomes from human placenta-derived mesenchymal stem cells (hpMSC exosomes) against sepsis-induced acute lung injury. Adult male C57BL/6 mice were divided into lipopolysaccharide (LPS), LPS plus engineered exosome (LEExo), or LPS plus hpMSC exosome (LMExo) groups, alongside control groups. The results showed that lung injury scores (based on pathohistological characteristics) and the levels of lung function alterations, tissue edema, and leukocyte infiltration in LEExo and LMExo groups were comparable and significantly lower than in the LPS group (all < 0.05). Furthermore, the levels of inflammation (nuclear factor-κB activation, cytokine upregulation), macrophage activation (hypoxia-inducible factor-1α activation, M1 phase polarization), oxidation, and apoptosis were diminished in LEExo and LMExo groups compared to the LPS group (all < 0.05). Inhibition of hsa-let-7i-5p attenuated the therapeutic effects of both engineered and hpMSC exosomes. These findings underscore the potent therapeutic capacity of engineered exosomes enriched with hsa-let-7i-5p and their potential as an alternative to hpMSC exosomes for sepsis treatment. Continued research into the mechanisms of action and optimization of engineered exosomes could pave the way for their future clinical application.
PubMed: 38929840
DOI: 10.3390/jpm14060619 -
Journal of Personalized Medicine Jun 2024Overlap syndrome (OS), the coexistence of chronic obstructive pulmonary disease and obstructive sleep apnea, is frequently characterized by the presence of daytime...
BACKGROUND
Overlap syndrome (OS), the coexistence of chronic obstructive pulmonary disease and obstructive sleep apnea, is frequently characterized by the presence of daytime hypercapnia (pCO ≥ 45 mmHg). The aim of this study was to investigate potential differences in anthropometric, sleep and respiratory characteristics between hypercapnic and normocapnic patients with OS.
METHODS
Consecutive patients who underwent polysomnography, pulmonary function testing and arterial blood gases and had been diagnosed with OS were enrolled in the study.
RESULTS
According to pCO levels in wakefulness, the patients were divided into group A, consisting of OS patients without hypercapnia ( = 108) or group B, consisting of OS patients with hypercapnia ( = 55). The majority of included patients in both groups were males ( = 92 in group A vs. = 50 in group B). Group B had increased BMI ( = 0.001), neck ( = 0.017) and waist circumference ( = 0.013), higher scores in Epworth sleepiness scale (ESS) ( = 0.008), increased sleep efficiency ( = 0.033), oxygen desaturation index ( = 0.004) and time with oxyhemoglobin saturation <90% ( = 0.006) than group A. Also, Group B had decreased average and minimum oxyhemoglobin saturation during sleep ( < 0.001). Hypercapnic patients had lower FEV% ( = 0.003), FVC% ( = 0.004), pO and pCO ( < 0.001 for both) values compared with normocapnic patients. In binary regression analysis, which assessed various predictors on the likelihood of having hypercapnia, it was found that BMI (OR: 1.313, 95% CI: 1.048-1.646, = 0.018) and FVC (OR: 0.913, 95% CI: 0.845-0.986, = 0.020) were the major determinants of hypercapnia in OS patients.
CONCLUSIONS
Hypercapnic OS patients were more obese and sleepy and presented worse respiratory function in wakefulness and sleep hypoxia characteristics compared with normocapnic OS patients.
PubMed: 38929821
DOI: 10.3390/jpm14060600 -
Life (Basel, Switzerland) Jun 2024: The embryo and the fetus develop in a physiologically hypoxic environment, where vascularization is sustained by HIF-1, VEGF, and the β-adrenergic system. In animals,...
: The embryo and the fetus develop in a physiologically hypoxic environment, where vascularization is sustained by HIF-1, VEGF, and the β-adrenergic system. In animals, β3-adrenoceptors (β3-ARs), up-regulated by hypoxia, favor global fetal wellness to such an extent that most diseases related to prematurity are hypothesized to be induced or aggravated by a precocious β3-AR down-regulation, due to premature exposure to a relatively hyperoxic environment. In animals, β3-AR pharmacological agonism is currently investigated as a possible new therapeutic opportunity to counteract oxygen-induced damages. Our goal is to translate the knowledge acquired in animals to humans. Recently, we have demonstrated that fetuses become progressively more hypoxemic from mid-gestation to near-term, but starting from the 33rd-34th week, oxygenation progressively increases until birth. The present paper aims to describe a clinical research protocol, evaluating whether the expression level of HIF-1, β3-ARs, and VEGF is modulated by oxygen during intrauterine and postnatal life, in a similar way to animals. : In a prospective, non-profit, single-center observational study we will enroll 100 preterm (group A) and 100 full-term newborns (group B). We will collect cord blood samples (T0) and measure the RNA expression level of HIF-1, β3-ARs, and VEGF by digital PCR. In preterms, we will also measure gene expression at 48-72h (T1), 14 days (T2), and 30 days (T3) of life and at 40 ± 3 weeks of post-menstrual age (T4), regardless of the day of life. We will compare group A (T0) vs. group B (T0) and identify any correlations between the values obtained from serial samples in group A and the clinical data of the patients. Our protocol has been approved by the Pediatric Ethical Committee for Clinical Research of the Tuscany region (number 291/2022). : The observation that in infants, the HIF-1/β3-ARs/VEGF axis shows similar modulation to that of animals could suggest that β3-ARs also promote fetal well-being in humans.
PubMed: 38929758
DOI: 10.3390/life14060776 -
Medicina (Kaunas, Lithuania) May 2024: Selenium deficiency represents a risk factor for the occurrence of severe diseases, such as acute kidney injury (AKI). Recently, selenoprotein-p1 (SEPP1), a selenium...
: Selenium deficiency represents a risk factor for the occurrence of severe diseases, such as acute kidney injury (AKI). Recently, selenoprotein-p1 (SEPP1), a selenium transporter, mainly released by the liver, has emerged as a promising plasmatic biomarker of AKI as a consequence of cardio-surgery operations. The aim of the present study was to investigate, on an in vitro model of hypoxia induced in renal tubular cells, HK-2, the effects of sodium selenite (NaSeO) and to evaluate the expression of SEPP1 as a marker of injury. : HK-2 cells were pre-incubated with 100 nM NaSeO for 24 h, and then, treated for 24 h with CoCl (500 µM), a chemical hypoxia inducer. The results were derived from an ROS assay, MTT, and Western blot analysis. : The pre-treatment determined an increase in cells' viability and a reduction in reactive oxygen species (ROS), as shown by MTT and the ROS assay. Moreover, by Western blot an increase in SEPP1 expression was observed after hypoxic injury as after adding sodium selenite. : Our preliminary results shed light on the possible role of selenium supplementation as a means to prevent oxidative damage and to increase SEPP1 after acute kidney injury. In our in vitro model, SEPP1 emerges as a promising biomarker of kidney injury, although further studies in vivo are necessary to validate our findings.
Topics: Humans; Selenoprotein P; Reperfusion Injury; Kidney Tubules, Proximal; Acute Kidney Injury; Sodium Selenite; Reactive Oxygen Species; Biomarkers; Cell Line; Cell Survival; In Vitro Techniques
PubMed: 38929492
DOI: 10.3390/medicina60060875 -
Antioxidants (Basel, Switzerland) May 2024Kidney diseases pose a significant global health issue, frequently resulting in the gradual decline of renal function and eventually leading to end-stage renal failure.... (Review)
Review
Kidney diseases pose a significant global health issue, frequently resulting in the gradual decline of renal function and eventually leading to end-stage renal failure. Abnormal iron metabolism and oxidative stress-mediated cellular dysfunction facilitates the advancement of kidney diseases. Iron homeostasis is strictly regulated in the body, and disturbance in this regulatory system results in abnormal iron accumulation or deficiency, both of which are associated with the pathogenesis of kidney diseases. Iron overload promotes the production of reactive oxygen species (ROS) through the Fenton reaction, resulting in oxidative damage to cellular molecules and impaired cellular function. Increased oxidative stress can also influence iron metabolism through upregulation of iron regulatory proteins and altering the expression and activity of key iron transport and storage proteins. This creates a harmful cycle in which abnormal iron metabolism and oxidative stress perpetuate each other, ultimately contributing to the advancement of kidney diseases. The crosstalk of iron metabolism and oxidative stress involves multiple signaling pathways, such as hypoxia-inducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. This review delves into the functions and mechanisms of iron metabolism and oxidative stress, along with the intricate relationship between these two factors in the context of kidney diseases. Understanding the underlying mechanisms should help to identify potential therapeutic targets and develop novel and effective therapeutic strategies to combat the burden of kidney diseases.
PubMed: 38929098
DOI: 10.3390/antiox13060659 -
International Journal of Molecular... Jun 2024Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In...
Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl) to simulate low-oxygen conditions. We found that CoCl treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein-protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies.
Topics: Tropomyosin; Myocytes, Cardiac; Animals; Cell Hypoxia; Cytoskeleton; Oxidative Stress; Cell Line; Rats; Cobalt; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38928503
DOI: 10.3390/ijms25126797 -
International Journal of Molecular... Jun 2024Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a... (Review)
Review
Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a stroke worldwide. Among them, 5 million people die, while 5 million people are left permanently disabled. In this sense, the research to find new treatments should be accompanied with new therapies to combat neuronal death and to avoid developing cognitive impairment and dementia. Phytocannabinoids are among the compounds that have been used by mankind for the longest period of history. Their beneficial effects such as pain regulation or neuroprotection are widely known and make them possible therapeutic agents with high potential. These compounds bind cannabinoid receptors CB and CB. Unfortunately, the psychoactive side effect has displaced them in the vast majority of areas. Thus, progress in the research and development of new compounds that show efficiency as neuroprotectors without this psychoactive effect is essential. On the one hand, these compounds could selectively bind the CB receptor that does not show psychoactive effects and, in glia, has opened new avenues in this field of research, shedding new light on the use of cannabinoid receptors as therapeutic targets to combat neurodegenerative diseases such as Alzheimer's, Parkinson's disease, or stroke. On the other hand, a new possibility lies in the formation of heteromers containing cannabinoid receptors. Heteromers are new functional units that show new properties compared to the individual protomers. Thus, they represent a new possibility that may offer the beneficial effects of cannabinoids devoid of the unwanted psychoactive effect. Nowadays, the approval of a mixture of CBD (cannabidiol) and Δ-THC (tetrahydrocannabinol) to treat the neuropathic pain and spasticity in multiple sclerosis or purified cannabidiol to combat pediatric epilepsy have opened new therapeutic possibilities in the field of cannabinoids and returned these compounds to the front line of research to treat pathologies as relevant as stroke.
Topics: Humans; Receptor, Cannabinoid, CB2; Receptor, Cannabinoid, CB1; Ischemic Stroke; Animals; Cannabidiol; Neuroprotective Agents
PubMed: 38928415
DOI: 10.3390/ijms25126708 -
International Journal of Molecular... Jun 2024Renal cell carcinoma (RCC) is one of the most common malignant tumors of the kidney, presenting significant challenges for clinical diagnosis and treatment. Macrophages...
Renal cell carcinoma (RCC) is one of the most common malignant tumors of the kidney, presenting significant challenges for clinical diagnosis and treatment. Macrophages play crucial roles in RCC, promoting tumor progression and warranting further investigation. Previous studies have identified as a transmembrane protein associated with reproduction, but its relationship with tumors or macrophages has not been discussed. This study utilized transcriptomic sequencing data from 609 KIRC patients in the TCGA database and single-cell sequencing data from 34,326 renal carcinoma cells for subsequent analysis. We comprehensively evaluated the expression of and its relationship with clinical features, tumor prognosis, immune infiltration, and mutations. Additionally, we further assessed the correlation between and macrophage M2 polarization using single-cell data and explored its potential as a cancer therapeutic target through molecular docking. The results demonstrated that is upregulated in RCC and associated with poor survival rates. In clinical staging, the proportion of malignant and high-metastasis patients was higher in the high- group than in the low- group. Furthermore, we found that influences RCC immune infiltration, with its expression positively correlated with various immune checkpoint and M2-related gene expressions, positively associated with M2 macrophage infiltration, and negatively correlated with activated NK cells. Moreover, showed specific expression in macrophages, with the high-expression subgroup exhibiting higher M2 polarization, hypoxia, immune evasion, and angiogenesis scores, promoting tumor progression. Finally, we predicted several potential drugs targeting , such as conivaptan and nilotinib. Our analysis elaborately delineates the immune characteristics of in the tumor microenvironment and its positive correlation with macrophage M2 polarization, providing new insights into tumor immunotherapy. We also propose potential FDA-approved drugs targeting this gene, which should be tested for their binding effects with in future studies.
Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Biomarkers, Tumor; Macrophages; Prognosis; Gene Expression Regulation, Neoplastic; Female; Male; Tumor Microenvironment; Molecular Docking Simulation
PubMed: 38928412
DOI: 10.3390/ijms25126707