Miracle-dz/UniFAR-FTUs huggingface dataset:
Adipose-Derived Mesenchymal Stem Cells Promote M2 Macrophage Phenotype through Exosomes

Accumulating evidence has shown that the paracrine factors derived from mesenchymal stem cells (MSCs) are capable of regulating the immune system via interaction with various immune cells. In this study, adipose-derived MSCs (AdMSCs) and human peripheral blood monocytes (PBMCs) were isolated and cultured to examine the effects of MSC-induced macrophages (iMΦ) on inflammation and immune modulation. Indirect coculture with MSCs increased the expression of arginase-1 and mannose receptor (CD206), markers of activated M2 macrophages, in the PBMCs demonstrating that MSC-secreted factors promoted M2-MΦ polarization. Additionally, iMΦ exhibited a similar higher inhibitory effect on the growth of activated T cells compared to that in the other groups (AdMSCs only, AdMSCs plus iMΦ), implying that iMΦ can play a sufficient functional role. Interestingly, the population of FoxP3 Treg cells significantly increased when cocultured with iMΦ, suggesting that iMΦ have an immunomodulatory effect on the Treg cells through the modulation of the FoxP3 expression. Notably, iMΦ expressed high levels of immunosuppressive and anti-inflammatory cytokines, namely IL-10 and TSG-6. Furthermore, we confirmed that the AdMSC-derived exosomes modulated macrophage polarization by upregulating the expression of M2 macrophage markers. Conclusively, our results suggest that iMΦ play a significant role in regulating the immunomodulatory- and inflammatory-mediated responses. Thus, iMΦ may be used as a novel stem cell-based cell-free therapy for the treatment of immune-mediated inflammatory disorders.
Dihydroartemisinin Protects against Dextran Sulfate Sodium-Induced Colitis in Mice through Inhibiting the PI3K/AKT and NF-κB Signaling Pathways

Ulcerative colitis is a common inflammatory bowel disease, and the activation of thePI3K/AKT and NF-κB signaling pathways plays a pivotal role in its pathogenesis. Dihydroartemisinin (DHA) is a widely used antimalarial drug and has shown anticancer effect partially through inhibiting the activation of PI3K/AKT and NF-κB. This study aimed to investigate the effect of dihydroartemisinin on ulcerative colitis and its mechanism. Adult male C57 mice were subjected to 3.0% dextran sulfate sodium (DSS) for seven days; simultaneously, dihydroartemisinin or control saline was administered by oral gavage once a day. In vitro, the intestinal epithelial cell-6 was treated with LPS for 24 hours with or without dihydroartemisinin combined with PI3K/Akt activator 740 Y-P or NF-κB activator phorbol myristate acetate. Western blotting was used to test the activation of PI3K/AKT and NF-κB. Dihydroartemisinin significantly ameliorated body weight loss, shortened colon length, and increased DAI in DSS-induced colitis. Meanwhile, histological damage was improved and was accompanied by decreased expression and secretion of proinflammatory cytokines. Moreover, DSS-induced elevation of phosphorylation of PI3K, AKT, IKKα, IκBα, and NF-κB (p65) was remarkably blunted by dihydroartemisinin both in vivo and in vitro, indicating an inhibitive property on the PI3K/AKT and NF-κB signaling pathways. Furthermore, administration of 740 Y-P or PMA significantly blocked protective activity of dihydroartemisinin against colitis in vitro. In conclusion, dihydroartemisinin can attenuate DSS-induced colitis, and its anticolitis effect might be mediated via the PI3K/AKT and NF-κB signaling pathways. DHA might serve as a promising drug for patients with ulcerative colitis.
Lifestyles, Depression, Anxiety, and Stress as Risk Factors in Nursing Apprentices: A Logistic Regression Analysis of 1193 Students in Lima, Peru

Currently, it is considered that mental disorders are related to different types of chronic pathologies; for this reason, efforts to improve general health should also focus on preserving mental health. Therefore, the objective of this study was to determine through logistic regression if the independent variables (risk factors) such as (X1) age, (X2) sex, (X3) marital status, (X4) number of children, and (X5) occupation have influence on the dependent variables such as lifestyles, depression, anxiety, and stress in Peruvian nursing students. The research study was descriptive, transversal, and prospective; 1193 nursing students from Chorrillos, Ica, and Chincha were evaluated, which constituted the total population for the 2018 semester. The Health Promoting Life Profile-II (HPLP-II) and the Depression and Anxiety Stress Scale-21 (DASS-21) were used as instruments. 53.9% of nursing students had unhealthy lifestyles; however, they presented moderate (19.7%), slight (14.2%), severe (2.5%), and extremely severe (2.4%) anxiety. With respect to depression, it was found that 61.2% and 59.9% of affected students were stressed. A significant association was found only between depression and age (p=0.040) and OR = 2.0 (95% CI 1.3–3.1), anxiety and marital status (p=0.043) and OR = 1.7 (95% CI 1.0–2.6), and lifestyles and sex of the students (p=0.003) and OR = 1.1 (95% CI 1.1–2.3). Finally, it is concluded that Peruvian nursing students showed levels of anxiety ranging from moderate to extremely severe, while most of them had “normal” states of depression and stress and also showed unhealthy lifestyles.
Integrated Analysis of miRNA-mRNA Interaction Network in Porcine Granulosa Cells Undergoing Oxidative Stress

Oxidative stress (OS), a common intracellular phenomenon induced by excess reactive oxygen species (ROS) generation, has been shown to be associated with mammalian ovarian follicular development blockage and granulosa cell (GC) impairment. However, the mechanism involved in these effects remains unknown, and the effect of OS on the transcriptome profiles in porcine GCs has not been fully characterized. In this study, we found that hydrogen peroxide-mediated oxidative stress induced porcine GC apoptosis and impaired cell viability. Moreover, RNA-seq analysis showed that oxidative stress induced dramatic changes in gene expression in porcine GCs. A total of 2025 differentially expressed genes (DEGs) were identified, including 1940 DEmRNAs and 55 DEmiRNAs. Functional annotation showed that the DEGs were mainly associated with cell states and function regulation. In addition, multiple hub genes (FOXO1, SOD2, BMP2, DICER1, BCL2L11, FZD4, ssc-miR-424, and ssc-miR-27b) were identified by constructing protein-protein interaction and DEmiRNA-DEmRNA regulatory networks. Furthermore, a gene-pathway-function coregulatory network was established and demonstrated that these hub genes were enriched in FoxO, TGF-β, Wnt, PIK3-Akt, MAPK, and cAMP signaling pathways, which play important roles in regulating cell apoptosis, cell proliferation, stress responses, and hormone secretion. The current research provides a comprehensive perspective of the effects of oxidative stress on porcine GCs and also identifies potential therapeutic targets for oxidative stress-induced female infertility.
Investigation of the Mechanism Underlying Calcium Dobesilate-Mediated Improvement of Endothelial Dysfunction and Inflammation Caused by High Glucose

Background/Aims Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. Recent studies have demonstrated that CaD exerts protective effects against diabetic nephropathy. The aim of this study was to elucidate the molecular and cellular mechanisms underlying the protective effects of CaD. Methods Human umbilical vein endothelial cells (HUVECs) were cultured with different D-glucose concentrations to determine the effects of high glucose on HUVEC gene expression. HUVECs were also incubated with CaD (25 μM, 50 μM, and 100 μM) for 3 days to determine the effects of CaD on HUVEC viability. db/db mice were treated with CaD. 2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) blocked the nuclear factor-κB (NF-κB) pathway in HUVECs. A pentraxin 3 (PTX3) small interfering RNA (siRNA) intervention experiment was performed in the cells. An adenovirus-encapsulated PTX3 siRNA intervention experiment was performed in db/db mice. Western blot and real-time PCR analyses were used to detect PTX3, p-IKBa/IKBa (I-kappa-B-alpha), and p-eNOS/eNOS (endothelial nitric oxide synthase) expression in mice and HUVECs. Hematoxylin-eosin (HE) staining and periodic acid-Schiff (PAS) staining were used to observe renal tissue damage in mice. PTX3 expression was observed by immunohistochemical staining. Results CaD downregulated the expression of PTX3 and p-IKBa/IKBa and upregulated the expression of p-eNOS/eNOS in vitro. When TPCA-1 was used, high glucose induced high PTX3 expression, and the expression of p-eNOS/eNOS increased. After PTX3 gene silencing, the expression of p-eNOS/eNOS also increased. In vivo, CaD reduced the expression of PTX3 and p-IKBa/IKBa in the kidneys of db/db mice and increased the expression of p-eNOS/eNOS. After PTX3 gene silencing, the urine protein and renal function of db/db mice were ameliorated, the glomerular extracellular matrix was decreased, and the expression of p-eNOS/eNOS was increased. Conclusions Our results suggested that CaD may inhibit the expression of PTX3 by altering the IKK/IKB/NF-κB pathway, thereby improving endothelial dysfunction in HUVECs. PTX3 may be a potential therapeutic target for DKD.
Platelet-Rich Plasma Improves the Wound Healing Potential of Mesenchymal Stem Cells through Paracrine and Metabolism Alterations

Chronic and acute nonhealing wounds represent a major public health problem, and replacement of cutaneous lesions by the newly regenerated skin is challenging. Mesenchymal stem cells (MSC) and platelet-rich plasma (PRP) were separately tested in the attempt to regenerate the lost skin. However, these treatments often remained inefficient to achieve complete wound healing. Additional studies suggested that PRP could be used in combination with MSC to improve the cell therapy efficacy for tissue repair. However, systematic studies related to the effects of PRP on MSC properties and their ability to rebuild skin barrier are lacking. We evaluated in a mouse exhibiting 4 full-thickness wounds, the skin repair ability of a treatment combining human adipose-derived MSC and human PRP by comparison to treatment with saline solution, PRP alone, or MSC alone. Wound healing in these animals was measured at day 3, day 7, and day 10. In addition, we examined in vitro and in vivo whether PRP alters in MSC their proangiogenic properties, their survival, and their proliferation. We showed that PRP improved the efficacy of engrafted MSC to replace lost skin in mice by accelerating the wound healing processes and ameliorating the elasticity of the newly regenerated skin. In addition, we found that PRP treatment stimulated in vitro, in a dose-dependent manner, the proangiogenic potential of MSC through enhanced secretion of soluble factors like VEGF and SDF-1. Moreover, PRP treatment ameliorated the survival and activated the proliferation of in vitro cultured MSC and that these effects were accompanied by an alteration of the MSC energetic metabolism including oxygen consumption rate and mitochondrial ATP production. Similar observations were found in vivo following combined administration of PRP and MSC into mouse wounds. In conclusion, our study strengthens that the use of PRP in combination with MSC might be a safe alternative to aid wound healing.
Cognitive Impairment among Cardiac Arrest Survivors in the ICU: A Retrospective Study

Background Recent studies have presented the effects of cardiac arrest on long-term cognitive function and quality of life. However, no study has evaluated cognitive function in the early stage after regaining consciousness. Purpose The objectives of this study were to analyse the incidence, clinical course, and associated factors of cognitive impairment of cardiac arrest survivors in intensive care unit (ICU). Patients and methods We administered the Mini-Mental State Examination (MMSE) to cardiac arrest survivors who were treated with targeted temperature management (TTM) immediately after regaining consciousness. Patients whose MMSE scores indicated impaired cognitive function (MMSE < 24) were retested before ICU discharge. Results In 92 patients, the median MMSE score was 21.0 (interquartile range (IQR), 16.0–24.0), and cognitive impairment was found in 64 patients. Fifty-three patients completed follow-up MMSEs, and the median scores were 20.0 (IQR, 13.5–23.0) for the first and 25.0 (IQR, 21.5–28.0) for the last test. Of the specific domains, recall (0.0 (IQR, 0.0–1.0) to 2.0 (IQR, 1.0–3.0)) and attention/calculation (3.0 (IQR, 1.0–4.0) to 4.0 (IQR, 2.0–5.0)) were the most affected domains until ICU discharge. The factors that were correlated with cognitive impairment on the last MMSE were older age (OR, 1.07 (95% CI, 1.01–1.14), p=0.016), increased time to return of spontaneous circulation (ROSC) (OR, 1.08 (95% CI, 1.02–1.15), p=0.012), and length of hospital stay (OR, 1.07 (95% CI, 1.00–1.14), p=0.044). Conclusions Cognitive impairments were common immediately after patients regained consciousness but recovered substantially before ICU discharge. Recall and attention/calculation still were impaired until ICU discharge, and older age, increased time to ROSC, and LOS were associated with this cognitive decline.
Safety and Mode of Action of Diabetes Medications in comparison with 5-Aminolevulinic Acid (5-ALA)

5-Aminolevulinic acid (5-ALA) is a delta amino acid naturally present in every living cell of the human body. 5-ALA is produced in the mitochondria as the first product of the porphyrin synthesis pathway and composes heme; exogenously supplemented 5-ALA helps in upregulating mitochondrial functions. Mitochondrial dysfunction has been associated with the pathophysiology of diabetes mellitus. Thus, in this review, we evaluate the mechanisms of action and adverse effects of common medications used to treat type 2 diabetes mellitus as well as 5-ALA including its mechanism and possible use in diabetes management.
Ashy Dermatosis and Lichen Planus Pigmentosus: The Histopathological Differences

Background Ashy dermatosis (AD) and lichen planus pigmentosus (LPP) are both acquired macular pigmentation of uncertain aetiology. Despite the controversy surrounding their entities, recent global consensus has concluded that they are 2 different diseases with distinct clinical presentations. Nevertheless, there are limited data on their histopathological comparisons. Objective To evaluate the differences in histopathological findings between AD and LPP. Methods Electronic records and photographs of patients with the diagnosis of AD or LPP from January 2008 to December 2018 were retrospectively reviewed by a dermatologist. Patients were then classified into groups with AD and LPP, based on the clinical descriptions from the recent consensus. Those with history/clinical presentations suggestive of other causes of macular pigmentation were excluded. The histopathological diagnosis of AD and LPP was then reevaluated by a blinded dermatopathologist. Results One hundred and twenty-four patients with acquired macular pigmentation were identified; 24 were excluded due to clinical history or photographs being inconsistent with AD or LPP. Of the remaining 100 patients, 71 had clinical findings consistent with LPP while 29 had AD. The prevalence of epidermal hyperkeratosis was significantly higher in LPP when compared to AD (33.8% vs. 0%, p < 0.001), as well as epidermal hypergranulosis (35.2% vs. 0%, p < 0.001), lichenoid dermatitis (49.3% vs. 7.1%, p < 0.001), perifollicular infiltration (47.9% vs.10.3%, p < 0.001), and perifollicular fibrosis (35.2% vs. 10.3%, p=0.01). In addition, the degree of pigmentary incontinence was more severe in LPP (21.1% vs. 3.5%, p=0.015). For AD, vacuolization of the epidermal basal cell layer was more common (96.4% vs. 77.5%, p=0.02). Conclusions Although most cases of AD and LPP can be diagnosed clinically, in doubtful cases, histopathological findings of lichenoid dermatitis, epidermal hyperkeratosis/hypergranulosis, and moderate to severe pigmentary incontinence can help distinguish LPP from AD.
Prognostic Value of MicroRNAs in Patients after Myocardial Infarction: A Substudy of PRAGUE-18

Background The evaluation of the long-term risk of major adverse cardiovascular events and cardiac death in patients after acute myocardial infarction (AMI) is an established clinical process. Laboratory markers may significantly help with the risk stratification of these patients. Our objective was to find the relation of selected microRNAs to the standard markers of AMI and determine if these microRNAs can be used to identify patients at increased risk. Methods Selected microRNAs (miR-1, miR-133a, and miR-499) were measured in a cohort of 122 patients from the PRAGUE-18 study (ticagrelor vs. prasugrel in AMI treated with primary percutaneous coronary intervention (pPCI)). The cohort was split into two subgroups: 116 patients who did not die (survivors) and 6 patients who died (nonsurvivors) during the 365-day period after AMI. Plasma levels of selected circulating miRNAs were then assessed in combination with high-sensitivity cardiac troponin T (hsTnT) and N-terminal probrain natriuretic peptide (NT-proBNP). Results miR-1, miR-133a, and miR-499 correlated positively with NT-proBNP and hsTnT 24 hours after admission and negatively with left ventricular ejection fraction (LVEF). Both miR-1 and miR-133a positively correlated with hsTnT at admission. Median relative levels of all selected miRNAs were higher in the subgroup of nonsurvivors (N = 6) in comparison with survivors (N = 116), but the difference did not reach statistical significance. All patients in the nonsurvivor subgroup had miR-499 and NT-proBNP levels above the cut-off values (891.5 ng/L for NT-proBNP and 0.088 for miR-499), whereas in the survivor subgroup, only 28.4% of patients were above the cut-off values (p = 0.001). Conclusions Statistically significant correlation was found between miR-1, miR-133a, and miR-499 and hsTnT, NT-proBNP, and LVEF. In addition, this analysis suggests that plasma levels of circulating miR-499 could contribute to the identification of patients at increased risk of death during the first year after AMI, especially when combined with NT-proBNP levels.
Antimicrobial Efficacy of Indolicidin Against Multi-Drug Resistant Enteroaggregative Escherichia coli in a Galleria mellonella Model

Antimicrobial resistance against enteroaggregative Escherichia coli (EAEC), an emerging food-borne pathogen, has been observed in an increasing trend recently. In the recent wake of antimicrobial resistance, alternate strategies especially, cationic antimicrobial peptides (AMPs) have attracted considerable attention to source antimicrobial technology solutions. This study evaluated the in vitro antimicrobial efficacy of Indolicidin against multi-drug resistant enteroaggregative Escherichia coli (MDR-EAEC) strains and further to assess its in vivo antimicrobial efficacy in Galleria mellonella larval model. The minimum inhibitory concentration (MIC; 32 μM) and minimum bactericidal concentration (MBC; 64 μM) of Indolicidin against MDR-EAEC was determined by micro broth dilution method. Indolicidin was also tested for its stability (high-end temperatures, physiological concentration of salts and proteases); safety (sheep RBCs; HEp-2 and RAW 264.7 cell lines); effect on beneficial microflora (Lactobacillus rhamnosus and Lactobacillus acidophilus) and its mode of action (flow cytometry; nitrocefin and ONPG uptake). In vitro time-kill kinetic assay of MDR-EAEC treated with Indolicidin was performed. Further, survival rate, MDR-EAEC count, melanization rate, hemocyte enumeration, cytotoxicity assay and histopathological examination were carried out in G. mellonella model to assess in vivo antimicrobial efficacy of Indolicidin against MDR-EAEC strains. Indolicidin was tested stable at high temperatures (70°C; 90°C), physiological concentration of cationic salts (NaCl; MgCl2) and proteases, except for trypsin and tested safe with sheep RBCs and cell lines (RAW 264.7; HEp-2) at MIC (1X and 2X); the beneficial flora was not inhibited. Indolicidin exhibited outer membrane permeabilization in a concentration- and time-dependent manner. In vitro time-kill assay revealed concentration-cum-time dependent clearance of MDR-EAEC in Indolicidin-treated groups at 120 min, while, in G. mellonella, the infected group treated with Indolicidin revealed an increased survival rate, immunomodulatory effect, reduced MDR-EAEC counts and were tested safe to the larval cells which was concurred histopathologically. To conclude, the results suggests Indolicidin as an effective antimicrobial candidate against MDR-EAEC and we recommend its further investigation in appropriate animal models (mice/piglets) before its application in the target host.
Whole Genome Re-sequencing Reveals Natural Variation and Adaptive Evolution of Phytophthora sojae

Due to the monocultural basis of agricultural crops, mutated plant microbes with increased pathogenicity can easily spread in the field and lead to serious yield losses. As a major threat to a wide range of crop plants, oomycete pathogens continuously undergo adaptive evolution to overcome plant defense barriers. However, the genetic basis of their evolution at the molecular level remains largely unknown. Here, we investigated the nature variation and the population genomics of the soybean pathogen Phytophthora sojae by high-throughput genome re-sequencing. Genomic variation analysis revealed uneven “two-speed” evolutionary pattern with genes in gene-sparse regions (GSRs) showing higher rates of structural polymorphisms and positive selection. GSRs are enriched in effector genes and transposase-related genes. Our results also suggested that the NADH oxidase and MIP transporter gene families undergo rapid and diversifying selection. Furthermore, we demonstrated that P. sojae isolates possess varying numbers of RxLR effectors with diverse sequences, totaling 471 members. Among them, 42 core RxLR effectors are assumed to be important for infection. Finally, we observed that Avr genes exhibit abundant sequence variation in P. sojae isolates. Several novel variants lead to the evading of host resistance, including a complete deletion in Avr3c and amino acid mutations in Avr1a. Taken together, our results provide an adaptive landscape of P. sojae at single-nucleotide resolution, as well as resources for further resistance breeding and disease prevention against this important plant pathogen.
Choroidal Neovascularization: Mechanisms of Endothelial Dysfunction

Many conditions affecting the heart, brain, and even the eyes have their origins in blood vessel pathology, underscoring the role of vascular regulation. In age-related macular degeneration (AMD), there is excessive growth of abnormal blood vessels in the eye (choroidal neovascularization), eventually leading to vision loss due to detachment of retinal pigmented epithelium. As the advanced stage of this disease involves loss of retinal pigmented epithelium, much less attention has been given to early vascular events such as endothelial dysfunction. Although current gold standard therapy using inhibitors of vascular endothelial growth factor (VEGF) have achieved initial successes, some drawbacks include the lack of long-term restoration of visual acuity, as well as a subset of the patients being refractory to existing treatment, alluding us and others to hypothesize upon VEGF-independent mechanisms. Against this backdrop, we present here a nonexhaustive review on the vascular underpinnings of AMD, implications with genetic and systemic factors, experimental models for studying choroidal neovascularization, and interestingly, on both endothelial-centric pathways and noncell autonomous mechanisms. We hope to shed light on future research directions in improving vascular function in ocular disorders.