Advancements in 3D-printable polysaccharides, proteins, and synthetic polymers for wound dressing and skin scaffolding - A review.

This review investigates the most recent advances in personalized 3D-printed wound dressings and skin scaffolding. Skin is the largest and most vulnerable organ in the human body. The human body has natural mechanisms to restore damaged skin through several overlapping stages. However, the natural wound healing process can be rendered insufficient due to severe wounds or disturbances in the healing process. Wound dressings are crucial in providing a protective barrier against the external environment, accelerating healing. Although used for many years, conventional wound dressings are neither tailored to individual circumstances nor specific to wound conditions. To address the shortcomings of conventional dressings, skin scaffolding can be used for skin regeneration and wound healing. This review thoroughly investigates polysaccharides (e.g., chitosan, Hyaluronic acid (HA)), proteins (e.g., collagen, silk), synthetic polymers (e.g., Polycaprolactone (PCL), Poly lactide-co-glycolic acid (PLGA), Polylactic acid (PLA)), as well as nanocomposites (e.g., silver nano particles and clay materials) for wound healing applications and successfully 3D printed wound dressings. It discusses the importance of combining various biomaterials to enhance their beneficial characteristics and mitigate their drawbacks. Different 3D printing fabrication techniques used in developing personalized wound dressings are reviewed, highlighting the advantages and limitations of each method. This paper emphasizes the exceptional versatility of 3D printing techniques in advancing wound healing treatments. Finally, the review provides recommendations and future directions for further research in wound dressings.

Deciphering the impact of microbial interactions on COPD exacerbation: An in-depth analysis of the lung microbiome.

In microbiome studies, the diversity and types of microbes have been extensively explored; however, the significance of microbial ecology is equally paramount. The comprehension of metabolic interactions among the wide array of microorganisms in the lung microbiota is indispensable for understanding chronic pulmonary disease and for the development of potent treatments. In this investigation, metabolic networks were simulated, and ecological theory was employed to assess the diagnosis of COPD, subsequently suggesting innovative treatment strategies for COPD exacerbation. Lung sputum 16S rRNA paired-end data from 112 COPD patients were utilized, and a supervised machine-learning algorithm was applied to identify taxa associated with sex and mortality. Subsequently, an OTU table with Greengenes 99 % dataset was generated. Finally, the interactions between bacterial species were analyzed using a simulated metabolic network. A total of 1781 OTUs and 1740 bacteria at the genus level were identified. We employed an additional dataset to validate our analyses. Notably, among the more abundant genera, Pseudomonas was detected in females, while Lactobacillus was detected in males. Additionally, a decrease in bacterial diversity was observed during COPD exacerbation, and mortality was associated with the high abundance of the Staphylococcus and Pseudomonas genera. Moreover, an increase in Proteobacteria abundance was observed during COPD exacerbations. In contrast, COPD patients exhibited decreased levels of Firmicutes and Bacteroidetes. Significant connections between microbial ecology and bacterial diversity in COPD patients were discovered, highlighting the critical role of microbial ecology in the understanding of COPD. Through the simulation of metabolic interactions among bacteria, the observed dysbiosis in COPD was elucidated. Furthermore, the prominence of anaerobic bacteria in COPD patients was revealed to be influenced by parasitic relationships. These findings have the potential to contribute to improved clinical management strategies for COPD patients.

Restoring the epigenetic landscape of lung microbiome: potential therapeutic approach for chronic respiratory diseases.

BACKGROUND: Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and bronchiectasis, present significant threats to global health. Recent studies have revealed the crucial role of the lung microbiome in the development of these diseases. Pathogens have evolved complex strategies to evade the immune response, with the manipulation of host cellular epigenetic mechanisms playing a pivotal role. There is existing evidence regarding the effects of Pseudomonas on epigenetic modifications and their association with pulmonary diseases. Therefore, this study aims to directly assess the connection between Pseudomonas abundance and chronic respiratory diseases. We hope that our findings will shed light on the molecular mechanisms behind lung pathogen infections. METHODS: We analyzed data from 366 participants, including individuals with COPD, acute exacerbations of COPD (AECOPD), bronchiectasis, and healthy individuals. Previous studies have given limited attention to the impact of Pseudomonas on these groups and their comparison with healthy individuals. Two independent datasets from different ethnic backgrounds were used for external validation. Each dataset separately analyzed bacteria at the genus level. RESULTS: The study reveals that Pseudomonas, a bacterium, was consistently found in high concentrations in all chronic lung disease datasets but it was present in very low abundance in the healthy datasets. This suggests that Pseudomonas may influence cellular mechanisms through epigenetics, contributing to the development and progression of chronic respiratory diseases. CONCLUSIONS: This study emphasizes the importance of understanding the relationship between the lung microbiome, epigenetics, and the onset of chronic pulmonary disease. Enhanced recognition of molecular mechanisms and the impact of the microbiome on cellular functions, along with a better understanding of these concepts, can lead to improved diagnosis and treatment.

Validity of ten analytical heat stress indices in predicting the physiological parameters of people under various occupational and meteorological conditions.

Until now, only a few comprehensive studies have validated analytical heat stress indices in different conditions. The present study aims to investigate the validity of these indicators in predicting the physiological parameters of workers. This cross-sectional study was conducted with 194 male employees working in warm environments. First, demographic information was collected. After participants rested for 30 min, their heart rate and tympanic temperature were measured. The subjects then performed their routine tasks. At the end of 90 min, their heart rate and tympanic temperature were again measured. Additionally, their metabolism rate and clothing thermal insulation were estimated. Environmental parameters were also measured at 30-, 60-, and 90-min time points. Additional information required to compute the indices was recorded. Then, the values of each of the indices were computed. Finally, the validity of the indices was assessed under different conditions. The results indicated that the highest regression coefficients with tympanic temperature were assigned to modified physiologically equivalent temperature (mPET) (0.7515), predicted heat strain (PHS) (0.7201), and predicted mean vote (PMV) (0.7082), index, respectively. Also, the greatest regression coefficients with heart rate belonged to mPET (0.7773), PMV (0.7624), and PHS (0.6479) index, respectively. Based on the results, the highest diagnostic accuracies of receiver operating characteristic (ROC) curves for tympanic temperature were related to indices of mPET, PHS, and PMV with the area under the ROC curve (AUC) of 0.945, 0.931, and 0.930, respectively. Of the studied indices, it was observed that mPET, PHS, PMV, and PPD showed more validity compared to others.

A Deep Learning-Based Ensemble Method for Early Diagnosis of Alzheimer's Disease using MRI Images.

Recently, the early diagnosis of Alzheimer's disease has gained major attention due to the growing prevalence of the disease and the resulting costs imposed on individuals and society. The main objective of this study was to propose an ensemble method based on deep learning for the early diagnosis of AD using MRI images. The methodology of this study consisted of collecting the dataset, preprocessing, creating the individual and ensemble models, evaluating the models based on ADNI data, and validating the trained model based on the local dataset. The proposed method was an ensemble approach selected through a comparative analysis of various ensemble scenarios. Finally, the six best individual CNN-based classifiers were selected to combine and constitute the ensemble model. The evaluation showed an accuracy rate of 98.57, 96.37, 94.22, 99.83, 93.88, and 93.92 for NC/AD, NC/EMCI, EMCI/LMCI, LMCI/AD, four-way and three-way classification groups, respectively. The validation results on the local dataset revealed an accuracy of 88.46 for three-way classification. Our performance results were higher than most reviewed studies and comparable with others. Although comparative analysis showed superior results of ensemble methods against individual architectures, there were no significant differences among various ensemble approaches. The validation results revealed the low performance of individual models in practice. In contrast, the ensemble method showed promising results. However, further studies on various and larger datasets are required to validate the generalizability of the model.

Immunogenicity of different nanoparticle adjuvants containing recombinant RBD coronavirus antigen in animal model.

Ongoing mutations of SARS-CoV-2 present challenges for vaccine development, promising renewed global efforts to create more effective vaccines against coronavirus disease (COVID-19). One approach is to target highly immunogenic viral proteins, such as the spike receptor binding domain (RBD), which can stimulate the production of potent neutralizing antibodies. This study aimed to design and test a subunit vaccine candidate based on the RBD. Bioinformatics analysis identified antigenic regions of the RBD for recombinant protein design. In silico analysis identified the RBD region as a feasible target for designing a recombinant vaccine. Bioinformatics tools predicted the stability and antigenicity of epitopes, and a 3D model of the RBD-angiotensin-converting enzyme 2 complex was constructed using molecular docking and codon optimization. The resulting construct was cloned into the pET-28a (+) vector and successfully expressed in Escherichia coli BL21DE3. As evidenced by sodium dodecyl-polyacrylamide gel electrophoresis and Western blotting analyses, the affinity purification of RBD antigens produced high-quality products. Mice were immunized with the RBD antigen alone or combined with aluminum hydroxide (AlOH), calcium phosphate (CaP), or zinc oxide (ZnO) nanoparticles (NPs) as adjuvants. Enzyme-linked immunosorbent assay assays were used to evaluate immune responses in mice. In-silico analysis confirmed the stability and antigenicity of the designed protein structure. RBD with CaP NPs generated the highest immunoglobulin G titer compared to AlOH and ZnO after three doses, indicating its effectiveness as a vaccine platform. In conclusion, the recombinant RBD antigen administered with CaP adjuvant NPs induces potent humoral immunity in mice, supporting further vaccine development. These results contribute to ongoing efforts to develop more effective COVID-19 vaccines.

Induction of Skin Allograft Chimerism by Pharmacological Mobilization of Endogenous Bone Marrow-Derived Stem Cells.

Skin substitutes including allografts remain a standard therapeutic approach to promote healing of both acute and chronic large wounds. However, none have resulted in the regrowth of lost and damaged tissues and scarless wound healing. Here, we demonstrate skin allograft chimerism and repair through the mobilization of endogenous bone marrow-derived stem and immune cells in rats and swine. We show that pharmacological mobilization of bone marrow stem cells and immune cells into the circulation promotes host repopulation of skin allografts and restoration of the skin's normal architecture without scarring and minimal contracture. When skin allografts from DA rats are transplanted into GFP transgenic Lewis recipients with a combination of AMD3100 and low-dose FK506 (AF) therapy, host-derived GFP-positive cells repopulate and/or regenerate cellular components of skin grafts including epidermis and hair follicles and the grafts become donor-host chimeric skin. Using AF combination therapy, burn wounds with skin allografts were healed by newly regenerated chimeric skin with epidermal appendages and pigmentation and without contracture in swine.

Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis.

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.

Unveiling promising immunogenic targets in Coxiella burnetii through in silico analysis: paving the way for novel vaccine strategies.

BACKGROUND: Coxiella burnetii, an intracellular pathogen, serves as the causative agent of zoonotic Q fever. This pathogen presents a significant threat due to its potential for airborne transmission, environmental persistence, and pathogenicity. The current whole-cell vaccine (WCV) utilized in Australia to combat Q fever exhibits notable limitations, including severe adverse reactions and limited regulatory approval for human use. This research employed the reverse vaccinology (RV) approach to uncover antigenic proteins and epitopes of C. burnetii, facilitating the development of more potent vaccine candidates. METHODS: The potential immunogenic proteins derived from C. burnetii RSA493/Nine Mile phase I (NMI) were extracted through manual, automated RV, and virulence factor database (VFDB) methods. Web tools and bioinformatics were used to evaluate physiochemical attributes, subcellular localization, antigenicity, allergenicity, human homology, B-cell epitopes, MHC I and II binding ratios, functional class scores, adhesion probabilities, protein-protein interactions, and molecular docking. RESULTS: Out of the 1850 proteins encoded by RSA493/NMI, a subset of 178 demonstrated the potential for surface or membrane localization. Following a series of analytical iterations, 14 putative immunogenic proteins emerged. This collection included nine proteins (57.1%) intricately involved in cell wall/membrane/envelope biogenesis processes (CBU_0197 (Q83EW1), CBU_0311 (Q83EK8), CBU_0489 (Q83E43), CBU_0939 (Q83D08), CBU_1190 (P39917), CBU_1829 (Q83AQ2), CBU_1412 (Q83BU0), CBU_1414 (Q83BT8), and CBU_1600 (Q83BB2)). The CBU_1627 (Q83B86 ) (7.1%) implicated in intracellular trafficking, secretion, and vesicular transport, and CBU_0092 (Q83F57) (7.1%) contributing to cell division. Additionally, three proteins (21.4%) displayed uncharacterized functions (CBU_0736 (Q83DJ4), CBU_1095 (Q83CL9), and CBU_2079 (Q83A32)). The congruent results obtained from molecular docking and immune response stimulation lend support to the inclusion of all 14 putative proteins as potential vaccine candidates. Notably, seven proteins with well-defined functions stand out among these candidates. CONCLUSIONS: The outcomes of this study introduce promising proteins and epitopes for the forthcoming formulation of subunit vaccines against Q fever, with a primary emphasis on cellular processes and the virulence factors of C. burnetii.

The Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE): protocol for a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Inflammation is a key mediator in the development and progression of the atherosclerotic disease process as well as its resultant complications, like myocardial infarction (MI), stroke and cardiovascular (CV) death, and is emerging as a novel treatment target. Trials involving anti-inflammatory medications have demonstrated outcome benefit in patients with known CV disease. In this regard, colchicine appears to hold great promise. However, there are potential drawbacks to colchicine use, as some studies have identified an increased risk of infection, and a non-significant trend for increased all-cause mortality. Thus, a more thorough understanding of the underlying mechanism of action of colchicine is needed to enable a better patient selection for this novel CV therapy. OBJECTIVE: The primary objective of the Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE) trial is to assess the effect of colchicine on vascular inflammation in the carotid arteries and ascending aorta measured with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with type 2 diabetes mellitus (T2DM) or pre-diabetes who have experienced a recent vascular event (acute coronary syndrome (ACS)/MI, transient ischaemic attack (TIA) or stroke). Secondary objectives include determining colchicine's effect on inflammatory biomarkers (high-sensitivity C reactive protein (hs-CRP) and interleukin-6 (IL-6)). Additionally, we will assess if baseline inflammation imaging or biomarkers are associated with a treatment response to colchicine determined by imaging. Exploratory objectives will look at: (1) the difference in the inflammatory response to colchicine in patients with coronary events compared with patients with cerebral events; (2) the difference in the inflammatory response to colchicine in different vascular beds; (3) the relationship of FDG-PET imaging markers with serum biomarkers and (4) assessment of quality-of-life changes. METHODS AND DESIGN: CADENCE is a multicentre, prospective, randomised, double-blinded, placebo-controlled study to determine the effect of colchicine on arterial inflammation as assessed with imaging and circulatory biomarkers, specifically carotid arteries and aortic FDG uptake as well as hs-CRP and IL-6 among others. Patients with T2DM or pre-diabetes who have recently experienced a CV event (within 30-120 days after an ACS (ie, ST-elevation MI (STEMI) or non-STEMI)) or TIA/stroke with documented large vessel atherosclerotic disease will be randomised to treatment with either colchicine 0.6 mg oral daily or placebo. Participants will undergo baseline clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan of the ascending aorta and left and right carotid arteries. Patients will undergo treatment for 6 months and have repeat clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan at the conclusion of the study. The primary outcome will be the change in the maximum target to background ratio (TBRmax) in the ascending aorta (or carotid arteries) from baseline to follow-up on FDG PET/CT imaging. DISCUSSION: Colchicine is an exciting potential new therapy for CV risk reduction. However, its use is associated with side effects and greater understanding of its underlying mechanism of action is needed. Importantly, the current study will determine whether its anti-inflammatory action is an indirect systemic effect, or a more local plaque action that decreases inflammation. The results will also help identify patients who will benefit most from such therapy. TRIAL REGISTRATION NUMBER: NCT04181996.

Twitter-based gender recognition using transformers.

Social media contains useful information about people and society that could help advance research in many different areas of health (e.g. by applying opinion mining, emotion/sentiment analysis and statistical analysis) such as mental health, health surveillance, socio-economic inequality and gender vulnerability. User demographics provide rich information that could help study the subject further. However, user demographics such as gender are considered private and are not freely available. In this study, we propose a model based on transformers to predict the user's gender from their images and tweets. The image-based classification model is trained in two different methods: using the profile image of the user and using various image contents posted by the user on Twitter. For the first method a Twitter gender recognition dataset, publicly available on Kaggle and for the second method the PAN-18 dataset is used. Several transformer models, i.e. vision transformers (ViT), LeViT and Swin Transformer are fine-tuned for both of the image datasets and then compared. Next, different transformer models, namely, bidirectional encoders representations from transformers (BERT), RoBERTa and ELECTRA are fine-tuned to recognize the user's gender by their tweets. This is highly beneficial, because not all users provide an image that indicates their gender. The gender of such users could be detected from their tweets. The significance of the image and text classification models were evaluated using the Mann-Whitney U test. Finally, the combination model improved the accuracy of image and text classification models by 11.73 and 5.26% for the Kaggle dataset and by 8.55 and 9.8% for the PAN-18 dataset, respectively. This shows that the image and text classification models are capable of complementing each other by providing additional information to one another. Our overall multimodal method has an accuracy of 88.11% for the Kaggle and 89.24% for the PAN-18 dataset and outperforms state-of-the-art models. Our work benefits research that critically require user demographic information such as gender to further analyze and study social media content for health-related issues.

p38 MAPK signaling in chronic obstructive pulmonary disease pathogenesis and inhibitor therapeutics.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar remodeling. Although the abnormalities are primarily prompted by chronic exposure to inhaled irritants, maladjusted and self-reinforcing immune responses are significant contributors to the development and progression of the disease. The p38 isoforms are regarded as pivotal hub proteins that regulate immune and inflammatory responses in both healthy and disease states. As a result, their inhibition has been the subject of numerous recent studies exploring their therapeutic potential in COPD. MAIN BODY: We performed a systematic search based on the PRISMA guidelines to find relevant studies about P38 signaling in COPD patients. We searched the PubMed and Google Scholar databases and used "P38" AND "COPD" Mesh Terms. We applied the following inclusion criteria: (1) human, animal, ex vivo and in vitro studies; (2) original research articles; (3) published in English; and (4) focused on P38 signaling in COPD pathogenesis, progression, or treatment. We screened the titles and abstracts of the retrieved studies and assessed the full texts of the eligible studies for quality and relevance. We extracted the following data from each study: authors, year, country, sample size, study design, cell type, intervention, outcome, and main findings. We classified the studies according to the role of different cells and treatments in P38 signaling in COPD. CONCLUSION: While targeting p38 MAPK has demonstrated some therapeutic potential in COPD, its efficacy is limited. Nevertheless, combining p38 MAPK inhibitors with other anti-inflammatory steroids appears to be a promising treatment choice. Clinical trials testing various p38 MAPK inhibitors have produced mixed results, with some showing improvement in lung function and reduction in exacerbations in COPD patients. Despite these mixed results, research on p38 MAPK inhibitors is still a major area of study to develop new and more effective therapies for COPD. As our understanding of COPD evolves, we may gain a better understanding of how to utilize p38 MAPK inhibitors to treat this disease. Video Abstract.

We wanted to determine what studies have been done on how a protein called p38 affects a lung disease called COPD. COPD is a condition that makes it hard to breathe and can cause coughing, wheezing, and chest infections. p38 is a protein that helps cells to respond to stress and inflammation, but it may also play a role in causing or worsening COPD. We searched two main online databases for studies that met our criteria. We looked for studies that involved humans, studies that used animals or cells in the lab, studies that reported new findings, studies that were written in English, and studies that focused on p38 and COPD. We did not include studies that were reviews, summaries, opinions, or letters or studies that were not related to p38 or COPD. We found 361 studies that matched our criteria. We read the titles and summaries of these studies and checked the full texts for quality and relevance. We collected information from each study, such as who did it, when and where it was done, how many people were involved, what type of cells were studied, what treatment was given, what outcome was measured, and what the main results were. We grouped the studies based on the type of cells and type of treatment they studied. We found that different types of cells (such as lung cells, immune cells, and blood cells) and different types of treatment can affect how p38 works in COPD.

Sense of Coherence or resilience as predictors of psychological distress in nursing students during the COVID-19 pandemic.

Background: The COVID-19 pandemic lead to the occurrence of numerous psychological distress among students. This study aimed to determine the level of psychological distress as well as the predictive role of Sense of Coherence (SOC) and resilience in nursing students. Methods: A cross-sectional descriptive study was conducted on 310 nursing students in Ahvaz Jundishapur University of Medical Sciences, Iran. The data of the study was collected through the demographic information questionnaire, the General Health Questionnaire (GHQ), the Academic Resilience Inventory (ARI), and the Sense of Coherence Scale (SOC-13). Results: Students' mean scores for the GHQ, ARI, and SOC were 5.81 ± 1.37, 102.88 ± 11.91, and 54.54 ± 6.46, respectively. Regression models showed that two domains of SOC [meaningfulness (ß = -0.28, p < 0.001), manageability (ß = -0.19, p = 0.001)], female gender (ß = 0.12, p = 0.015), and overall ARI (ß = -0.12, p = 0.037), were significantly associated with the GH of nursing students. SOC domains [meaningfulness (ß = -0.19, p = 0.002), manageability (ß = -0.15, p = 0.006)], problem-oriented/positive thinking domain of ARI (ß = -0.15, p = 0.011), sex (ß = 0.12, p = 0.015), and history of death in first-degree relatives (ß = 0.12, p = 0.021) were significantly associated with social dysfunction domain of GH. Three domains of SOC [meaningfulness (ß = -0.26, p < 0.001), manageability (ß = -0.13, p = 0.032), and comprehensibility (ß = -0.13, p = 0.039)], were significantly associated with psychological distress domain of GH. Conclusion: Our results indicated that low SOC and resilience were predictors of psychological distress in nursing students. Accordingly, interventions such as teaching stress management skills, the skills of using positive coping methods in dealing with stressful situations, and self-management skills are necessary to improve the level of resilience and SOC in nursing students.

Autophagy, a critical element in the aging male reproductive disorders and prostate cancer: a therapeutic point of view.

Autophagy is a highly conserved, lysosome-dependent biological mechanism involved in the degradation and recycling of cellular components. There is growing evidence that autophagy is related to male reproductive biology, particularly spermatogenic and endocrinologic processes closely associated with male sexual and reproductive health. In recent decades, problems such as decreasing sperm count, erectile dysfunction, and infertility have worsened. In addition, reproductive health is closely related to overall health and comorbidity in aging men. In this review, we will outline the role of autophagy as a new player in aging male reproductive dysfunction and prostate cancer. We first provide an overview of the mechanisms of autophagy and its role in regulating male reproductive cells. We then focus on the link between autophagy and aging-related diseases. This is followed by a discussion of therapeutic strategies targeting autophagy before we end with limitations of current studies and suggestions for future developments in the field.

Identification of novel metallo-ß-lactamases inhibitors using ligand-based pharmacophore modelling and structure-based virtual screening.

Metallo-ß-lactamases (MBLs) are a group of enzymes that hydrolyze the most commonly used ß-lactam-based antibiotics, leading to the development of multi-drug resistance. The three main clinically relevant groups of these enzymes are IMP, VIM, and NDM. This study aims to introduce potent novel overlapped candidates from a ZINC database retrieved from the 200,583-member natural library against the active sites of IMP-1, VIM-2, and NDM-1 through a straightforward computational workflow using virtual screening approaches. The screening pipeline started by assessing Lipinski's rule of five (RO5), drug-likeness, and pan-assay interference compounds (PAINS) which were used to generate a pharmacophore model using D-captopril as a standard inhibitor. The process was followed by the consensus docking protocol and molecular dynamic (MD) simulation combined with the molecular mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method to compute the total binding free energy and evaluate the binding characteristics. The absorption, distribution, metabolism, elimination, and toxicity (ADMET) profiles of the compounds were also analyzed, and the search space decreased to the final two inhibitory candidates for B1 subclass MBLs, which fulfilled all criteria for further experimental evaluation.Communicated by Ramaswamy H. Sarma.

Association between single-nucleotide polymorphism of cytokines genes and chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease with high morbidity and mortality rates worldwide. Cytokines, which are the main regulators of immune responses, play crucial roles in inflammatory diseases such as COPD. Moreover, certain genetic variations can alter cytokine expression, and changes in cytokine level or function can affect disease susceptibility. Therefore, investigating the association between genetic variations and disease progression can be useful for prevention and treatment. Several studies have explored the association between common genetic variations in cytokine genes and COPD susceptibility. In this study, we summarized the reported studies and, where possible, conducted a systematic review and meta-analysis to evaluate the genetic association between various cytokines and COPD pathogenesis. We extracted relevant articles from PubMed and Google Scholar databases using a standard systematic search strategy. We included a total of 183 studies from 78 separate articles that evaluated 50 polymorphisms in 12 cytokine genes in this study. Our analysis showed that among all reported cytokine polymorphisms (including TNF-α, TGF-ß, IL1, IL1RN, IL4, IL4R, IL6, IL10, IL12, IL13, IL17, IL18, IL27, and IL33), only four variants, including TNF-α-rs1800629, TGF-ß1-rs6957, IL13-rs1800925, and IL6-rs1800796, were associated with the risk of COPD development. This updated meta-analysis strongly supports the association of TNF-α-rs1800629, TGF-ß1-rs6957, IL13-rs1800925, and IL6-rs1800796 variants with a high risk of COPD.

A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects.

Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).

Exploring Co-occurrence patterns and microbial diversity in the lung microbiome of patients with non-small cell lung cancer.

BACKGROUND: It has been demonstrated in the literature that a dysbiotic microbiome could have a negative impact on the host immune system and promote disease onset or exacerbation. Co-occurrence networks have been widely adopted to identify biomarkers and keystone taxa in the pathogenesis of microbiome-related diseases. Despite the promising results that network-driven approaches have led to in various human diseases, there is a dearth of research pertaining to key taxa that contribute to the pathogenesis of lung cancer. Therefore, our primary goal in this study is to explore co-existing relationships among members of the lung microbial community and any potential gained or lost interactions in lung cancer. RESULTS: Using integrative and network-based approaches, we integrated four studies assessing the microbiome of lung biopsies of cancer patients. Differential abundance analyses showed that several bacterial taxa are different between tumor and tumor-adjacent normal tissues (FDR adjusted p-value < 0.05). Four, fifteen, and twelve significantly different associations were found at phylum, family, and genus levels. Diversity analyses suggested reduced alpha diversity in the tumor microbiome. However, beta diversity analysis did not show any discernible pattern between groups. In addition, four distinct modules of bacterial families were detected by the DBSCAN clustering method. Finally, in the co-occurrence network context, Actinobacteria, Firmicutes, Bacteroidetes, and Chloroflexi at the phylum level and Bifidobacterium, Massilia, Sphingobacterium, and Ochrobactrum at the genus level showed the highest degree of rewiring. CONCLUSIONS: Despite the absence of statistically significant differences in the relative abundance of certain taxa between groups, it is imperative not to overlook them for further exploration. This is because they may hold pivotal central roles in the broader network of bacterial taxa (e.g., Bifidobacterium and Massilia). These findings emphasize the importance of a network analysis approach for studying the lung microbiome since it could facilitate identifying key microbial taxa in lung cancer pathogenesis. Relying exclusively on differentially abundant taxa may not be enough to fully grasp the complex interplay between lung cancer and the microbiome. Therefore, a network-based approach can offer deeper insights and a more comprehensive understanding of the underlying mechanisms.

Novel N'-substituted benzylidene benzohydrazides linked to 1,2,3-triazoles: potent α-glucosidase inhibitors.

Herein, various N'-substituted benzylidene benzohydrazide-1,2,3-triazoles were designed, synthesized, and screened for their inhibitory activity toward α-glucosidase. The structure of derivatives was confirmed using 1H- and 13C-NMR, FTIR, Mass spectrometry, and elemental analysis. All derivatives exhibited good inhibition with IC50 values in the range of 0.01 to 648.90 µM, compared with acarbose as the positive control (IC50 = 752.10 µM). Among them, compounds 7a and 7h showed significant potency with IC50 values of 0.02 and 0.01 µM, respectively. The kinetic study revealed that they are noncompetitive inhibitors toward α-glucosidase. Also, fluorescence quenching was used to investigate the interaction of three inhibitors 7a, 7d, and 7h, with α-glucosidase. Accordingly, the binding constants, the number of binding sites, and values of thermodynamic parameters were determined for the interaction of candidate compounds toward the enzyme. Finally, the in silico cavity detection plus molecular docking was performed to find the allosteric site and key interactions between synthesized compounds and the target enzyme.

The association between Vitamin D deficiency and fibrocystic breast disorder.

BACKGROUND: The role of deficiency of vitamin D in a wide range of human cancer, including breast cancer, has been proven, but its role in benign breast diseases remains unknown. This study aimed to determine the prevalence of vitamin D deficiency in patients with fibrocystic breast (FB) disease. METHODS: First, the hospital prevalence of fibrocystic breast was determined by a cross-sectional study. Then, patients were divided into two groups by a case-control study; women with confirmed fibrocystic breasts based on breast pain, physical examination, and ultrasonography were included as a case group (N=48) and age-matched women without fibrocystic breasts were also included as a control group (N=48). After recording the demographic and gynecological characteristics and exposure to the sun, gynecological records, and family history of fibrocystic breast, the blood sample was taken to determine vitamin D. Data were analyzed by Stata software. RESULTS: The result indicated that the studied groups had significant differences in regards to weight, breast pain, the severity of breast pain, breast heaviness, family history of fibrocystic breast, history of breast disease, caffeine consumption, and exposure to sunlight (p <0.05), but did not show significant differences based on age, occupation, education, gynecological history, diabetes mellitus, hypertension, obesity and hypothyroidism, vegetable, fast food, and dairy products consumption. The frequency of vitamin D deficiency in the case group was 45.8%, and in the control group, it was 20.8%, and there was a statistically significant difference (p <0.05). CONCLUSION: Vitamin D deficiency is more common in women with fibrocystic breast disease and may play a role in the development of the disease.