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Background: Primary dysmenorrhea is considered to be one of the most common gynecological complaints, affecting women’s daily activities and social life. The severity of dysmenorrhea varies among women, and its management is of high importance for them. Given that non-steroidal anti-inflammatory drugs (NSAIDs), the established treatment for dysmenorrhea, are associated with many adverse events, alternative therapeutic options are under evaluation. Emerging evidence correlates management of dysmenorrhea with micronutrients, especially vitamins. Purpose: The aim of this narrative review is to highlight and provide evidence of the potential benefits of vitamins for the management of dysmenorrhea. Methods: The articles were searched on PubMed, Scopus and Google Scholar. The searching process was based on keywords, such as “primary dysmenorrhea”, “vitamins”, “supplementation”, “vitamin D”, “vitamin E” and others. Our search focused on data derived from clinical trials, published only during the last decade (older articles were excluded). Results: In this review, 13 clinical trials were investigated. Most of them supported the anti-inflammatory, antioxidant and analgesic properties of vitamins. Particularly, vitamins D and E revealed a desirable effect on dysmenorrhea relief Conclusion: Despite the scarcity and heterogeneity of related research, the studies indicate a role of vitamins for the management of primary dysmenorrhea, proposing that they should be considered as alternative therapeutic candidates for clinical use. Nevertheless, this correlation warrants further research. Full article

AMPs are small oligopeptides acting as integral elements of the innate immune system and are of tremendous potential in the medical field owing to their antimicrobial and immunomodulatory activities. They offer a multitude of immunomodulatory properties such as immune cell differentiation, inflammatory responses, cytokine production, and chemoattraction. Aberrancy in neutrophil or epithelial cell-producing AMPs leads to inflammation culminating in various autoimmune responses. In this review, we have tried to explore the role of prominent mammalian AMPs—defensins and cathelicidins, as immune regulators with special emphasis on their role in neutrophil extracellular traps which promotes autoimmune disorders. When complexed with self-DNA or self-RNA, AMPs act as autoantigens which activate plasmacytoid dendritic cells and myeloid dendritic cells leading to the production of interferons and cytokines. These trigger a series of self-directed inflammatory reactions, leading to the emergence of diverse autoimmune disorders. Since AMPs show both anti- and pro-inflammatory abilities in different ADs, there is a dire need for a complete understanding of their role before developing AMP-based therapy for autoimmune disorders. Full article

Phase-separation proteins (PSPs) are a class of proteins that play a role in the process of liquid–liquid phase separation, which is a mechanism that mediates the formation of membranelle compartments in cells. Identifying phase separation proteins and their associated function could provide insights into cellular biology and the development of diseases, such as neurodegenerative diseases and cancer. Here, PSPs and non-PSPs that have been experimentally validated in earlier studies were gathered as positive and negative samples. Each protein’s corresponding Gene Ontology (GO) terms were extracted and used to create a 24,907-dimensional binary vector. The purpose was to extract essential GO terms that can describe essential functions of PSPs and build efficient classifiers to identify PSPs with these GO terms at the same time. To this end, the incremental feature selection computational framework and an integrated feature analysis scheme, containing categorical boosting, least absolute shrinkage and selection operator, light gradient-boosting machine, extreme gradient boosting, and permutation feature importance, were used to build efficient classifiers and identify GO terms with classification-related importance. A set of random forest (RF) classifiers with F1 scores over 0.960 were established to distinguish PSPs from non-PSPs. A number of GO terms that are crucial for distinguishing between PSPs and non-PSPs were found, including GO:0003723, which is related to a biological process involving RNA binding; GO:0016020, which is related to membrane formation; and GO:0045202, which is related to the function of synapses. This study offered recommendations for future research aimed at determining the functional roles of PSPs in cellular processes by developing efficient RF classifiers and identifying the representative GO terms related to PSPs. Full article

Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. With the advent of highly effective modulator therapy targeting the abnormal CFTR protein, people with CF (PwCF) are living more than 40 years longer than the pre-modulator therapy era. As a result, PwCF are facing new challenges of managing similar comorbidities affecting the average aging population. While CF is notoriously identified as a chronic respiratory disease, the multisystem presence of the CFTR gene can contribute to other organ-related complications acutely, but also heighten the likelihood of chronic conditions not routinely encountered in this cohort. In this overview, we will focus on risk factors and epidemiology for PwCF as they relate to cardiovascular disease, dyslipidemia, CF-related diabetes, pulmonary hypertension, obstructive sleep apnea, CF-liver disease, bone health and malignancy. With increased awareness of diseases affecting a newly aging CF population, a focus on primary and secondary prevention will be imperative to implementing a comprehensive care plan to improve long-term morbidity and mortality. Full article

Vaccines trigger an immunological response that includes B and T cells, with B cells producing antibodies. SARS-CoV-2 immunity weakens over time after vaccination. Discovering key changes in antigen-reactive antibodies over time after vaccination could help improve vaccine efficiency. In this study, we collected data on blood antibody levels in a cohort of healthcare workers vaccinated for COVID-19 and obtained 73 antigens in samples from four groups according to the duration after vaccination, including 104 unvaccinated healthcare workers, 534 healthcare workers within 60 days after vaccination, 594 healthcare workers between 60 and 180 days after vaccination, and 141 healthcare workers over 180 days after vaccination. Our work was a reanalysis of the data originally collected at Irvine University. This data was obtained in Orange County, California, USA, with the collection process commencing in December 2020. British variant (B.1.1.7), South African variant (B.1.351), and Brazilian/Japanese variant (P.1) were the most prevalent strains during the sampling period. An efficient machine learning based framework containing four feature selection methods (least absolute shrinkage and selection operator, light gradient boosting machine, Monte Carlo feature selection, and maximum relevance minimum redundancy) and four classification algorithms (decision tree, k-nearest neighbor, random forest, and support vector machine) was designed to select essential antibodies against specific antigens. Several efficient classifiers with a weighted F1 value around 0.75 were constructed. The antigen microarray used for identifying antibody levels in the coronavirus features ten distinct SARS-CoV-2 antigens, comprising various segments of both nucleocapsid protein (NP) and spike protein (S). This study revealed that S1 + S2, S1.mFcTag, S1.HisTag, S1, S2, Spike.RBD.His.Bac, Spike.RBD.rFc, and S1.RBD.mFc were most highly ranked among all features, where S1 and S2 are the subunits of Spike, and the suffixes represent the tagging information of different recombinant proteins. Meanwhile, the classification rules were obtained from the optimal decision tree to explain quantitatively the roles of antigens in the classification. This study identified antibodies associated with decreased clinical immunity based on populations with different time spans after vaccination. These antibodies have important implications for maintaining long-term immunity to SARS-CoV-2. Full article

Phytochemicals from various medicinal plants are well known for their antioxidant properties and anti-cancer effects. Many of these bioactive compounds or natural products have demonstrated effects against inflammation, while some showed a role that is only approximately described as anti-inflammatory. In particular, naphthoquinones are naturally-occurring compounds with different pharmacological activities and allow easy scaffold modification for drug design approaches. Among this class of compounds, Plumbagin, a plant-derived product, has shown interesting counteracting effects in many inflammation models. However, scientific knowledge about the beneficial effect of Plumbagin should be comprehensively reported before candidating this natural molecule into a future drug against specific human diseases. In this review, the most relevant mechanisms in which Plumbagin plays a role in the process of inflammation were summarized. Other relevant bioactive effects were reviewed to provide a complete and compact scenario of Plumbagin's potential therapeutic significance. Full article

Plant malectin/malectin-like receptor-like kinases (MRLKs) play crucial roles throughout the life course of plants. Here, we identified 23 SiMRLK genes from foxtail millet. All the SiMRLK genes were named according to the chromosomal distribution of the SiMRLKs in the foxtail millet genome and grouped into five subfamilies based on phylogenetic relationships and structural features. Synteny analysis indicated that gene duplication events may take part in the evolution of SiMRLK genes in foxtail millet. The expression profiles of 23 SiMRLK genes under abiotic stresses and hormonal applications were evaluated through qRT-PCR. The expression of SiMRLK1, SiMRLK3, SiMRLK7 and SiMRLK19 were significantly affected by drought, salt and cold stresses. Exogenous ABA, SA, GA and MeJA also obviously changed the transcription levels of SiMRLK1, SiMRLK3, SiMRLK7 and SiMRLK19. These results signified that the transcriptional patterns of SiMRLKs showed diversity and complexity in response to abiotic stresses and hormonal applications in foxtail millet. Full article

Neurofilament levels are elevated in many neurodegenerative diseases and have shown promise as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), the most common form of Motor Neuron Disease (MND). This study assesses serum neurofilament light (NFL) and neurofilament heavy (NFH) chain concentrations in patients with ALS, other variants of motor neuron disease such as Progressive Muscular Atrophy (PMA) and Primary Lateral Sclerosis (PLS), and a range of other neurological diseases. It aims to evaluate the use of NFL and NFH to differentiate these conditions and for the prognosis of MND disease progression. NFL and NFH levels were quantified using electrochemiluminescence immunoassays (ECLIA). Both were elevated in 47 patients with MND compared to 34 patients with other neurological diseases and 33 healthy controls. NFL was able to differentiate patients with MND from the other groups with a Receiver Operating Characteristic (ROC) curve area under the curve (AUC) of 0.90 (p < 0.001). NFL correlated with the rate of disease progression in MND (rho 0.758, p < 0.001) and with the ALS Functional Rating Scale (rho −0.335, p = 0.021). NFL levels were higher in patients with ALS compared to both PMA (p = 0.032) and PLS (p = 0.012) and were able to distinguish ALS from both PMA and PLS with a ROC curve AUC of 0.767 (p = 0.005). These findings support the use of serum NFL to help diagnose and differentiate types of MND, in addition to providing prognostic information to patients and their families. Full article

The natural product Kochiae Fructus (KF) is the ripe fruit of Kochia scoparia (L.) Schrad and is renowned for its anti-inflammatory, anticancer, anti-fungal, and anti-pruritic effects. This study examined the anticancer effect of components of KF to assess its potential as an adjuvant for cancer treatment. Network-based pharmacological and docking analyses of KF found associations with oral squamous cell carcinoma. The molecular docking of oleanolic acid (OA) with LC3 and SQSTM1 had high binding scores, and hydrogen binding with amino acids of the receptors suggests that OA is involved in autophagy, rather than the apoptosis pathway. For experimental validation, we exposed SCC-15 squamous carcinoma cells derived from a human tongue lesion to KF extract (KFE), OA, and cisplatin. The KFE caused SCC-15 cell death, and induced an accumulation of the autophagy marker proteins LC3 and p62/SQSTM1. The novelty of this study lies in the discovery that the change in autophagy protein levels can be related to the regulatory death of SCC-15 cells. These findings suggest that KF is a promising candidate for future studies to provide insight into the role of autophagy in cancer cells and advance our understanding of cancer prevention and treatment. Full article

Chronic obstructive pulmonary disease (COPD) is considered one of the leading causes of mortality. Cardiovascular comorbidities are diagnosed often in COPD patients, not only because of the common risk factors these two diseases share, but also because of the systemic inflammation which characterizes COPD and has deleterious effects in the cardiovascular system. The comorbid cardiovascular diseases in COPD result in several difficulties in the holistic treatment of these patients and affect outcomes such as morbidity and mortality. Several studies have reported that mortality from cardiovascular causes is common among COPD patients, while the risk for acute cardiovascular events increases during COPD exacerbations and remains high for a long time even after recovery. In this review, we focus on the prevalence of cardiovascular comorbidities in COPD patients, presenting the evidence regarding the interaction of the pathophysiological pathways which characterize each disease. Furthermore, we summarize information regarding the effects of cardiovascular treatment on COPD outcomes and vice versa. Finally, we present the current evidence regarding the impact of cardiovascular comorbidities on exacerbations, quality of life and survival of COPD patients. Full article

Alzheimer’s disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future. Full article

The formose reaction is a plausible prebiotic chemistry, famed for its production of sugars. In this work, we demonstrate that the Cannizzaro process is the dominant process in the formose reaction under many different conditions, thus necessitating a catalyst for the formose reaction under various environmental circumstances. The investigated formose reactions produce primarily organic acids associated with metabolism, a protometabolic system, and yield very little sugar left over. This is due to many of the acids forming from the degradation and Cannizaro reactions of many of the sugars produced during the formose reaction. We also show the heterogeneous Lewis-acid-based catalysis of the formose reaction by mineral systems associated with serpentinization. The minerals that showed catalytic activity include olivine, serpentinite, and calcium, and magnesium minerals including dolomite, calcite, and our Ca/Mg-chemical gardens. In addition, computational studies were performed for the first step of the formose reaction to investigate the reaction of formaldehyde, to either form methanol and formic acid under a Cannizzaro reaction or to react to form glycolaldehyde. Here, we postulate that serpentinization is therefore the startup process necessary to kick off a simple proto metabolic system—the formose protometabolic system. Full article

Hyperglycemia is the hallmark of diabetes mellitus that results in oxidative stress, apoptosis, and diabetic vascular endothelial dysfunction. An increasing number of microRNAs (miRNAs) have been found to be involved in the pathogenesis of diabetic vascular complications. However, there is a limited number of studies that characterize the miRNA profile of endothelial cells exposed to hyperglycemia. Therefore, this study aims to analyze the miRNA profile of human umbilical-vein endothelial cells (HUVECs) exposed to hyperglycemia. HUVECs were divided into two groups: the control (treated with 5.5 mM glucose) and hyperglycemia (treated with 33.3 mM glucose) groups. RNA sequencing identified 17 differentially expressed miRNAs between the groups (p < 0.05). Of these, 4 miRNAs were upregulated, and 13 miRNAs were downregulated. Two of the most differentially expressed miRNAs (novel miR-1133 and miR-1225) were successfully validated with stem-loop qPCR. Collectively, the findings show that there is a differential expression pattern of miRNAs in HUVEC following exposure to hyperglycemia. These 17 differentially expressed miRNAs are involved in regulating cellular functions and pathways related to oxidative stress and apoptosis that may contribute to diabetic vascular endothelial dysfunction. The findings provide new clues on the role of miRNAs in the development of diabetic vascular endothelial dysfunction, which could be useful in future targeted therapy. Full article

Poultry is the first source of animal protein for human consumption. In a changing world, this sector is facing new challenges, such as a projected increase in demand, higher standards of food quality and safety, and reduction of environmental impact. Chicken coccidiosis is a highly widespread enteric disease caused by Eimeria spp. which causes significant economic losses to the poultry industry worldwide; however, the impact on family poultry holders or backyard production—which plays a key role in food security in small communities and involves mainly rural women—has been little explored. Coccidiosis disease is controlled by good husbandry measures, chemoprophylaxis, and/or live vaccination. The first live vaccines against chicken coccidiosis were developed in the 1950s; however, after more than seven decades, none has reached the market. Current limitations on their use have led to research in next-generation vaccines based on recombinant or live-vectored vaccines. Next-generation vaccines are required to control this complex parasitic disease, and for this purpose, protective antigens need to be identified. In this review, we have scrutinised surface proteins identified so far in Eimeria spp. affecting chickens. Most of these surface proteins are anchored to the parasite membrane by a glycosylphosphatidylinositol (GPI) molecule. The biosynthesis of GPIs, as well as the role of currently identified surface proteins and interest as vaccine candidates has been summarised. The potential role of surface proteins in drug resistance and immune escape and how these could limit the efficacy of control strategies was also discussed. Full article

Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus (p < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi (p < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi (p < 0.01), and 93% and 143% increase in both neocortices (p < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group (p > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi (p < 0.001) and 51% and 92% increase in both cortices (p < 0.001). Kindled + TFS group presented no changes (p > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients. Full article

Traditionally, the brain has been regarded as a relatively insensitive late-reacting tissue, with radiologically detectable damage not being reported at doses < 60 Gy. When NASA proposed interplanetary exploration missions, it was required to conduct an intensive health and safety evaluation of cancer, cardiovascular, and cognitive risks associated with exposure to deep space radiation (SR). The SR dose that astronauts on a mission to Mars are predicted to receive is ~300 mGy. Even after correcting for the higher RBE of the SR particles, the biologically effective SR dose (<1 Gy) would still be 60-fold lower than the threshold dose for clinically detectable neurological damage. Unexpectedly, the NASA-funded research program has consistently reported that low (<250 mGy) doses of SR induce deficits in multiple cognitive functions. This review will discuss these findings and the radical paradigm shifts in radiobiological principles for the brain that were required in light of these findings. These included a shift from cell killing to loss of function models, an expansion of the critical brain regions for radiation-induced cognitive impediments, and the concept that the neuron may not be the sole critical target for neurocognitive impairment. The accrued information on how SR exposure impacts neurocognitive performance may provide new opportunities to reduce neurocognitive impairment in brain cancer patients. Full article

A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity, a state that leads to increased systemic inflammatory markers. Leptin plays a vital role in forming thyroid nodules and cancer through several mechanisms. Together with chronic inflammation, there is an augmentation in the secretion of tumor necrosis factor (TNF) and the cytokine interleukin 6 (IL-6), which contributed to cancer development, progression and metastasis. In addition, leptin exerts a modulatory action in the growth, proliferation and invasion of thyroid carcinoma cell lines via activating various signal pathways, such as Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). Through several proposed mechanisms, aberrant endogenous estrogen levels have been suggested to play a vital role in the development of both benign and malignant nodules. Metabolic syndrome triggers the development of thyroid nodules by stimulating thyroid proliferation and angiogenesis due to hyperinsulinemia, hyperglycemia and dyslipidemia. Insulin resistance influences the distribution and structure of the thyroid blood vessels. Insulin growth factor 1 (IGF-1) and insulin affect the regulation of the expression of thyroid genes and the proliferation and differentiation of thyroid cells. TSH can promote the differentiation of pre-adipocytes to mature adipocytes but also, in the presence of insulin, TSH possesses mitogenic properties. This review aims to summarize the underlying mechanisms explaining the role of obesity in the pathophysiology of thyroid nodules and discuss potential clinical implications. Full article

Lung cancer is one of the most frequently diagnosed cancers worldwide and the leading cause of cancer-related death. The 2021 World Health Organization (WHO) classification provided a detailed and updated categorization of lung adenocarcinomas with a special focus on rare histological types, including enteric, fetal and colloid types, as well as not otherwise specified adenocarcinoma, overall accounting for about 5–10% of all cases. However, rare entities are nowadays difficult to diagnose in most centers, and evidence of optimal therapeutic management for these patients is still lacking. In recent years, increasing knowledge about the mutational profile of lung cancer, in addition to the spreading diffusion of next-generation sequencing (NGS) in different centers, have been helpful in the identification of rare variants of lung cancer. Hence, the hope is that several new drugs will be available in the near future to treat these rare lung tumors, such as in targeted therapy and immunotherapy, which are often used in clinical practice for several malignancies. The aim of this review is to summarize the current knowledge about the molecular pathology and clinical management of the most common rare adenocarcinoma subtypes in order to provide a concise and updated report that can drive clinicians’ choices in their routine practice. Full article

Introduction: Successful R0 resection is crucial for the survival of patients with primary liver cancer (PLC) or liver metastases. Up to date, surgical resection lacks a sensitive, real-time intraoperative imaging modality to determine R0 resection. Real-time intraoperative visualization with near-infrared light fluorescence (NIRF) using indocyanine green (ICG) may have the potential to meet this demand. This study evaluates the value of ICG visualization in PLC and liver metastases surgery regarding R0 resection rates. Materials and Methods: Patients with PLC or liver metastases were included in this prospective cohort study. ICG 10 mg was administered intravenously 24 h before surgery. Real-time intraoperative NIRF visualization was created with the Spectrum^TM fluorescence imaging camera system. First, all liver segments were inspected with the fluorescence imaging system and intraoperative ultrasound for identification of the known tumor, as well as additional lesions, and were compared to preoperative MRI images. PLC, liver metastases, and additional lesions were then resected according to oncological principles. In all resected specimens, the resection margins were analyzed with the fluorescence imaging system for ICG-positive spots immediately after resection. Histology of additional detected lesions, as well as ICG fluorescence compared to histological resection margins, were assessed. Results: Of the 66 included patients, median age was 65.5 years (IQR 58.7–73.9), 27 (40.9%) were female, and 18 (27.3%) were operated on laparoscopically. Additional ICG-positive lesions were detected in 23 (35.4%) patients, of which 9 (29%) were malignant. In patients with no fluorescent signal at the resection margin, R0 rate was 93.9%, R1 rate was 6.1%, and R2 rate was 0% compared to an ICG-positive resection margin with an R0 rate of 64.3%, R1 rate of 21.4%, and R2 rate of 14.3% (p = 0.005). One- and two-year overall survival rates were 95.2% and 88.4%, respectively. Conclusion: The presented study provides significant evidence that ICG NIRF guidance helps to identify R0 resection intraoperatively. This offers true potential to verify radical resection and improve patient outcomes. Furthermore, implementation of NIRF-guided imaging in liver tumor surgery allows us to detect a considerable amount of additional malignant lesions. Full article