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Background: Pneumonia is a ubiquitous health condition with severe outcomes. The advancement of ultrasonography techniques allows its application in evaluating pulmonary diseases, providing safer and accessible bedside therapeutic decisions compared to chest X-ray and chest computed tomography (CT) scan. Because of its aforementioned benefits, we aimed to confirm the diagnostic accuracy of lung ultrasound (LUS) for pneumonia in adults. Methods: A systematic literature search was performed of Medline, Cochrane and Crossref, independently by two authors. The selection of studies proceeded based on specific inclusion and exclusion criteria without restrictions to particular study designs, language or publication dates and was followed by data extraction. The gold standard reference in the included studies was chest X-ray/CT scan or both. Results: Twenty-nine (29) studies containing 6702 participants were included in our meta-analysis. Pooled sensitivity, specificity and PPV were 92% (95% CI: 91–93%), 94% (95% CI: 94 to 95%) and 93% (95% CI: 89 to 96%), respectively. Pooled positive and negative likelihood ratios were 16 (95% CI: 14 to 19) and 0.08 (95% CI: 0.07 to 0.09). The area under the ROC curve of LUS was 0. 9712. Conclusions: LUS has high diagnostic accuracy in adult pneumonia. Its contribution could form an optimistic clue in future updates considering this condition.

Thyroid cancer (TC) is the most common endocrine cancer, which contributes to more than 43,600 deaths and 586,000 cases worldwide every year. Among the TC types, PTC and FTC comprise 90% of all TCs. Genetic modifications in genes are responsible for encoding proteins of mitogen-associated protein kinase cascade, which is closely related with numerous cellular mechanisms, including controlling programmed cell death, differentiation, proliferation, gene expression, as well as in genes encoding the PI3K (phosphatidylinositol 3-kinase)/protein kinase B (AKT) cascade, which has contribution in controlling cell motility, adhesion, survival, and glucose metabolism, have been associated with the TC pathogenesis. Various genetic modifications including BRAF mutations, RAS mutations, RET mutations, paired-box gene 8/peroxisome proliferator-activated receptor-gamma fusion oncogene, RET/PTC rearrangements, telomerase reverse transcriptase mutations, neurotrophic tyrosine receptor kinase fusion genes, TP53 mutations, and eukaryotic translation initiation factor 1A X-linked mutations can effectively serve as potential biomarkers in both diagnosis and prognosis of TC. On the other hand, epigenetic modifications can lead to aberrant functions or suppression of a range of signalling cascades, which can ultimately result in cancer. Various studies have observed the link between epigenetic modification and multiple cancers including TC. It has been reported that several epigenetic alterations including histone modifications, aberrant DNA methylation, and epigenetic modulations of non-coding RNAs can play significant roles as potential biomarkers in the diagnosis and prognosis of TC. Therefore, a good understanding regarding the genetic and epigenetic modifications is not only essential for the diagnosis and prognosis of TC, but also for the development of novel therapeutics. In this review, most of the major TC-related genetic and epigenetic modifications and their potential as biomarkers for TC diagnosis and prognosis have been extensively discussed.

ABSTRACT Aims Lack of obstructive sleep apnea (OSA) awareness both directly and indirectly causes a medical and financial burden worldwide. The objective of this study is to provide new insights, focusing on type 2 diabetics and their knowledge levels about OSA in King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia, and to recognize obesity as a common risk factor contributing to OSA in type 2 diabetes mellitus (T2DM) participants. Methods An analytical cross‐sectional study was conducted from July 2022 to December 2022 with a convenience sampling method of 386 participants (18 years old and above). The study was done face‐to‐face using an electronic questionnaire. The inclusion criterion was all T2DM patients at the waiting area of KKUH Diabetes Center in Riyadh, excluding participants with other metabolic disorders. Results Overall knowledge levels were poor, with 70.2% of participants not knowledgeable about the disease and 81.3% of participants having no knowledge concerning the bidirectional relationship between T2DM and OSA. Statistical significance was found between the risk of developing OSA symptoms and body mass index ≥30 (p ≤ 0.001). Conclusion The majority have very little to no knowledge regarding OSA and its bidirectional relationship with T2DM, indicating the need to put more effort into improving participant's awareness in this regard. Moreover, obesity should be considered as a common risk factor, recommending patients to practice healthier habits to minimize the risks and decrease mortality.

Rheumatoid arthritis (RA) is a debilitating autoimmune condition characterized by chronic synovitis, joint damage, and inflammation, leading to impaired joint functionality. Existing RA treatments, although effective to some extent, are not without side effects, prompting a search for more potent therapies. Recent research has revealed the critical role of FAS-associated death domain protein (FADD) microvesicular shedding in RA pathogenesis, expanding its scope beyond apoptosis to include inflammatory and immune pathways. This study aimed to investigate the intricate relationship between mi-RNA 128a, autoimmune and inflammatory pathways, and adenosine levels in modulating FADD expression and microvesicular shedding in a Freund’s complete adjuvant (FCA) induced RA rat model and further explore the antirheumatoid potency of trimetazidine (TMZ). The FCA treated model exhibited significantly elevated levels of serum fibrogenic, inflammatory, immunological and rheumatological diagnostic markers, confirming successful RA induction. Our results revealed that the FCA-induced RA model showed a significant reduction in the expression of FADD in paw tissue and increased microvesicular FADD shedding in synovial fluid, which was attributed to the significant increase in the expression of the epigenetic miRNA 128a gene in addition to the downregulation of adenosine levels. These findings were further supported by the significant activation of the TLR4/MYD88 pathway and its downstream inflammatory IkB/NFB markers. Interestingly, TMZ administration significantly improved, with a potency similar to methotrexate (MTX), the deterioration effect of FCA treatment, as evidenced by a significant attenuation of fibrogenic, inflammatory, immunological, and rheumatological markers. Our investigations indicated that TMZ uniquely acted by targeting epigenetic miRNA128a expression and elevating adenosine levels in paw tissue, leading to increased expression of FADD of paw tissue and mitigated FADD microvesicular shedding in synovial fluid. Furthermore, the group treated with TMZ showed significant downregulation of TLR4/MYD88 and their downstream TRAF6, IRAK and NF-kB. Together, our study unveils the significant potential of TMZ as an antirheumatoid candidate, offering anti-inflammatory effects through various mechanisms, including modulation of the FADD-epigenetic regulator mi-RNA 128a, adenosine levels, and the TLR4 signaling pathway in joint tissue, but also attenuation of FADD microvesicular shedding in synovial fluid. These findings further highlight the synergistic administration of TMZ and MTX as a potential approach to reduce adverse effects of MTX while improving therapeutic efficacy.

Abstract In the present study, we explored the potential of coumarin-based compounds, known for their potent anticancer properties, by designing and synthesizing a novel category of 8-methoxycoumarin-3-carboxamides. Our aim was to investigate their antiproliferative activity against liver cancer cells. Toward this, we developed a versatile synthetic approach to produce a series of 8-methoxycoumarin-3-carboxamide analogues with meticulous structural features. Assessment of their antiproliferative activity demonstrated their significant inhibitory effects on the growth of HepG2 cells, a widely studied liver cancer cell line. Among screened compounds, compound 5 exhibited the most potent antiproliferative activity among the screened compounds (IC50 = 0.9 µM), outperforming the anticancer drug staurosporine (IC50 = 8.4 µM), while showing minimal impact on normal cells. The flow cytometric analysis revealed that compound 5 induces cell cycle arrest during the G1/S phase and triggers apoptosis in HepG2 cells by increasing the percentage of cells arrested in the G2/M and pre-G1 phases. Annexin V-FITC/PI screening further supported the induction of apoptosis without significant necrosis. Further, compound 5 exhibited the ability to activate caspase3/7 protein and substantially inhibited β-tubulin polymerization activity in HepG2 cells. Finally, molecular modelling analysis further affirmed the high binding affinity of compound 5 toward the active cavity of β-tubulin protein, suggesting its mechanistic involvement. Collectively, our findings highlight the therapeutic potential of the presented class of coumarin analogues, especially compound 5, as promising candidates for the development of effective anti-hepatocellular carcinoma agents.

Sodium nitrite (NaNO2) is a widely used food ingredient, although excessive concentrations can pose potential health risks. In the present study, we evaluated the deterioration effects of NaNO2 additives on hematology, metabolic profile, liver function, and kidney function of male Wistar rats. We further explored the therapeutic potential of supplementation with S. costus root ethanolic extract (SCREE) to improve NaNO2-induced hepatorenal toxicity. In this regard, 65 adult male rats were divided into eight groups; Group 1: control, Groups 2, 3, and 4 received SCREE in 200, 400, and 600 mg/kg body weight, respectively, Group 5: NaNO2 (6.5 mg/kg body weight), Groups 6, 7 and 8 received NaNO2 (6.5 mg/kg body weight) in combination with SCREE (200, 400, and 600 mg/kg body weight), respectively. Our results revealed that the NaNO2-treated group shows a significant change in deterioration in body and organ weights, hematological parameters, lipid profile, and hepatorenal dysfunction, as well as immunohistochemical and histopathological alterations. Furthermore, the NaNO2-treated group demonstrated a considerable increase in the expression of TNF-α cytokine and tumor suppressor gene P53 in the kidney and liver, while a significant reduction was detected in the anti-inflammatory cytokine IL-4 and the apoptosis suppressor gene BCL-2, compared to the control group. Interestingly, SCREE administration demonstrated the ability to significantly alleviate the toxic effects of NaNO2 and improve liver function in a dose-dependent manner, including hematological parameters, lipid profile, and modulation of histopathological architecture. Additionally, SCREE exhibited the ability to modulate the expression levels of inflammatory cytokines and apoptotic genes in the liver and kidney. The phytochemical analysis revealed a wide set of primary metabolites in SCREE, including phenolics, flavonoids, vitamins, alkaloids, saponins and tannins, while the untargeted UPLC/T-TOF–MS/MS analysis identified 183 metabolites in both positive and negative ionization modes. Together, our findings establish the potential of SCREE in mitigating the toxic effects of NaNO2 by modulating metabolic, inflammatory, and apoptosis. Together, this study underscores the promise of SCREE as a potential natural food detoxifying additive to counteract the harmful impacts of sodium nitrite.

Microbial infections pose a significant global health threat, affecting millions of individuals and leading to substantial mortality rates. The increasing resistance of microorganisms to conventional treatments requires the development of novel antimicrobial agents. Pyrroloquinoline quinone (PQQ), a natural medicinal drug involved in various cellular processes, holds promise as a potential antimicrobial agent. In the present study, our aim was, for the first time, to explore the antimicrobial activity of PQQ against 29 pathogenic microbes, including 13 fungal strains, 8 Gram-positive bacteria, and 8 Gram-negative bacteria. Our findings revealed potent antifungal properties of PQQ, particularly against Syncephalastrum racemosum, Talaromyces marneffei, Candida lipolytica, and Trichophyton rubrum. The MIC values varied between fungal strains, and T. marneffei exhibited a lower MIC, indicating a greater susceptibility to PQQ. In addition, PQQ exhibited notable antibacterial activity against Gram-positive and -negative bacteria, with a prominent inhibition observed against Staphylococcus epidermidis, Proteus vulgaris, and MRSA strains. Remarkably, PQQ demonstrated considerable biofilm inhibition against the MRSA, S. epidermidis, and P. vulgaris strains. Transmission electron microscopy (TEM) studies revealed that PQQ caused structural damage and disrupted cell metabolism in bacterial cells, leading to aberrant morphology, compromised cell membrane integrity, and leakage of cytoplasmic contents. These findings were further affirmed by shotgun proteomic analysis, which revealed that PQQ targets several important cellular processes in bacteria, including membrane proteins, ATP metabolic processes, DNA repair processes, metal-binding proteins, and stress response. Finally, detailed molecular modeling investigations indicated that PQQ exhibits a substantial binding affinity score for key microbial targets, including the mannoprotein Mp1P, the transcriptional regulator TcaR, and the endonuclease PvuRTs1I. Taken together, our study underscores the effectiveness of PQQ as a broad-spectrum antimicrobial agent capable of combating pathogenic fungi and bacteria, while also inhibiting biofilm formation and targeting several critical biological processes, making it a promising therapeutic option for biofilm-related infections.

AbstractCanagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants (P237, P338, PVA, and PVP K30) were prepared by the Sono-homo-assisted precipitation ion technique. The optimized formula prepared with PVP-K30 showed the smallest particle size (157 ± 0.32 nm), Zeta-potential (−18 ± 0.01), and morphology by TEM analysis. The optimized formula was subsequently formulated into a sublingual tablet containing Pharma burst-V® with a shorter disintegration time (51s) for the in-vivo study. The selected sublingual tablet improved histological and biochemical markers (blood glucose, liver, and kidney function), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) pathway compared to the market formula, increased CFZ’s antidiabetic potency in diabetic rabbits, boosted bioavailability by five-fold, and produced faster onset of action. These findings suggest successful treatment of diabetes with CFZ nanocrystal-sublingual tablets.

Abstract Chronic kidney disease (CKD) is a serious public health problem characterized by progressive kidney function loss leading to end-stage renal disease (ESRD) that demands dialysis or kidney transplantation. Early detection can prevent or delay progression to ESRD. The study aimed to gain new insights into the perturbed biochemical reactions and to identify novel distinct biomarkers between ESRD and CKD. Serum samples of 32 patients with ESRD (n = 13) and CKD (n = 19) were analyzed using chemical isotope labeling liquid chromatography-mass spectrometry metabolomics approach. A total of 193 metabolites were significantly altered in ESRD compared to CKD and were mainly involved in aminoacyl-tRNA biosynthesis, branched-chain amino acid (BCAA) biosynthesis, taurine metabolism, and tryptophan metabolism. Three kynurenine derivatives, namely, 2-aminobenzoic acid, xanthurenic acid, and hydroxypicolinic acid were upregulated in ESRD compared to CKD due to the significant decrease in glomerular filtration rate with the progression of CKD to ESRD. N-Hydroxy-isoleucine, 2-aminobenzoic acid, and picolinic acid yielded AUC > 0.99 when analyzed using Receiver Operating Characteristic (ROC) analysis. Our findings suggest that inhibiting the kynurenine pathway might be a promising target to delay CKD progression and that metabolites with high discriminative ability might serve as potential prognostic biomarkers to monitor the progression of CKD to ESRD or used in combination with current markers to indicate the status of kidney damage better.

Autism spectrum disorders (ASD) represent a diverse group of neuropsychiatric conditions, and recent evidence has suggested a connection between ASD and microbial dysbiosis. Immune and gastrointestinal dysfunction are associated with dysbiosis, and there are indications that modulating the microbiota could improve ASD-related behaviors. Additionally, recent findings highlighted the significant impact of microbiota on the development of autoimmune liver diseases, and the occurrence of autoimmune liver disease in children with ASD is noteworthy. In the present study, we conducted both an in vivo study and a clinical study to explore the relationship between indomethacin-induced dysbiosis, autoimmune hepatitis (AIH), and the development of ASD. Our results revealed that indomethacin administration induced intestinal dysbiosis and bacterial translocation, confirmed by microbiological analysis showing positive bacterial translocation in blood cultures. Furthermore, indomethacin administration led to disturbed intestinal permeability, evidenced by the activation of the NLRP3 inflammasomes pathway and elevation of downstream biomarkers (TLR4, IL18, caspase 1). The histological analysis supported these findings, showing widened intestinal tight junctions, decreased mucosal thickness, inflammatory cell infiltrates, and collagen deposition. Additionally, the disturbance of intestinal permeability was associated with immune activation in liver tissue and the development of AIH, as indicated by altered liver function, elevated ASMA and ANA in serum, and histological markers of autoimmune hepatitis. These results indicate that NSAID-induced intestinal dysbiosis and AIH are robust triggers for ASD existence. These findings were further confirmed by conducting a clinical study that involved children with ASD, autoimmune hepatitis (AIH), and a history of NSAID intake. Children exposed to NSAIDs in early life and complicated by dysbiosis and AIH exhibited elevated serum levels of NLRP3, IL18, liver enzymes, ASMA, ANA, JAK1, and IL6. Further, the correlation analysis demonstrated a positive relationship between the measured parameters and the severity of ASD. Our findings suggest a potential link between NSAIDs, dysbiosis-induced AIH, and the development of ASD. The identified markers hold promise as indicators for early diagnosis and prognosis of ASD. This research highlights the importance of maintaining healthy gut microbiota and supports the necessity for further investigation into the role of dysbiosis and AIH in the etiology of ASD.

Numerous measures have been taken to slow the Coronavirus disease (COVID-19) rapid spread. Such population control techniques may have a substantial impact on people’s attitudes, knowledge, and perception of COVID-19. This web-based cross-sectional survey aimed to assess Knowledge, Attitude, and Practices (KAP) towards COVID-19 among Hadhramout University Medical Students in Yemen from 15 June to 26 June 2020. This survey was performed using social media via the Google Platform among 422 Hadhramout University Medical students. After consenting, participants completed an online survey assessing sociodemographic data, 21 knowledge items, 15 attitudes items, and 5 perception items towards COVID-19. Of the total 422 participants, 389 (92.18%) were surveyed online, and 256 (65.8%) were females, and 133 (34.2%) were males aged 19-24 years (88.7%), studying medicine (58.9%), and living in urban areas (80.7%). The survey revealed that 64.0% of participants had good knowledge about the disease and 52.7% had positive attitudes towards protective measures against the virus. The majority of participants (98.2%) thought that the virus was transmitted through nasal droplets, and 59.6% agreed that the disease is dangerous. The majority of participants agreed that fever (99.2%), dry cough (97.9%), and difficulty breathing (99.5%) are the most common symptoms of the disease. The survey also showed high knowledge levels about preventive measures against the virus spreading, such as regular proper hand hygiene (99.7%), maintaining an appropriate distance (99.2%), avoiding touching eyes and nose (98.7%), and wearing facemasks in public places (97.4%). Moreover, 69.7% of participants agreed to be isolated at home if they got an infected person, 64.3% implemented washing hands with soap and water, 41.9% agreed to be separated at the hospital until they proved free from the disease, 46.0% agreed to inform the health authorities if they had any symptoms associated with the disease. By using sample T-test and analysis of variance (ANOVA), mean knowledge score about COVID-19 was significantly higher in males than in females (p = 0.029). Additionally, medicine students had significantly higher mean knowledge score than students of medical laboratory (p < 0.001) and nursing (p = 0.008). In general, our research revealed that participants had favorable opinions regarding the disease’s preventative measures and a good awareness of it. However, more educational initiatives and campaigns that take into account KAP modifying elements are needed.

Being the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the disease, toxicity to healthy cells, and the potential for drug resistance. There is ample evidence that coumarin-based compounds are potent anticancer agents, with numerous analogues currently being investigated in preclinical and clinical studies. The current study aimed to explore the antitumor potency of a new class of 8-methoxycoumarin-3-carboxamides against liver cancer. Toward this aim, we have designed, synthesized, and characterized a new set of N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamide analogues. The assessment of antitumor activity revealed that the synthesized class of compounds possesses substantial cytotoxicity toward Hep-G2 cells when compared to staurosporine, without significant impact on normal cells. Out of the synthesized compounds, compound 7 demonstrated the most potent cytotoxic effect against Hep-G2 cells with an IC50 of 0.75 µM, which was more potent than the drug staurosporine (IC50 = 8.37 µM). The investigation into the mechanism behind the antiproliferative activity of compound 7 revealed that it interferes with DNA replication and induces DNA damage, leading to cell cycle arrest as demonstrated by a significant decrease in the percentage of cells in the G1 and G2/M phases, along with an increase in the percentage of cells in the S phase. Flow cytometric analysis further revealed that compound 7 has the ability to trigger programmed cell death by inducing necrosis and apoptosis in HepG-2 cells. Further explorations into the mechanism of action demonstrated that compound 7 displays a potent dual-inhibitory activity toward cytochrome P450 and vascular endothelial growth factor receptor-2 (VEGFR-2) proteins, as compared to sorafenib drug. Further, detailed computational studies revealed that compound 7 displays a considerable binding affinity toward the binding cavity of VEGFR2 and CYP450 proteins. Taken together, our findings indicate that the newly synthesized class of compounds, particularly compound 7, could serve as a promising scaffold for the development of highly effective anticancer agents against liver cancer.

Sugar beet is one of the greatest sources for producing sugar worldwide. However, a group of bacteria grows on beets during the storage process, leading to a reduction in sucrose yield. Our study focused on identifying common bacterial species that grow on beets during manufacturing and contribute to sucrose loss. The ultimate goal was to find a potential antibacterial agent from various plant extracts and oils to inhibit the growth of these harmful bacteria and reduce sucrose losses. The screening of bacterial species that grow on beet revealed that a large group of mesophilic bacteria, such as Bacillus subtilis, Leuconostoc mesenteroides, Pseudomonas fluorescens, Escherichia coli, Acinetobacter baumannii, Staphylococcus xylosus, Enterobacter amnigenus, and Aeromonas species, in addition to a dominant thermophilic species called Bacillus thermophilus, were found to be present during the manufacturing of beets. The application of 20 plant extracts and 13 different oils indicated that the extracts of Geranium gruinum, Datura stramonium, and Mentha spicata were the best antibacterials to reduce the growth of B. thermophilus with inhibition zones equal to 40, 39, and 35 mm, respectively. In contrast, the best active oils for inhibiting the growth of B. thermophilus were Mentha spicata and Ocimum bacilicum, with an inhibitory effect of 50 and 45 mm, respectively. RAPD-PCR with different primers indicated that treating sugar juice with the most effective oils against bacteria resulted in new recombinant microorganisms, confirming their roles as strong antibacterial products. The characterization of Mentha spicata and Ocimum bacilicum oils using GC/MS analysis identified cis-iso pulegone and hexadecanoic acid as the two main bioactive compounds with potential antibacterial activity. An analysis of five genes using DD-PCR that have been affected due to antibacterial activity from the highly effective oil from Mentha spicata concluded that all belonged to the family of protein defense. Our findings indicate that the application of these pure antibacterial plant extracts and oils would minimize the reduction of sucrose during sugar production.

Abstract Background Pain is a major obstacle and one of the main reasons people seek medical attention and is a frequent stressor for many clients in the intensive care unit (ICU). However, clients should not be left complaining, especially when solutions are available; each patient has the right to assess and manage their pain in the best way possible. Therefore, the objective of this study was to analyze nurses' knowledge, attitudes, and practice (KAPs) regarding pain management in Palestinian ICU settings and to determine the possible obstacles that may hinder effective and competent pain management for critically ill clients. Methods This cross-sectional research was conducted online through social media. An approved questionnaire was used to assess KAPs and obstacles in pain treatment approaches for critically ill patients. Bloom’s cutoff points for adequate practice, appropriate knowledge, and a positive attitude were applied. IBM SPSS Statistics for Windows, Version 21.0 was used for analyses. Results One hundred ninety-one nurses were approached, the majority of the participants in this investigation were males (n = 127, 66.5%), and the mean age of the study participant was 29 ± 7 (year). The overall knowledge score was 15, measured for median knowledge = 7 with an interquartile range (IQR) of 4–8, and higher scores indicate more knowledge about the management and control of pain. The total attitude score = 11, the median = 6, with an IQR of 5–7. The reluctance to prescribe opioids was 79.6%, the lack of proficiency in pain management knowledge was 78.5%, and rigorous controls over opioid use were 77.5%, which was the lion's share of commonly recognized hurdles. The overall practice score was 10, with a median of 5.0 with an IQR of 3.0 to 6.0, and nurses revealed that they would evaluate all the steps involved in pain management in each round they have. Conclusions This research reveals a knowledge, attitude, and practice gap among the working nurses. Therefore, adequate and efficient plans must be aimed at ICU nurses to foster the level of knowledge and direct attitudes toward pain control through applicable interventional programs.

According to studies, the microbiome may contribute to the emergence and spread of breast cancer. E. coli is one of the Enterobacteriaceae family recently found to be present as part of the breast tissue microbiota. In this study, we focused on the effect of E. coli secretome free of cells on MCF-7 metabolism. Liquid chromatography–mass spectrometry (LC-MS) metabolomics was used to study the E. coli secretome and its role in MCF-7 intra- and extracellular metabolites. A comparison was made between secretome-exposed cells and unexposed controls. Our analysis revealed significant alterations in 31 intracellular and 55 extracellular metabolites following secretome exposure. Several metabolic pathways, including lactate, aminoacyl-tRNA biosynthesis, purine metabolism, and energy metabolism, were found to be dysregulated upon E. coli secretome exposure. E. coli can alter the breast cancer cells’ metabolism through its secretome which disrupts key metabolic pathways of MCF-7 cells. These microbial metabolites from the secretome hold promise as biomarkers of drug resistance or innovative approaches for cancer treatment, either as standalone therapies or in combination with other medicines.

Seed dispersal is a key process for the distribution of wild fruit plants in forests and/or rangeland. The ecological role of Alectoris chukar as a seed dispersal agent was hardly known to date, though its diet consists of herbs, shrubs, and fleshy fruits of wild plants. Here we report the first evidence of seed dispersal and germination of wild pistachio plant (Pistacia khinjuk Stocks) favored by Alectoris chukar from the district Killa Saifullah and Pishin in Balochistan, Pakistan. Fecal droppings of Alectoris chukar were collected by a suitable sampling method from August to September 2020. Fecal droppings were kept in plastic bags, and later washed thoroughly, identified, and counted for Pistacia khinjuk seeds, which have a characteristic rounded and tough seed coat easily distinguishable from other seeds. Out of a total of 840 fecal samples collected, 557 were identified as Pistacia khinjuk seeds. A comparative germination trial was carried out for pistachio seeds both from Alectoris chukar fecal droppings and manually collected from mother trees in the forest. After passing through the chukar gut, the seeds were still viable and showed a faster germination rate as compared with seeds collected from mother trees and directly sown in the soil. The results revealed that Alectoris chukar is an important spreading and germinating agent for seeds of pistachio plants in suitable habitats and could contribute in the long term to modify the ground vegetation of (sub)arid regions depending on its dietary preferences.

Abstract Background Postoperative pulmonary complications (PPCs) often occur after cardiac operations and are a leading cause of morbidity, inhibit oxygenation, and increase hospital length of stay and mortality. Although clinical evidence for PPCs prevention is often unclear and crucial, measures occur to reduce PPCs. One device usually used for this reason is incentive spirometry (IS). The aim of the study is to evaluate the effect of preoperative incentive spirometry to prevent postoperative pulmonary complications, improve postoperative oxygenation, and decrease hospital stay following coronary artery bypass graft (CABG) surgery patients. Methods This was a clinical randomized prospective study. A total of 80 patients were selected as candidates for CABG at An-Najah National University Hospital, Nablus-Palestine. Patients had been randomly assigned into two groups: incentive spirometry group (IS), SI performed before surgery (study group) and control group, preoperative spirometry was not performed. The 40 patients in each group received the same protocol of anesthesia and ventilation in the operating room. Result The study findings showed a significant difference between the IS and control groups in the incidence of postoperative atelectasis. There were 8 patients (20.0%) in IS group and 17 patients (42.5%) in the control group (p = 0.03). Mechanical ventilation duration was significantly less in IS group. The median was four hours versus six hours in the control group (p

The pharmacodynamics of the purinergic receptor type Y, subtype 12 (P2Y12) inhibitors has evolved. Our understanding of the metabolism of P2Y12 inhibitors has revealed polymorphisms that impact drug metabolism and antiplatelet efficacy, leading to genetic testing guided therapy. In addition, assays of platelet function and biochemistry have provided insight into our understanding of the efficacy of “antiplatelet” therapy, identifying patients with high or low platelet reactivity on P2Y12 therapy. Despite the data, the implementation of these testing modalities has not gained mainstream adoption across hospital systems. Given differences in potency between the three clinically available P2Y12 inhibitors, the balance between thrombotic and bleeding complications must be carefully considered, especially for the large proportion of patients at higher risk for bleeding. Here we review the current data for genetic and functional testing, risk assessment strategies, and guidelines for P2Y12 inhibitors guided therapy.

Abstract Background The COVID-19 pandemic has caused a global health crisis. Numerous cancer patients from non-Western countries, including the United Arab Emirates (UAE), seek cancer care outside their home countries and many are sponsored by their governments for treatment. Many patients interrupted their cancer treatment abruptly and so returned to their home countries with unique challenges. In this review we will discuss practical challenges and recommendations for all cancer patients returning to their home countries from treatment abroad. Method Experts from medical, surgical and other cancer subspecialties in the UAE were invited to form a taskforce to address challenges and propose recommendations for patients returning home from abroad after medical tourism during the SARS-COV-19 Pandemic. Results The taskforce which consisted of experts from medical oncology, hematology, surgical oncology, radiation oncology, pathology, radiology and palliative care summarized the current challenges and suggested a practical approaches to address these specific challenges to improve the returning cancer patients care. Lack of medical documentation, pathology specimens and radiology images are one of the major limitations on the continuation of the cancer care for returning patients. Difference in approaches and treatment recommendations between the existing treating oncologists abroad and receiving oncologists in the UAE regarding the optimal management which can be addressed by early and empathic communications with patients and by engaging the previous treating oncologists in treatment planning based on the available resources and expertise in the UAE. Interruption of curative radiotherapy (RT) schedules which can potentially increase risk of treatment failure has been a major challenge, RT dose-compensation calculation should be considered in these circumstances. Conclusion The importance of a thorough clinical handover cannot be overstated and regulatory bodies are needed to prevent what can be considered unethical procedure towards returning cancer patients with lack of an effective handover. Clear communication is paramount to gain the trust of returning patients and their families. This pandemic may also serve as an opportunity to encourage patients to receive treatment locally in their home country. Future studies will be needed to address the steps to retain cancer patients in the UAE rather than seeking cancer treatment abroad.

Objective: To assess awareness of diabetic retinopathy (DR) for Saudis with diabetes mellitus (DM) type 2 in Riyadh City. Methods: A cross-sectional study that used self-administered questionnaires conducted in primary healthcare centers in Riyadh City between October and December 2019. Results: There were 267 Saudi participants with diabetes mellitus type 2 visiting primary healthcare clinics. (52.4%) were aged 40 years or above at time of diagnosis with diabetes. (73%) had diabetes for at least 5 years. Most of the participants have a good blood glucose control and they do home measurements. In regard to DR, (64.4%) of participants had no subjective or objective indicators of retinopathy, and (70%) had visited ophthalmology clinics. Majority of the participants were advised about DR or referred to an ophthalmologist by their primary physician, with the percentages being (64.8%) and (59.6%), respectively. Regarding other risk factors of DR, (19.5%) had a family history of DR, (23.2%) of participant are smokers and (41.6%) were hypertensives. Majority of the participants were aware about all the aspects of DR, its consequences, and appropriate management except the laser therapy. In terms of area of living and education respondents, who lived in the center of Riyadh City and the secondary level or less educated participants had the lowest level of education. Conclusions: Awareness of DR is acceptable but should not lead this information to reduced awareness and educational programs. Outreach researchers' efforts should cover other directions instead awareness of DR.

Objective: The aim of this study was to estimate the awareness of Saudi population in Riyadh regarding cardiovascular diseases (CVDs) and their risk factors. Methods: This was a cross-sectional study that used self-administered questionnaires conducted in universities, primary care centers, and electronic copies distributed in social media websites. Results: Overall, 47.1% of the respondents had a good awareness of CVD and associated risk factors. However, awareness of the symptoms of stroke and heart attack was low. Pulmonary embolism and deep vein thrombosis were the most commonly identified types of CVD, with 39.2% aware of these conditions. The most well-known symptom of heart attack was shortness of breath (known by 54.4% of the respondents). In relation to stroke, the most commonly recognized symptom was “sudden dizziness, trouble walking, or loss of balance” (45.4%). Respondents' awareness of CVD risk factors was moderate. The most common factors—identified by over two-thirds of participants—were unhealthy diet, smoking, dyslipidemia, and physical inactivity. Independent predictors of good CVD awareness were age 35–44 years, living in the north of Riyadh and following a healthy diet. Conclusions: The awareness of CVD and associated risk factors is insufficient among Saudis in Riyadh City. This study emphasizes the necessity for effective education to increase the awareness about CVD in Saudi Arabia. High awareness may lead to early recognition of the risk factors and lead to early implementation of primary prevention which the cornerstone of family medicine practice.

Antimicrobial resistance (AMR) is one of the most important global public health problems. The imprudent use of antibiotics in humans and animals has resulted in the emergence of antibiotic-resistant bacteria. The dissemination of these strains and their resistant determinants could endanger antibiotic efficacy. Therefore, there is an urgent need to identify and develop novel strategies to combat antibiotic resistance. This review provides insights into the evolution and the mechanisms of AMR. Additionally, it discusses alternative approaches that might be used to control AMR, including probiotics, prebiotics, antimicrobial peptides, small molecules, organic acids, essential oils, bacteriophage, fecal transplants, and nanoparticles.

As the ninth leading cause of death globally, diabetes mellitus (DM) is considered to be the worst chronic metabolic disease requiring an enormous need for healthcare with over 578 million expected cases by 2023. Several recent findings have demonstrated that mediating the activity of carbohydrate-hydrolyzing enzymes, including α-amylase and α-glucosidase, could be a potential strategy for managing the development of DM. In the presented study, a novel set of 1,3,5-trisubstituted-2-thioxoimidazolidin-4-ones was designed, synthesized, and characterized. The antidiabetic activity of the synthesized compounds was explored by assessing their inhibitory activity toward α-amylase and α-glucosidase enzymes. The results demonstrated that this class of compounds exhibits considerable inhibitory activity toward both α-amylase and α-glucosidase enzymes. Among the synthesized compounds, compound 5a demonstrated the most inhibitory activity with IC50 of 5.08 and µg/mL and 0.21 µg/mL toward α-glucosidase and α-amylase activities, respectively, as compared to the drug Acarbose (IC50 = 5.76 µg/mL and 0.39 µg/mL, respectively). To gain insights into the antidiabetic potential of compound 5a, we assessed the cytotoxic and antioxidant activities. Our findings indicated that compound 5a displays considerable cytotoxicity toward WI-38 cells with an IC50 of 88.54 µg/mL, as compared to the drug Celecoxib (IC50 = 93.05 µg/mL). Further, compound 5a exhibited a high scavenging activity toward 2,2-Diphenyl1-picrylhydrazyl (DPPH) free radicals (IC50 = 51.75 µg/mL) and showed a low potential to produce ROS as indicated by the monitoring of the generated H2O2 (132.4 pg/mL), as compared to Trolox (IC50 = 58.09 µg/mL) and Celecoxib (171.6 pg/mL). Finally, we performed extensive molecular modeling studies to affirm the binding affinity of this class of compounds to the binding pocket of α-amylase and α-glucosidase enzymes. Collectively, our findings indicate that this class of compounds, particularly compound 5a, could be utilized as a lead structure for the development of novel compounds with potential antidiabetic and antioxidant activities.

With the rising incidence of hepatocellular carcinoma (HCC) from non-alcoholic steatohepatitis (NASH), identifying new metabolic readouts that function in metabolic pathway perpetuation is still a demand. The study aimed to compare the metabolic signature between NASH and NASH-HCC patients to explore novel reprogrammed metabolic pathways that might modulate cancer progression in NASH patients. NASH and NASH-HCC patients were recruited and screened for metabolomics, and isotope-labeled lipidomics were targeted and profiled using the EXION-LCTM system equipped with a Triple-TOFTM 5600+ system. Results demonstrated significantly (p ≤ 0.05) higher levels of triacylglycerol, AFP, AST, and cancer antigen 19-9 in NASH-HCC than in NASH patients, while prothrombin time, platelet count, and total leukocyte count were decreased significantly (p ≤ 0.05). Serum metabolic profiling showed a panel of twenty metabolites with 10% FDR and p ≤ 0.05 in both targeted and non-targeted analysis that could segregate NASH-HCC from NASH patients. Pathway analysis revealed that the metabolites are implicated in the down-regulation of necroptosis, amino acid metabolism, and regulation of lipid metabolism by PPAR-α, biogenic amine synthesis, fatty acid metabolism, and the mTOR signaling pathway. Cholesterol metabolism, DNA repair, methylation pathway, bile acid, and salts metabolism were significantly upregulated in NASH-HCC compared to the NASH group. Metabolite–protein interactions network analysis clarified a set of well-known protein encoding genes that play crucial roles in cancer, including PEMT, IL4I1, BAAT, TAT, CDKAL1, NNMT, PNP, NOS1, and AHCYL. Taken together, reliable metabolite fingerprints are presented and illustrated in a detailed map for the most predominant reprogrammed metabolic pathways that target HCC development from NASH.

Nephrotic syndrome (NS) is a kidney illness characterized by excessive proteinuria, hypoalbuminemia, edema, and hyperlipidemia, which may lead to kidney failure and necessitate renal transplantation. End-stage renal disease, cardiovascular issues, and mortality are much more common in those with NS. Therefore, the present study aimed to identify potential new biomarkers associated with the pathogenesis and diagnosis of NS. The liquid chromatography–mass spectrometry (LC–MS) metabolomics approach was applied to profile the metabolome of human serum of patients with NS. A total of 176 metabolites were significantly altered in NS compared to the control. Arginine, proline, and tryptophan metabolism; arginine, phenylalanine, tyrosine, and tryptophan biosynthesis were the most common metabolic pathways dysregulated in NS. Furthermore, alanyl-lysine and isoleucyl-threonine had the highest discrimination between NS and healthy groups. The candidate biomarkers may lead to understanding the possible metabolic alterations associated with NS and serve as potential diagnostic biomarkers.

Inflammation is the main cause of several autoimmune diseases, including type I diabetes, rheumatoid arthritis, bullous pemphigoid, paraneoplastic pemphigoid, and multiple sclerosis. Currently, there is an urgent demand for the discovery of novel anti-inflammatory drugs with potent activity but also safe for long-term application. Toward this aim, the present study reported the design, synthesis, and characterization of a set of novel 1,3-disubstituted-2-thiohydantoins derivatives. The anti-inflammatory activity of synthesized compounds was assessed against murine leukemia cell line (RAW264.7) by evaluating the cytotoxicity activity and their potency to prevent nitric oxide (NO) production. The results revealed that the synthesized compounds possess a considerable cytotoxic activity together with the ability to reduce the NO production in murine leukemia cell line (RAW264.7). Among synthesized compounds, compound 7 exhibited the most potent cytotoxic activity with IC50 of 197.68 μg/mL, compared to celecoxib drug (IC50 value 251.2 μg/mL), and demonstrated a significant ability to diminish the NO production (six-fold reduction). Exploring the mode of action responsible for the anti-inflammatory activity revealed that compound 7 displays a significant and dose-dependent inhibitory effect on the expression of pro-inflammatory cytokines IL-1β. Furthermore, compound 7 demonstrated the ability to significantly reduce the expression of the inflammatory cytokines IL-6 and TNF-α at 50 μg/mL, as compared to Celecoxib. Finally, detailed molecular modelling studies indicated that compound 7 exhibits a substantial binding affinity toward the binding pocket of the cyclooxygenase 2 enzyme. Taken together, our study reveals that 1,3-disubstituted-2-thiohydantoin could be considered as a promising scaffold for the development of potent anti-inflammatory agents.

Abstract Non‐small cell lung cancer patients with anaplastic lymphoma kinase or c‐ros oncogene 1 mutations who are treated with the tyrosine kinase inhibitor crizotinib rarely develop crizotinib‐associated renal cysts (CARCs). Here, we present a case report and review of the literature supporting the hypothesis that CARCs may correlate positively with progression‐free survival.

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia–reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (−14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.

Background and Objectives: Folic acid (FA) is a necessary ingredient for numerous bodily activities including pregnancy. Because of this, women should have knowledge and awareness of the health benefits of FA supplementation. Thus, we aimed to investigate the level of knowledge on the importance of FA and determine associated factors for knowledge among female college students at King Saud University in Riyadh, Saudi Arabia. Material and Methods: We conducted a cross-sectional study using a questionnaire between January 2020 and February 2021 among female college students aged 17 to 26 years old. The questionnaire adapted with permission from Alnaami et al. included questions on the demographic profile of the participants as well as questions related to their knowledge and awareness of FA, FA supplementation, the importance of supplementation and their sources of knowledge of FA. Results: A total of 437 female undergraduate students participated in the study, 285 (65.2%) of whom were from the non-health colleges and 152 (34.8%) from the health colleges. The majority of participants were between ages 17 and 21 years old (n = 361, 82.6%). Half of the respondents were in their 3rd and 4th year of study (n = 122, 50.8%), 138 respondents (31.6%) were married, and 111 of these married women (80.4%) had children. There were 266 respondents (61.0%) who had heard and had knowledge of FA, 241 (55.3%) knew of FA timing of intake, 243 (55.7%) of FA duration of intake and 362 (83.0%) knew of the diseases prevented by FA supplementation. Linear regression analysis showed that being in the health college (B = 1.464, t = 11.37, p < 0.001, 95% CI = 1.211, 1.717) and a higher educational year level (B = 0.139, t = 2.442, p = 0.015, 95% CI = 0.027, 0.251) were the significant predictors of knowledge of FA. Conclusions: Knowledge of FA and FA supplementation was low at 61% considering that our study population were college students. Being enrolled in a health college and in a higher educational year level were significant positive correlates of higher knowledge of FA and FA supplementation. Despite this, there exists a gap of information regarding FA and FA supplementation particularly among single women and college educated women in the early years of their college life as well as those in non-health colleges.

In the presented study, Bacillus subtilis strain AG4 isolated from marine was identified based on morphological, physiological, phylogenetic characteristics and an examination of 16S rRNA sequences. Novel exopolysaccharide (EPSR4) was extracted and isolated from the Bacillus subtilis strain as a major fraction of exopolysaccharide (EPS). The analysis of structural characterization indicated that EPSR4 is a β-glycosidic sulphated heteropolysaccharide (48.2%) with a molecular weight (Mw) of 1.48 × 104 g/mole and has no uronic acid. Analysis of monosaccharide content revealed that EPSR4 consists of glucose, rhamnose and arabinose monosaccharide in a molar ratio of 5:1:3, respectively. Morphological analysis revealed that EPSR4 possess a high crystallinity degree with a significant degree of porosity, and its aggregation and conformation in the lipid phase might have a significant impact on the bioactivity of EPSR4. The biological activity of EPSR4 was screened and evaluated by investigating its antioxidant, cytotoxicity, anti-inflammatory, and anti-Alzheimer activities. The antioxidant activity results showed that EPSR4 has 97.6% scavenging activity toward DPPH free radicals at 1500 µg/mL, with an IC50 value of 300 µg/mL, and 64.8% at 1500 µg/mL toward hydrogen peroxide free radicals (IC50 = 1500 µg/mL, 30 min). Furthermore, EPSR4 exhibited considerable inhibitory activity towards the proliferation of T-24 (bladder carcinoma), A-549 (lung cancer) and HepG-2 (hepatocellular carcinoma) cancer cell lines with IC50 of 244 µg/mL, 148 µg/mL and 123 µg/mL, respectively. An evaluation of anti-inflammatory activity revealed that EPSR4 has potent lipoxygenase (LOX) inhibitory activity (IC50 of 54.3 µg/mL) and a considerable effect on membrane stabilization (IC50 = 112.2 ± 1.2 µg/mL), while it showed cyclooxygenase (COX2) inhibitory activity up to 125 µg/mL. Finally, EPSR4 showed considerable inhibitory activity towards acetylcholine esterase activity. Taken together, this study reveals that Bacillus subtilis strain AG4 could be considered as a potential natural source of novel EPS with potent biological activities that would be useful for the healthcare system.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle loss, leading to difficulties in movement. Mutations in the DMD gene that code for the protein dystrophin are responsible for the development of DMD disorder, where the synthesis of this protein is completely halted. Therefore, circulating dystrophin protein could be a promising biomarker of DMD disease. Current methods for diagnosing DMD have sensitivity, specificity, and reproducibility limitations. Herein, a quantitative liquid chromatography–tandem spectrometry (LC–MS/MS) technique in multiple reaction monitoring (MRM) mode was designed and validated for accurate dystrophin protein measurement in a dried blood spot (DBS). The method was successfully validated on the basis of international guidelines regarding calibration curves, precision, and accuracy. In addition, patients and healthy controls were used to test the amount of dystrophin protein circulating in DBS samples as a potential biomarker for DMD disorders. DMD patients were found to have considerably lower levels than controls. To the best of our knowledge, this is the first study to report dystrophin levels in DBS through LC–MS/MS as a diagnostic marker for DMD to the proposed MRM method, providing a highly specific and sensitive approach to dystrophin quantification in a DBS that can be applied in DMD screening.

Alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. Here authors solve the Xray structure of human ACER3 and uncover a Ca2+ binding site providing an explanation for the known regulatory role of Ca2+ on ACER3 activity.

Background: To evaluate robotic-assisted partial nephrectomy (RAPN) renal outcomes associated with ancillary pathology findings in non-neoplastic renal parenchymal tissue.Methods: Tissue samples from 378 RAPNs were analyzed for glomerular disease (GD), vascular disease (VD), and tubulointerstitial disease (TD). One hundred and fifty-two patients were excluded due to insufficient non-neoplastic tissue for analysis and 4 patients were excluded due to calyceal diverticulum. Non-neoplastic tissue was evaluated for GD (negative, moderate, or global), VD (absent, mild, moderate, or severe), and TD (present or absent). Associations of ancillary pathology factors with patient characteristics were explored using the non-parametric Kendall tau-test and propensity score adjusted longitudinal mixed effects regression models were used to evaluate associations of these pathology factors with changes in estimated glomerular filtration rate (eGFR) following RAPN.Results: One hundred and fifty-three (68.9%) patients had hypertension and 50 (22.5%) patients had diabetes. The majority of patients did not have any GD (N = 158, 71.2%) or TD (N = 186, 83.8%) while 129 (58.1%) had VD. VD was categorized as absent (N = 93, 41.9%), mild (N = 45, 20.3%), moderate (N = 76, 34.2%), and severe (N = 8, 6.8%). Older age (P = 0.018), hypertension (P < 0.001), and high grade MAP score (P = 0.047) were associated with a higher number of ancillary pathology factors. High grade MAP score (P = 0.03, P = 0.002) and hypertension (P = 0.02, P < 0.001) were individually associated with GD severity and VD severity, respectively. Older age was also individually associated with VD severity (P = 0.002) and hypertension was associated with TD (P = 0.04). Moderate-to-severe VD was associated with a worse change in eGFR from pre-RAPN to 1-month post-RAPN compared to those with mild or no VD (difference in mean change, −3.4 ml/kg/1.73m2; 95% CI, −6.6 to −0.2 ml/kg/1.73m2; P = 0.036).Conclusions: Moderate-to-severe VD in non-neoplastic renal parenchyma is associated with post-operative changes in eGFR. Older age, hypertension, and high grade MAP scores are associated with the number of ancillary pathologies observed in RAPN specimens.

Background and Objectives: In this study, we aimed to investigate the link between common -2548G>A (rs7799039) promoter variant of the human leptin gene (LEP) with leptin and serum glucose leptin levels in obese Saudi patients. Materials and Methods: A total of 206 Saudi adults (80 obese normotensive nondiabetics, 76 obese hypertensive with Type 2 Diabetes and 50 normotensive nondiabetic controls) were genotyped for -2548G>A LEP polymorphism using the polymerase chain reaction-restriction fragment-length polymorphism technique. Results: Participants with minor AA genotype had significantly higher blood glucose levels (6.8 ± 0.55 mmol/L vs. 5.8 ± 0.30 mmol/L; p < 0.04) and HOMA-IR (4.1 ± 0.84 vs. 2.6 ± 0.67; p = 0.03) against those carrying major GG genotype. Participants with heterozygous GA genotype had significantly higher serum leptin levels against those carrying major GG genotype (40.0 ± 2.6 ng/mL vs. 29.6 ± 2.6 ng/mL; p = 0.04). Further investigation showed that individuals with AA, GA, GA + AA genotypes are at greater risk of developing hyperglycemia compared to those with GG genotype [OR 3.7(1.6–8.4), p = 0.001; 3.2 (1.2–8.6), p = 0.03; 3.5 (1.6–7.7), p = 0.001, respectively]. Additionally, the -2548AA allele was shown to be a risk factor for hyperglycemia [OR 1.9 (1.2–3.0), p = 0.006]. Our data revealed no relationship between this variant of the LEP gene with systolic and diastolic BP, signifying that this genetic variant is not a significant marker of obesity and hypertension in the Saudi population. Conclusions: AA and GA genotypes and LEP gene -2548AA alleles may signify potent risk factors predisposing healthy individuals to develop T2DM regardless of blood-pressure profile.

Alcoholism is one of the most common diseases that can lead to the development of several chronic diseases including steatosis, and cognitive dysfunction. Statins are lipid-lowering drugs that are commonly prescribed for patients with fatty liver diseases; however, the exact effect of statins on cognitive function is still not fully understood. In the present study, we have investigated the molecular and microscopic basis of cognitive impairment induced by alcohol and/or Atorvastatin (ATOR) administration to male Wistar albino rats and explored the possible protective effect of acetylsalicylic acid (ASA). The biochemical analysis indicated that either alcohol or ATOR or together in combination produced a significant increase in the nucleotide-binding domain–like receptor 3 (NLRP3), interleukin-1β (IL-1β) miRNA155 expression levels in the frontal cortex of the brain tissue. The histological and morphometric analysis showed signs of degeneration in the neurons and the glial cells with aggregations of inflammatory cells and a decrease in the mean thickness of the frontal cortex. Immunohistochemical analysis showed a significant increase in the caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex. Interestingly, administration of ASA reversed the deleterious effect of the alcohol and ATOR intake and improved the cognitive function as indicated by biochemical and histological analysis. ASA significantly decreased the expression levels of miRNA155, NLRP3, and IL1B, and produced a significant decrease in caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex with a reduction in the process of neuroinflammation and neuronal damage. To further investigate these findings, we have performed an extensive molecular docking study to investigate the binding affinity of ASA to the binding pockets of the NLRP3 protein. Our results indicated that ASA has high binding scores toward the active sites of the NLRP3 NACHT domain with the ability to bind to the NLRP3 pockets by a set of hydrophilic and hydrophobic interactions. Taken together, the present study highlights the protective pharmacological effect of ASA to attenuate the deleterious effect of alcohol intake and long term ATOR therapy on the cognitive function via targeting miRNA155 and NLRP3 proteins.

Different laboratory methods are used to measure serum ferritin levels as a marker of iron status in the general population. This study aimed to compare serum ferritin levels using enzyme-linked immunosorbent assay (ELISA) versus immunochemiluminescence (Cobas e411) and immunoturbidimetric (Cobas Integra 400) methods in terms of sensitivity, specificity and accuracy, and whether they can be used interchangeably. A comparative cross-sectional study enrolled one hundred and six adult Yemeni patients (33 males and 73 females) aged 18–55 years, recruited from the dermatology and cosmetic center of Hadhramout Modern Hospital, Mukalla, Yemen. Serum ferritin levels were measured using ELISA, Cobas e411, and Cobas Integra 400 methods. For method comparison, a paired-sample t-test was used. For the consistency between the three methods, they were analyzed with regression and Pearson correlation coefficient. For determining accuracy, a receiver operating curve (ROC) was used. Bias error between the methods was determined through a Bland–Altman plot analysis. Our results did not show any significant statistical difference between ELISA and Cobas e411 (52.55 ± 7.4 µg/L vs. 52.58 ± 7.5 µg/L, p = 0.967), while there were significantly higher values from Cobas Integra 400 results than Cobas e411 (56.31 ± 7.8 µg/L vs. 52.58 ± 7.5 µg/L, p < 0.001) and ELISA (52.55 ± 7.4 µg/L vs. 56.31 ± 7.8 µg/L, p < 0.001). According to the correlation coefficient and linear regression analysis, a strong association between ELISA with Cobas e411 (r = 0.993, p < 0.001) and Cobas Integra 400 results (r = 0.994, p < 0.001) were revealed. For determining accuracy, Cobas e411 and Cobas Integra 400 results showed higher sensitivity (92.0%; 90.0%) and specificity (97.7%; 99.9%) respectively. Additionally, the Bland–Altman plot analysis showed a high agreement between the ELISA and Cobas e411 methods (bias: −0.035). In contrast, there was a low agreement between the ELISA and Cobas Integra 400 methods (bias: −3.75). Similarly, the agreement between Cobas e411 and Cobas Integra 400 methods was low (bias: −3.72). Serum ferritin levels were measured by Cobas e411, and Cobas Integra 400 methods were strongly correlated with the ELISA results, with higher sensitivity, specificity, and accuracy. However, further investigations with larger samples are required for improved accuracy and more precise results, and to determine whether they can be used interchangeably.

The generation of most sphingolipids (SPLs) starts with condensation between serine and an activated long-chain fatty acid catalyzed by serine palmitoyltransferase (SPT). SPT can also use other amino acids to generate small quantities of noncanonical SPLs. The balance between serine-derived and noncanonical SPLs is pivotal; for example, hereditary sensory and autonomic neuropathy type I results from SPT mutations that cause an abnormal accumulation of alanine-derived SPLs. The regulatory mechanism for SPT amino acid selectivity and physiological functions of noncanonical SPLs are unknown. We investigated SPT selection of amino acid substrates by measuring condensation products of serine and alanine in yeast cultures and SPT use of serine and alanine in a TSC3 knockout model. We identified the Tsc3 subunit of SPT as a regulator of amino acid substrate selectivity by demonstrating its primary function in promoting alanine utilization by SPT and confirmed its requirement for the inhibitory effect of alanine on SPT utilization of serine. Moreover, we observed downstream metabolic consequences to Tsc3 loss: serine influx into the SPL biosynthesis pathway increased through Ypk1-depenedent activation of SPT and ceramide synthases. This Ypk1-dependent activation of serine influx after Tsc3 knockout suggests a potential function for deoxy-sphingoid bases in modulating Ypk1 signaling.

Testicular torsion (TT) is the most common urological emergency in children and young adults that can lead to infertility in many cases. The ischemia-reperfusion (IR) injury due to TT has been implicated in the pathogenesis of testicular damage. The main pathological mechanisms of contralateral injury after ipsilateral TT are not fully understood. In the presented study, we investigated the molecular and microscopic basis of ipsilateral and contralateral testicular injury following ipsilateral testicular torsion detorsion (T/D) and explored the possible protective role of vitamin D3. The biochemical analysis indicated that IR injury following T/D significantly decreased the activity of testicular glutathione peroxidase (GPx) enzyme, level of serum testosterone, serum inhibin B, and expression of testicular miRNA145, while increased the activity of testicular myeloperoxidase (MPO) enzyme, level of testicular malondialdehyde (MDA), level of serum antisperm-antibody (AsAb), and expression of ADAM-17. The histological and semen analysis revealed that torsion of the testis caused damages on different tissues in testis. Interestingly, administration of vitamin D3 prior to the IR injury reversed the deterioration effect of IR injury on the testicular tissues as indicated by biochemical and histological analysis which revealed normal appearance of the seminiferous tubules with an apparent decrease in collagen fiber deposition in both ipsilateral and contralateral testes. Our results revealed that the protective effect of vitamin D3 treatment could be attributed to target miRNA145 and ADAM17 protein. To further investigate these findings, we performed a detailed molecular modelling study in order to explore the binding affinity of vitamin D3 toward ADAM17 protein. Our results revealed that vitamin D3 has the ability to bind to the active site of ADAM17 protein via a set of hydrophobic and hydrophilic interactions with high docking score. In conclusion, this study highlights the protective pharmacological application of vitamin D3 to ameliorate the damages of testicular T/D on the testicular tissues via targeting miRNA145 and ADAM17 protein.

In 2019, the world suffered from the emergence of COVID-19 infection, one of the most difficult pandemics in recent history. Millions of confirmed deaths from this pandemic have been reported worldwide. This disaster was caused by SARS-CoV-2, which is the last discovered member of the family of Coronaviridae. Various studies have shown that natural compounds have effective antiviral properties against coronaviruses by inhibiting multiple viral targets, including spike proteins and viral enzymes. This review presents the classification and a detailed explanation of the SARS-CoV-2 molecular characteristics and structure–function relationships. We present all currently available crystal structures of different SARS-CoV-2 proteins and emphasized on the crystal structure of different virus proteins and the binding modes of their ligands. This review also discusses the various therapeutic approaches for COVID-19 treatment and available vaccinations. In addition, we highlight and compare the existing data about natural compounds extracted from algae, fungi, plants, and scorpion venom that were used as antiviral agents against SARS-CoV-2 infection. Moreover, we discuss the repurposing of select approved therapeutic agents that have been used in the treatment of other viruses.

Cystic renal disease (CRD) comprises a heterogeneous group of genetic and acquired disorders. The cystic lesions are detected through imaging, either incidentally or after symptoms develop, due to an underlying disease process. In this study, we aim to study the metabolomic profiles of CRD patients for potential disease-specific biomarkers using unlabeled and labeled metabolomics using low and high-resolution mass spectrometry (MS), respectively. Dried-blood spot (DBS) and serum samples, collected from CRD patients and healthy controls, were analyzed using the unlabeled and labeled method. The metabolomics profiles for both sets of samples and groups were collected, and their data were processed using the lab’s standard protocol. The univariate analysis showed (FDR p < 0.05 and fold change 2) was significant to show a group of potential biomarkers for CRD discovery, including uridine diphosphate, cystine-5-diphosphate, and morpholine. Several pathways were involved in CRD patients based on the metabolic profile, including aminoacyl-tRNA biosynthesis, purine and pyrimidine, glutathione, TCA cycle, and some amino acid metabolism (alanine, aspartate and glutamate, arginine and tryptophan), which have the most impact. In conclusion, early CRD detection and treatment is possible using a metabolomics approach that targets alanine, aspartate, and glutamate pathway metabolites.

Magnesium oxide nanoparticles (MgO-NPs) were synthesized using the fungal strain Aspergillus terreus S1 to overcome the disadvantages of chemical and physical methods. The factors affecting the biosynthesis process were optimized as follows: concentration of Mg(NO3)2·6H2O precursor (3 mM), contact time (36 min), pH (8), and incubation temperature (35 °C). The characterization of biosynthesized MgO-NPs was accomplished using UV-vis spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy—energy dispersive X-ray (SEM-EDX), X-ray diffraction (XRD), and dynamic light scattering (DLS). Data confirmed the successful formation of crystallographic, spherical, well-dispersed MgO-NPs with a size range of 8.0–38.0 nm at a maximum surface plasmon resonance of 280 nm. The biological activities of biosynthesized MgO-NPs including antimicrobial activity, biotreatment of tanning effluent, and chromium ion removal were investigated. The highest growth inhibition of pathogenic Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans was achieved at 200 μg mL–1 of MgO-NPs. The biosynthesized MgO-NPs exhibited high efficacy to decolorize the tanning effluent (96.8 ± 1.7% after 150 min at 1.0 µg mL–1) and greatly decrease chemical parameters including total suspended solids (TSS), total dissolved solids (TDS), biological oxygen demand (BOD), chemical oxygen demand (COD), and conductivity with percentages of 98.04, 98.3, 89.1, 97.2, and 97.7%, respectively. Further, the biosynthesized MgO-NPs showed a strong potential to remove chromium ions from the tanning effluent, from 835.3 mg L–1 to 21.0 mg L–1, with a removal percentage of 97.5%.

Sphingolipids are ubiquitous in eukaryotic plasma membranes and play major roles in human and animal physiology and disease. This class of lipids is usually defined as being derivatives of sphingosine, a long-chain 1,3-dihydroxy-2-amino alcohol. Various pathological conditions such as diabetes or neuropathy have been associated with changes in the sphingolipidome and an increased biosynthesis of structurally altered non-canonical sphingolipid derivatives. These unusual or non-canonical sphingolipids hold great promise as potential diagnostic markers. However, due to their low concentrations and the unavailability of suitable standards, the research to explore the secret of this class of ‘Sphinx’ lipids is ultimately hampered. Therefore, the development of efficient and facile syntheses of standard compounds is a key endeavor. Here, we present various chemical approaches for stereoselective synthesis and in-depth chemical characterization of a set of novel sphingoid bases which were recently utilized as valuable tools to explore the metabolism and biophysical properties of sphingolipids, but also to develop efficient analytical methods for their detection and quantification.

The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D.

Epithelioid hemangioendothelioma (EHE) is a rare tumor that is vascular in origin, arising from the endothelial or preendothelial cells. It can occur at different sites of the body, commonly in the liver, lungs, and bone. Pulmonary EHE is usually symptomatic, sometimes presenting with a cough, dyspnea, or chest pain. Rarely, it presents with pleural effusion. Here, we are presenting a case of pleural epithelioid hemangioendothelioma presenting as a case of spontaneous bilateral hemothorax.

Herein, we report the synthesis of eight new mononuclear and binuclear Co2+, Ni2+, Cu2+, and Zn2+ methoxy thiosemicarbazone (MTSC) complexes aiming at obtaining thiosemicarbazone complex with potent biological activity. The structure of the MTSC ligand and its metal complexes was fully characterized by elemental analysis, spectroscopic techniques (NMR, FTIR, UV-Vis), molar conductivity, thermogravimetric analysis (TG), and thermal differential analysis (DrTGA). The spectral and analytical data revealed that the obtained thiosemicarbazone-metal complexes have octahedral geometry around the metal center, except for the Zn2+-thiosemicarbazone complexes, which showed a tetrahedral geometry. The antibacterial and antifungal activities of the MTSC ligand and its (Co2+, Ni2+, Cu2+, and Zn2+) metal complexes were also investigated. Interestingly, the antibacterial activity of MTSC- metal complexes against examined bacteria was higher than that of the MTSC alone, which indicates that metal complexation improved the antibacterial activity of the parent ligand. Among different metal complexes, the MTSC- mono- and binuclear Cu2+ complexes showed significant antibacterial activity against Bacillus subtilis and Proteus vulgaris, better than that of the standard gentamycin drug. The in silico molecular docking study has revealed that the MTSC ligand could be a potential inhibitor for the oxidoreductase protein.

Cyanobacteria are photosynthetic prokaryotic organisms which represent a significant source of novel, bioactive, secondary metabolites, and they are also considered an abundant source of bioactive compounds/drugs, such as dolastatin, cryptophycin 1, curacin toyocamycin, phytoalexin, cyanovirin-N and phycocyanin. Some of these compounds have displayed promising results in successful Phase I, II, III and IV clinical trials. Additionally, the cyanobacterial compounds applied to medical research have demonstrated an exciting future with great potential to be developed into new medicines. Most of these compounds have exhibited strong pharmacological activities, including neurotoxicity, cytotoxicity and antiviral activity against HCMV, HSV-1, HHV-6 and HIV-1, so these metabolites could be promising candidates for COVID-19 treatment. Therefore, the effective large-scale production of natural marine products through synthesis is important for resolving the existing issues associated with chemical isolation, including small yields, and may be necessary to better investigate their biological activities. Herein, we highlight the total synthesized and stereochemical determinations of the cyanobacterial bioactive compounds. Furthermore, this review primarily focuses on the biotechnological applications of cyanobacteria, including applications as cosmetics, food supplements, and the nanobiotechnological applications of cyanobacterial bioactive compounds in potential medicinal applications for various human diseases are discussed.