Search

Thrombin, also known as an active plasma coagulation factor II, belongs to the family of serine proteases and plays a crucial role in blood coagulation process. The process of thrombin generation is the central event of the hemostatic process and regulates blood coagulant activity. For this reason, thrombin inhibition is key to successful novel antithrombotic pharmacotherapy. The aim of our present study was to examine the effects of the well-known polyphenolic compounds on the activity of thrombin, by characterization of its interaction with selected polyphenols using different biochemical methods and biosensor BIAcore analyses. Only six compounds, cyanidin, quercetin, silybin, cyanin, (+)-catechin and (−)-epicatechin, of all examined in this study polyphenols caused the inhibition of thrombin amidolytic activity. But only three of the six compounds (cyanidin, quercetin and silybin) changed thrombin proteolytic activity. BIAcore analyses demonstrated that cyanidin and quercetin caused a strong response in the interaction with immobilized thrombin, while cyanin and (−)-epicatechin induced a low response. Lineweaver-Burk curves show that used polyphenol aglycones act as competitive thrombin inhibitors. Our results suggest that polyphenolic compounds might be potential structural bases and source to find and project nature-based, safe, orally bioavailable direct thrombin inhibitors. [ABSTRACT FROM AUTHOR]

The effect of repeated treatment with various antidepressant drugs on the reactivity of CA1 neurons to the 5-HT receptor agonist zacopride was examined. Zacopride decreased the calcium-activated afterhyperpolarization and adaptation, it also elicited a slow membrane depolarization associated with an increase in input resistance. All those effects may have contributed to the zacopride-induced increase in the amplitude of population spikes, evoked in the CA1 cell layer by stimulation of the Schaffer collateral/commissural pathway. The later effect of zacopride was concentration-dependent and was antagonized by the 5-HT receptor antagonist DAU 62805. Repeated (14 days, twice daily), but not single, administration of the antidepressant drugs imipramine, citalopram, fluvoxamine and paroxetine (10 mg/kg) attenuated the effect of zacopride on population spikes. Because inhibitory 5-HT and excitatory 5-HT receptors are colocalized on pyramidal neurons, and our previous data demonstrated an increase in the 5-HT receptor-mediated inhibition after repeated treatment with antidepressants, we conclude that treatment with antidepressant drugs may enhance the inhibitory effect of 5-HT directly, by increasing the 5-HT receptor responsiveness, and indirectly, by inducing subsensitivity to the 5-HT receptor activation. [ABSTRACT FROM AUTHOR]

Evidence suggests that metabotropic glutamate receptors (mGluR) are involved in mediating seizures and epileptogenesis. In the present experiments, the selective, group II mGluR agonist (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid (LY354740, 0.1–1.0 µM) inhibited spontaneous epileptiform discharges which developed in rat cortical slices in Mg2+- free medium. LY354740 (4–16 mg/kg) administered prior to an injection of pentylenetetrazol (80 mg/kg) or picrotoxin (3.2 mg/kg) produced a dose-dependent decrease in the number of mice exhibiting clonic convulsions, but had no effect on N-methyl-d-aspartate (NMDA, 150 mg/kg)-induced convulsions. LY354740 (4–16 mg/kg) did not affect lethality induced in mice by pentylenetetrazol, picrotoxin or NMDA. LY354740 potentiated the anticonvulsant activity of the conventional antiepileptic drug diazepam, significantly decreasing the ED50 for that drug's effect on pentylenetetrazol-induced convulsions by 30%, but had no influence on anticonvulsant activity of ethosuximide and valproic acid. A pharmacokinetic interaction between LY354740 and diazepam, leading to the lowering of the plasma level of free diazepam, was also demonstrated. Our data suggest that the group II mGluR agonist LY354740 possesses anti-seizure activity and may modify the effects of some conventional antiepileptic drugs. [ABSTRACT FROM AUTHOR]

This study aimed to determine the longitudinal predictors of lifestyle behaviours among stroke survivors in New South Wales, Australia. This longitudinal study utilised data from the baseline survey (2005–2009) and a sub-study survey (2017) of the 45 and Up Study. Physical activity, alcohol consumption, smoking status, and supplement use were included as dependent variables. Generalised estimating equation models were employed to assess the longitudinal association between the dependent variable and demographic and health status measures. The average age of the participants (n = 576) was 67 (SD = 9) years at baseline and 76 (SD = 9) years at the sub-study survey time, with 54.9% being male. The longitudinal analysis revealed that the likelihood of moderate/high physical activity significantly declined over time and was lower among participants with diabetes, but was higher among those with university education. The likelihood of smoking was significantly higher in females, moderate/high-risk alcohol consumers, and those with depression, but was lower among supplement users. The likelihood of moderate/high-risk alcohol consumption significantly declined with time, and was lower among females, but higher among smokers. The likelihood of supplement use significantly declined over time, but was higher among females and/or those with asthma. Our findings help illustrate that many stroke survivors may benefit from further support in adopting and maintaining a healthy lifestyle as part of their stroke management and long-term rehabilitation, which is crucial to optimising their quality of life and successful secondary stroke prevention. [ABSTRACT FROM AUTHOR]

Fibrinogen, a blood plasma protein with a key role in hemostasis and thrombosis, is highly susceptible to post-translational modifications (PTMs), that significantly influence clot formation, structure, and stability. These PTMs, which include acetylation, amidation, carbamylation, citrullination, dichlorination, glycation, glycosylation, guanidinylation, hydroxylation, homocysteinylation, malonylation, methylation, nitration, oxidation, phosphorylation and sulphation, can alter fibrinogen biochemical properties and affect its functional behavior in coagulation and fibrinolysis. Oxidation and nitration are notably associated with oxidative stress, impacting fibrin fiber formation and promoting the development of more compact and resistant fibrin networks. Glycosylation and glycation contribute to altered fibrinogen structural properties, often resulting in changes in fibrin clot density and susceptibility to lysis, particularly in metabolic disorders like diabetes. Acetylation and phosphorylation, influenced by medications such as aspirin, modulate clot architecture by affecting fiber thickness and clot permeability. Citrullination and homocysteinylation, although less studied, are linked to autoimmune conditions and cardiovascular diseases, respectively, affecting fibrin formation and stability. Understanding these modifications provides insights into the pathophysiology of thrombotic disorders and highlights potential therapeutic targets. This review comprehensively examines the current literature on fibrinogen PTMs, their specific sites, biochemical pathways, and their consequences on fibrin clot architecture, clot formation and clot lysis. [ABSTRACT FROM AUTHOR]

Medical waste management is a crucial issue due to its potential health risks to humans and harm to the environment. The World Health Organization (WHO) advises separating medical waste into seven groups based on its type. However, despite the implementation of color-coded bin bags, cases of missegregation still occur frequently, leading to injuries and spreading diseases. Infectious waste such as sharps, human tissue, and body parts are often found mixed in waste bins, posing a severe threat to waste employees. To address this issue, this paper proposes exploring the potential of digitalization in waste segregation. The literature on current segregation methods and technology applications is analysed and compared, and a framework for utilizing barcode tagging and scanning to ensure waste is correctly categorized is presented. The barcodes and scanner will be connected through a monitoring system, which can notify waste generators and collectors of misplacing or mixed waste. This digitalization system is expected to serve as a monitoring agent for segregating waste before it is collected from any health facilities. Additionally, the exchanged data from waste generator bins can inform collectors and other waste stakeholders about the waste's condition, potentially opening up opportunities for recycling companies to purchase used plastics or metals from hospital wastes. By implementing digitalization in medical waste management, waste segregation can improve, reduce the spread of diseases and injuries, and promote the recycling of hospital waste materials. [ABSTRACT FROM AUTHOR]

This study explored the effect of geographical and floral origins on the antioxidant activities of Saudi honey samples related to their content of short peptides originated from honeybee proteins. The studied antioxidants were the total protein concentration, catalase activity, phenolic acids and flavonoids. The antioxidant activity assays included were the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, the ferric reducing antioxidant power (FRAP) assay and Ascorbic acid Equivalent Antioxidant Capacity (AEAC). The studied honey samples were obtained from the southwestern region of Saudi Arabia, namely Asir (65) and Jazan (25). The floral origins of the honey samples were Acacia (51), Ziziphus (4) and polyfloral (35). The LC/MS technique was used to detect the short peptides and the mascot database was used to identify the short peptides, their precursor proteins and the protease enzymes that produce them. Jazan honey was characterized by high number of short peptides. The short peptides were originated from honeybee proteins by the action of proteases from the honeybees and bacteria. The antioxidant activity of the honey samples increase with the increase of their content of short peptides and proteins. The amino acids type and sequence of the short peptides qualify them to act as antioxidant, antimicrobial, anti-diabetic, anti-hypertension, immunomodulatory and cholesterol lowering peptides. [ABSTRACT FROM AUTHOR]

Emerging research on the microbiome highlights the significant role of gut health in the development of kidney stones, indicating that an imbalance in gut bacteria or dysbiosis can influence the formation of stones by altering oxalate metabolism and urinary metabolite profiles. In particular, the overabundance of specific bacteria such as Enterococcus and Oxalobacter spp., which are known to affect oxalate absorption, is observed in patients with urolithiasis. This study investigates the effects of gut dysbiosis on urolithiasis through fecal microbiota transplantation (FMT) from patients to rats and its impact on urinary mineral excretion and stone formation. Fecal samples from eight patients with calcium oxalate stones and ten healthy volunteers were collected to assess the gut microbiome. These samples were then transplanted to antibiotic-pretreated Wistar rats for a duration of four weeks. After transplantation, we evaluated changes in the fecal gut microbiome profile, urinary mineral excretion rates, and expression levels of intestinal zonula occluden-1 (ZO-1), SLC26A6 and renal NF-κB. In humans, patients with urolithiasis exhibited increased urinary calcium and oxalate levels, along with decreased citrate excretion and increased urinary supersaturation index. The fecal microbiota showed a notable abundance of Bacteroidota. In rodents, urolithiasis-FMT rats showed urinary disturbances similar to patients, including elevated pH, oxalate level, and supersaturation index, despite negative renal pathology. In addition, a slight elevation in the expression of renal NF-κB, a significant intestinal SLC26A6, and a reduction in ZO-1 expression were observed. The gut microbiome of urolithiasis-FMT rats showed an increased abundance of Bacteroidota, particularly Muribaculaceae, compared to their healthy FMT counterparts. In conclusion, the consistent overabundance of Bacteroidota in both urolithiasis patients and urolithiasis-FMT rats is related to altered intestinal barrier function, hyperoxaluria, and renal inflammation. These findings suggest that gut dysbiosis, characterized by an overgrowth of Bacteroidota, plays a crucial role in the pathogenesis of calcium oxalate urolithiasis, underscoring the potential of targeting the gut microbiota as a therapeutic strategy. [ABSTRACT FROM AUTHOR]

The interplay between crystals and epithelial cells forms the cornerstone of kidney stone development, communication between epithelial cells and macrophages emerging as a pivotal role in this process. We conducted next-generation sequencing on the secreted exosomes of TCMK-1 cells treated with calcium oxalate monohydrate (OX_EXO) or controls (NC_EXO), and on the macrophage cell line RAW264.7 stimulated with OX_EXO or NC_EXO, followed by validation of differentially expressed target proteins and miRNAs through Western blot and PCR. UPSET plots were employed to identify genes co-targeted by exosomal miRNAs. Various bioinformatic analyses were employed to predict potential mechanisms of the dysregulated genes. We integrated sequencing data from the GEO database, and validated findings using clinical patient urine and kidney tissues. We identified 665 differentially expressed exosomal miRNAs between OX_EXO and NC_EXO. Among the top 10 down-regulated miRNAs, the most targeted genes were AAK1 and NUFIP2, whereas PLCB1 was significantly targeted among the top 10 up-regulated miRNAs. In clinical specimens, we confirmed the differential expressions of five homologous miRNAs, as well as CNOT3, CNCNA1C, APEX1, and TMEM199. In conclusion, treatment of TCMK-1 cells with calcium oxalate significantly alerted the expression profile of exosomal miRNAs, subsequently influencing gene expression in macrophages, thereby modulating the processes of kidney stone formation. [ABSTRACT FROM AUTHOR]

The causal relationship between lipid levels and bladder cancer is still inconclusive currently. We aimed to reveal the causal relationship between triglycerides, HDL, and LDL and the risk of bladder cancer by univariable and multivariable Mendelian randomization (MR) analysis. The single nucleotide polymorphisms (SNPs) of exposure (triglycerides: 441,016 samples; HDL: 403,943 samples; LDL: 440,546 samples) were obtained from UK Biobank. The Genetic variation related to bladder cancer included 1554 cases and 359,640 controls. Univariable and multivariable MR methods were conducted with subsequent analysis, and smoking was regarded as a confounder. The inverse-variance weighted (IVW), MR-Egger, weighted-median method, Cochran's Q test, and MR-PRESSO were considered the main MR analysis and sensitivity analysis methods. Univariable MR analysis results suggested the triglycerides level (P = 0.011, OR = 1.001, 95% CI = 1.000–1.002) was causally associated with increased risk of bladder cancer. Multivariable MR results indicated that higher triglyceride levels could still increase the risk of bladder cancer after adjusting the effects of HDL, LDL, and smoking (P = 0.042, OR = 1.001, 95% CI = 1.000–1.002). Our findings supported that triglyceride level is causally associated with an increased risk of bladder cancer independent of LDL and HDL at the genetic level. Timely attention to changes in blood lipid levels might reduce the risk of bladder cancer. [ABSTRACT FROM AUTHOR]

Heavy metal toxicity is associated with cancer progression. Studies have reported the relation between some metal ions and bladder cancer (BC). Direct influence of such agents in bladder carcinogenesis is still needed. Total 49 BC patients were included in the study. Level of Pb, Cr, Hg and Cd, oxidative stress markers, and gene expression of Bcl-2, Bax, IL-6, AKT, and P38 genes were detected in cancer and non-cancerous tissues obtained from bladder cancer patients. Concentrations of Pb, Cr, and Cd were significantly elevated in cancer tissues than normal, while Hg level was significantly increased in normal tissue than cancer. MDA level was significantly higher and SOD activity was lower in the cancer tissues compared to non-cancerous. The expressions of Bcl-2, IL-6, AKT, and P38 were significantly increased in the cancer tissues than in normal tissues while Bax level was significantly increased in non-cancerous tissue than in cancer tissue. In cancer tissue, there were significant correlations between Cr level with expression of Bax, AKT, and P38 while Cd level was significantly correlate with Bax, IL-6, AKT, and P38expression. The correlation between Cr and Cd with the expression of Bax, IL-6, AKT, and P38 may indicate a carcinogenic role of these metals on progression of bladder cancer. [ABSTRACT FROM AUTHOR]

Neutrophil-activating peptide 2 (NAP-2, CXCL7), a platelet-derived neutrophil chemoattractant, is involved in inflammation. We investigated associations between NAP-2 levels, neutrophil extracellular traps (NETs) formation, and fibrin clot properties in atrial fibrillation (AF). We recruited 237 consecutive patients with AF (mean age, 68 ± 11 years; median CHA2DS2VASc score of 3 [2–4]) and 30 apparently healthy controls. Plasma NAP-2 concentrations were measured, along with plasma fibrin clot permeability (Ks) and clot lysis time (CLT), thrombin generation, citrullinated histone H3 (citH3), as a marker of NETs formation, and 3-nitrotyrosine reflecting oxidative stress. NAP-2 levels were 89% higher in AF patients than in controls (626 [448–796] vs. 331 [226–430] ng/ml; p < 0.0001). NAP-2 levels were not associated with demographics, CHA2DS2-VASc score, or the AF manifestation. Patients with NAP-2 in the top quartile (> 796 ng/ml) were characterized by higher neutrophil count (+ 31.7%), fibrinogen (+ 20.8%), citH3 (+ 86%), and 3-nitrotyrosine (+ 111%) levels, along with 20.2% reduced Ks and 8.4% prolonged CLT as compared to the remaining subjects (all p < 0.05). NAP-2 levels were positively associated with fibrinogen in AF patients (r = 0.41, p = 0.0006) and controls (r = 0.65, p < 0.01), along with citH3 (r = 0.36, p < 0.0001) and 3-nitrotyrosine (r = 0.51, p < 0.0001) in the former group. After adjustment for fibrinogen, higher citH3 (per 1 ng/ml β = -0.046, 95% CI -0.029; -0.064) and NAP-2 (per 100 ng/ml β = -0.21, 95% CI -0.14; -0.28) levels were independently associated with reduced Ks. Elevated NAP-2, associated with increased oxidative stress, has been identified as a novel modulator of prothrombotic plasma fibrin clot properties in patients with AF. [ABSTRACT FROM AUTHOR]

Fruit seeds are leftovers from a variety of culinary sectors. They are generally unutilized and contribute greatly to global disposals. These seeds not only possess various nutritional attributes but also have many heath-beneficial properties. One way to make use of these seeds is to extract their bioactive components and create fortified food items. Nowadays, researchers are highly interested in creating innovative functional meals and food components from these unconventional resources. The main objective of this manuscript was to determine the usefulness of seed powder from 70 highly consumed fruits, including Apple, Apricot, Avocado, Banana, Blackberry, Blackcurrant, Blueberry, Cherry, Common plum, Cranberry, Gooseberry, Jackfruit, Jamun, Kiwi, Lemon, Mahua, Mango, Melon, Olive, Orange, and many more have been presented. The nutritional attributes, phytochemical composition, health advantages, nanotechnology applications, and toxicity of these fruit seeds have been fully depicted. This study also goes into in-depth detailing on creating useful food items out of these seeds, such as bakery goods, milk products, cereal-based goods, and meat products. It also identifies enzymes purified from these seeds along with their biochemical applications and any research openings in this area. [ABSTRACT FROM AUTHOR]

Immunotherapy based on immune checkpoint genes (ICGs) has recently made significant progress in the treatment of bladder cancer patients, but many patients still cannot benefit from it. In the present study, we aimed to perform a comprehensive analysis of ICGs in bladder cancer tissues with the aim of evaluating patient responsiveness to immunotherapy and prognosis. We scored ICGs in each BLCA patient from TCGA and GEO databases by using ssGSEA and selected genes that were significantly associated with ICGs scores by using the WCGNA algorithm. NMF clustering analysis was performed to identify different bladder cancer molecular subtypes based on the expression of ICGs-related genes. Based on the immune related genes differentially expressed among subgroups, we further constructed a novel stratified model containing nine genes by uni-COX regression, LASSO regression, SVM algorithm and multi-COX regression. The model and the nomogram constructed based on the model can accurately predict the prognosis of bladder cancer patients. Besides, the patients classified based on this model have large differences in sensitivity to immunotherapy and chemotherapy, which can provide a reference for individualized treatment of bladder cancer. [ABSTRACT FROM AUTHOR]

Gene therapy represents a significant potential to revolutionize the field of hematology with applications in correcting genetic mutations, generating cell lines and animal models, and improving the feasibility and efficacy of cancer immunotherapy. Compared to different genetic engineering tools, clustered regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated protein 9 (Cas9) emerged as an effective and versatile genetic editor with the ability to precisely modify the genome. The applications of genetic engineering in various hematological disorders have shown encouraging results. Monogenic hematological disorders can conceivably be corrected with single gene modification. Through the use of CRISPR-CAS9, restoration of functional red blood cells and hemostasis factors were successfully attained in sickle cell anemia, beta-thalassemia, and hemophilia disorders. Our understanding of hemato-oncology has been advanced via CRIPSR-CAS9 technology. CRISPR-CAS9 aided to build a platform of mutated genes responsible for cell survival and proliferation in leukemia. Therapeutic application of CRISPR-CAS9 when combined with chimeric antigen receptor (CAR) T cell therapy in multiple myeloma and acute lymphoblastic leukemia was feasible with attenuation of CAR T cell therapy pitfalls. Our review outlines the latest literature on the utilization of CRISPR-Cas9 in the treatment of beta-hemoglobinopathies and hemophilia disorders. We present the strategies that were employed and the findings of preclinical and clinical trials. Also, the review will discuss gene engineering in the field of hemato-oncology as a proper tool to facilitate and overcome the drawbacks of chimeric antigen receptor T cell therapy (CAR-T). [ABSTRACT FROM AUTHOR]

Respiratory diseases caused by viruses are a serious global health threat. Although the use of hand sanitizers containing alcohol and synthetic antiseptic agents is recognized as an effective, simple, and low-cost measure to combat viral transmission, they can harm human health and the environment. Thus, this work aimed to study the efficacy of combining Camellia sinensis and Chamomilla recutita extracts in a skin- and eco-friendly leave-on hand sanitizer to prevent the spread of respiratory viruses. An oil-in-water emulsion containing C. recutita oily extract (5.0%), C. recutita glycolic extract (0.2%) and C. sinensis glycolic extract (5.0%) showed virucidal activity against HAdV-2 (respiratory virus) and two surrogate viruses of SARS-CoV-2 (HSV-1 and MVH-3), showing great potential to prevent the spread of respiratory viruses. These natural extracts combined are also promising to combat a broad spectrum of other viruses, in the form of antiseptic mouthwashes or throat sprays, surface disinfectants, and veterinary products, among others. Complementally, the developed hand sanitizer demonstrated efficacy against bacteria and fungus. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an incurable chronic neurodegenerative disease where autoimmunity, oxidative stress, and neuroinflammation collaboration predispose myelin sheath destruction. Interestingly, curcumin, a natural polyphenol, showed a neuroprotective effect in numerous neurodegenerative diseases, including MS. Nevertheless, the influence of curcumin against MS-induced cognitive impairment is still vague. Hence, we induced experimental autoimmune encephalomyelitis (EAE) in mice using spinal cord homogenate (SCH) and complete Freund's adjuvant, which eventually mimic MS. This study aimed not only to evaluate curcumin efficacy against EAE-induced cognitive and motor dysfunction, but also to explore a novel mechanism of action, by which curcumin exerts its beneficial effects in MS. Curcumin (200 mg/kg/day) efficacy was evaluated by behavioral tests, histopathological examination, and biochemical tests. Concisely, curcumin amended EAE-induced cognitive and motor impairments, as demonstrated by the behavioral tests and histopathological examination of the hippocampus. Interestingly, curcumin activated the adenosine monophosphate (AMP)-activated protein kinase/silent mating type information regulation 2 homolog 1 (AMPK/SIRT1) axis, which triggered cyclic AMP response element-binding protein/brain-derived neurotrophic factor/myelin basic protein (CREB/BDNF/MBP) pathway, hindering demyelination of the corpus callosum. Furthermore, AMPK/SIRT1 activation augmented nuclear factor erythroid 2-related factor 2 (Nrf2), a powerful antioxidant, amending EAE-induced oxidative stress. Additionally, curcumin abolished EAE-induced neuroinflammation by inhibiting Janus kinase 2 /signal transducers and activators of transcription 3 (JAK2/STAT3) axis, by various pathways, including AMPK/SIRT1 activation. JAK2/STAT3 inhibition halts inflammatory cytokines synthesis. In conclusion, curcumin's neuroprotective effect in EAE is controlled, at least in part, by AMPK/SIRT1 activation, which ultimately minimizes EAE-induced neuronal demyelination, oxidative stress, and neuroinflammation. Graphical illustration of putative molecular pathways implicated in the management of EAE by curcumin. Curcumin activates AMPK/SIRT1, which in turn activates multiple pathways that hinder neurodegeneration, oxidative stress, and neuroinflammation. Moreover, curcumin conquers the inflammatory pathway JAK2/STAT3/NF-kβ. [ABSTRACT FROM AUTHOR]