The effect of Astragali Radix-Radix Angelica Sinensis on acute kidney injury: a network pharmacology and molecular docking study.

Background: Acute kidney injury (AKI) is a devastating clinical syndrome with high mortality rate attributed to lack of effective treatment. The herbal pair of Astragali Radix (AR) and Radix Angelica Sinensis (RAS) is a commonly prescribed herbal formula or is added to other traditional Chinese medicine (TCM) prescriptions for the treatment of kidney diseases. AR-RAS has certain protective effects on AKI in experiments, but the relevant mechanisms have yet to be clear. So this study aims to explore the mechanism of action of AR-RAS in AKI by combining network pharmacology and molecular docking methods. Methods: In Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), the major AR-RAS chemical components and associated action targets were found and screened. The DrugBank and GeneCards databases were used to find AKI-related targets. The targets that are in close relationship with AKI were obtained from Therapeutic Target database (TTD), Online Mendelian Inheritance in Man (OMIM), and PharmGKB databases. The "herb-active ingredient-target" network was drawn by Cytoscape 3.8.0 software. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to build the protein-protein interaction network. Bioconductor/R was used to examine Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. AR-RAS components and critical targets were docked using the AutoDock Vina program. Results: A compound-target network, built by screening and analyzing the results, allowed to identify 19 active components and 101 possible therapeutic targets for AKI. The main ingredients were quercetin, kaempferol, 7-o-methylisocronulatol, formononetin and isorhamnetin. The key targets included AKT serine/threonine kinase 1 (AKT1), nuclear receptor coactivator 1 (NCOA1), JUN, estrogen receptor alpha (ESR1) and mitogen-activated protein kinase 8 (MAPK8). These molecules are targeted by pathways such as the calcium signaling route, the tumor necrosis factor (TNF) signaling pathway and the interleukin-17 (IL-17) signaling pathway, as well as the development of T helper 17 cells. Molecular docking demonstrated that AR-active RAS components exhibited strong binding activities to probable targets of AKI. Conclusions: We described here the potential active ingredients, possible targets responsible for the efficacy of AR-RAS in AKI treatment, providing a theoretical basis for further research.

Serum Vitamin D Concentration Is Lower in Patients with Tinnitus: A Meta-Analysis of Observational Studies.

BACKGROUND: Tinnitus is a highly prevalent and frequently disabling condition, such that the identification of possible causal mechanisms would yield significant clinical and social benefits. Since vitamin D (Vit D) is involved in the pathogenesis of several ear disturbances, we review here the current scientific literature addressing the relationship between Vit D status and tinnitus. METHODS: An electronic search was conducted in PubMed, Scopus and Web of Science with the keywords "tinnitus" and "Vitamin D" or "Vit D" or "25OH-D" or "cholecalciferol" or "ergocalciferol" or "hydroxycholecalciferol", without date (i.e., up to 8 February 2023) or language restrictions, in accordance with a protocol based on the transparent reporting of systematic reviews and meta-analysis (PRISMA) 2020 checklist, for identifying studies which assayed serum Vit D concentration in patients with or without tinnitus. RESULTS: Three observational, case-control studies encompassing four cohorts and totaling 468 patients with (n = 268) or without tinnitus (n = 200) were included in this meta-analysis. Pooled analysis with quality effects models evidenced significantly reduced serum Vit D levels in patients with tinnitus compared to those without (weighted mean difference [WMD], -6.2 ng/mL; 95% CI, -10.3 to -2.1 ng/mL; I2, 56%). Serum Vit D was found to be 22% lower in patients with tinnitus compared to those without. CONCLUSIONS: Lower serum Vit D levels may be associated with tinnitus, thus paving the way to plan future trials aimed at exploring whether Vit D supplementation may aid in preventing and/or improving tinnitus.

Do Antioxidant Vitamins Prevent Exercise-Induced Muscle Damage? A Systematic Review.

Free radicals produced during exercise play a role in modulating cell signaling pathways. High doses of antioxidants may hamper adaptations to exercise training. However, their benefits are unclear. This review aims to examine whether vitamin C (VitC) and/or vitamin E (VitE) supplementation (SUP) prevents exercise-induced muscle damage. The PubMed, Web of Science, Medline, CINAHL, and SPORTDiscus databases were searched, and 21 articles were included. Four studies examined the effects of acute VitC SUP given pre-exercise: in one study, lower CK levels post-exercise was observed; in three, no difference was recorded. In one study, acute VitE SUP reduced CK activity 1 h post-exercise in conditions of hypoxia. In three studies, chronic VitE SUP did not reduce CK activity after an exercise session. Chronic VitE SUP did not reduce creatine kinase (CK) concentrations after three strength training sessions, but it was effective after 6 days of endurance training in another study. Chronic SUP with VitC + E reduced CK activity post-exercise in two studies, but there was no such effect in four studies. Finally, three studies described the effects of chronic VitC + E SUP and long-term exercise, reporting dissimilar results. To conclude, although there is some evidence of a protective effect of VitC and/or VitE against exercise-induced muscle damage, the available data are not conclusive.

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis.

Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

Kiwifruit and Cancer: An Overview of Biological Evidence.

Kiwifruit consumption is associated with many favorable health benefits. This article is hence aimed to provide an overview on potential effects of kiwifruit on cancer development or progression. An electronic search was performed in Medline and Web of Science, for identifying original studies exploring the relationship between kiwifruit and cancer development or progression, both in vivo and in vitro. The following keywords were used: "Kiwifruit" OR "Kiwi" OR "Actinidia deliciosa" OR "Actinidia chinensis," in combination with "cancer" OR "malignancy" OR "neoplasm." Overall, 58 items could be retrieved, fifty of which were excluded since they did not fulfilled all our search criteria. Eight studies (five in vitro studies, two human intervention trials, and one both in vivo and in human study) were finally included in this critical literature review. Taken together, the results of these published studies suggest that kiwifruit supplementation may be associated with direct and indirect anticancer effects, the former likely due to ascorbic acid-mediated reduction of DNA oxidative injury and cytotoxic effect on cancer cell lines, the latter more likely attributable to enhanced daily bowel movements and increased intestinal fecal content of lactic acid bacteria, which would finally contribute to lower the risk of malignancies, especially colorectal cancer.

Neuromuscular Electrical Stimulation: A New Therapeutic Option for Chronic Diseases Based on Contraction-Induced Myokine Secretion.

Myokines are peptides known to modulate brain neuroplasticity, adipocyte metabolism, bone mineralization, endothelium repair and cell growth arrest in colon and breast cancer, among other processes. Repeated skeletal muscle contraction induces the production and secretion of myokines, which have a wide range of functions in different tissues and organs. This new role of skeletal muscle as a secretory organ means skeletal muscle contraction could be a key player in the prevention and/or management of chronic disease. However, some individuals are not capable of optimal physical exercise in terms of adequate duration, intensity or muscles involved, and therefore they may be virtually deprived of at least some of the physiological benefits induced by exercise. Neuromuscular electrical stimulation (NMES) is emerging as an effective physical exercise substitute for myokine induction. NMES is safe and efficient and has been shown to improve muscle strength, functional capacity, and quality of life. This alternative exercise modality elicits hypertrophy and neuromuscular adaptations of skeletal muscles. NMES stimulates circulating myokine secretion, promoting a cascade of endocrine, paracrine, and autocrine effects. We review the current evidence supporting NMES as an effective physical exercise substitute for inducing myokine production and its potential applications in health and disease.

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art.

Anticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59-7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.

Vitamin D and Gastrointestinal Cancers: A Narrative Review.

Calcitriol (1,25(OH)2D3) performs various activities throughout the body. Although low serum 25-hydroxyvitamin D [25(OH)D] levels are associated with several disease processes such as risk of fractures and falls, hypertension, cardiovascular disease, and diabetes mellitus, recent evidence attests that this important hormone also regulates several cellular pathways involved in cancer development and progression. Calcitriol modulates several genes controlling gut physiology and calcium homeostasis and also maintains the integrity of epithelial barriers, regulates the absorption of phosphate and calcium, and modulates host defense against pathogens and inflammatory response by interplaying with several types of secretory and immune cells. Vitamin D deficiency is significantly related to increased risk of developing certain types of cancer. This deficiency can be prevented by vitamin D supplementation which is both economical and safe. This can lower the risk of developing cancer and also improve the prognosis of patients with gastrointestinal malignancy, but epidemiological data remain inconsistent. Several retrospective observational studies have demonstrated the benefits of vitamin D supplementation, but a few randomized controlled trials have not seemingly supported the beneficial role of vitamin D supplementation in gastrointestinal cancers. Therefore, in this literature review, we aimed to examine the possible role of vitamin D in gastrointestinal malignancies, including gastric, esophageal, pancreatic, hepatic, and colorectal cancers.

Diabetes alert dogs: a narrative critical overview.

Owing to their virtually incomparable olfactory apparatus and the mutual loving relationship with man, the use of dogs for assisting humans in many activities has become commonplace. Dogs have been used for long for livestock herding, hunting and pulling. More recently, they have been employed for servicing or assisting people with disabilities, for rescuing, for pet therapy and, last but not least, for detecting a vast array of volatile organic compounds related to drugs, narcotics, explosives and foods. Although cancer detection seems the most distinguished use of "man's best friends" in science and medicine, increasing emphasis is being placed on their capacity to perceive chemical changes or human expressions associated with harmful, even life-threating, blood glucose variations. The evidence available in the current scientific literature attests that diabetes alerting dogs (DADs) have a heterogeneous efficiency for warning owners of episodes of hypoglycemia or hyperglycemia, with sensitivities and specificities ranging between 0.29-0.80 and 0.49-0.96, respectively. Although the adoption of DADs seems effective for improving the quality of life of many diabetics patients, some important drawbacks can be highlighted. These typically include adoption and keeping expenditures, lack of certification or accreditation of dog providers, poor harmonization of training procedures, significant inter-breed, intra-breed and intra-dog variabilities, wide-ranging alert behaviors, ability of owners to identify dog's alerts, as well as lack of quality assessment of a dog's "diagnostic" performance. Overcoming many of these limitations shall probably make DADs more efficient tools for improving diabetes management.

Natural approaches in metabolic syndrome management.

Metabolic syndrome (MetS) is characterized as a group of cardiometabolic risk factors that raise the risk for heart disease and other health problems, such as diabetes mellitus and stroke. Treatment strategies include pharmacologic interventions and supplementary (or "alternative") treatments. Nutraceuticals are derived from food sources (isolated nutrients, dietary supplements and herbal products) that are purported to provide health benefits, in addition to providing basic nutritional value. Nutraceuticals are claimed to prevent chronic diseases, improve health, delay the aging process, increase life expectancy, and support the structure and function of the body. The study of the beneficial effects of nutraceuticals in patients with MetS, including product standardization, duration of supplementation and definition of optimal dosing, could help better define appropriate treatment. This review focuses on widely marketed nutraceuticals (namely polyphenols, omega-3 fatty acids, macroelements and vitamins) with clinically demonstrated effects on more than one component of MetS.

ß-Sitosterol Reduces the Expression of Chemotactic Cytokine Genes in Cystic Fibrosis Bronchial Epithelial Cells.

Extracts from Nigella arvensis L. seeds, which are widely used as anti-inflammatory remedies in traditional medicine of Northern Africa, were able to inhibit the expression of the pro-inflammatory neutrophil chemokine Interleukin (IL)-8 in Cystic Fibrosis (CF) bronchial epithelial IB3-1 cells exposed to the Gram-negative bacterium Pseudomonas aeruginosa. The chemical composition of the extracts led to the identification of three major components, ß-sitosterol, stigmasterol, and campesterol, which are the most abundant phytosterols, cholesterol-like molecules, usually found in plants. ß-sitosterol (BSS) was the only compound that significantly reproduced the inhibition of the P. aeruginosa-dependent expression of IL-8 at nanomolar concentrations. BSS was tested in CF airway epithelial CuFi-1 cells infected with P. aeruginosa. BSS (100 nM), showed a significant and consistent inhibitory activity on expression of the P. aeruginosa-stimulated expression chemokines IL-8, GRO-α GRO-ß, which play a pivotal role in the recruitment of neutrophils in CF inflamed lungs. Preliminary mechanistic analysis showed that BSS partially inhibits the P. aeruginosa-dependent activation of Protein Kinase C isoform alpha, which is known to be involved in the transmembrane signaling activating IL-8 gene expression in bronchial epithelial cells. These data indicate BSS as a promising molecule to control excessive lung inflammation in CF patients.

Impact of experimental hypercalcemia on routine haemostasis testing.

BACKGROUND: The blood to anticoagulant ratio is standardized according to the physiological calcium concentration in blood samples conventionally used for hemostasis testing. Specifically, one fixed volume of 0.109 mmol/L sodium citrate is added to 9 volumes of blood. Since little is known about the impact of hypercalcemia on the calcium-binding capacity of citrate, this study was planned to investigate the effect of experimental hypercalcemia on routine hemostasis testing. METHODS: Fifteen pooled citrated plasmas with matching lithium-heparin pooled plasma from patients with different values of prothrombin time (PT) were divided in three aliquots of 0.6mL each. The first paired aliquots of both citrate and lithium-heparin plasma were supplemented with 60µL of saline, the second paired aliquots with 30µL of saline and 30µL of calcium chloride and the third paired aliquots with 60µL of calcium chloride. Total and ionized calcium was measured in all aliquots of citrate and lithium-heparin plasma, whereas PT, activated partial thromboplastin time (APTT) and fibrinogen were measured in citrate plasma aliquots. RESULTS: Total calcium concentration gradually increased in both lithium-heparin and citrate plasma aliquots 2 and 3 compared to baseline aliquot 1. The concentration of ionized calcium also gradually increased in lithium-heparin plasma aliquots 2 and 3, whereas it remained immeasurable (i.e., <0.10 mmol/L) in all citrate plasma aliquots. No significant differences were observed for values of PT, APTT and fibrinogen in citrate plasma aliquots 2 and 3 compared to the baseline aliquot 1, with a mean bias was always comprised within the desirable quality specifications derived from biological variability data. CONCLUSION: Hypercalcemia, up to severe hypercalcemia does not generate significant bias in results of first-line coagulations tests, so that hypothetical consideration of adjusting citrate-blood ratio is unjustified in hypercalcemic patients.

Hypoglycemia Alert Dogs: A Novel, Cost-effective Approach for Diabetes Monitoring?

The recent publication of the results of 3 small trials, and as many as 5 case reports on dogs producing clear and intelligible alerts in the presence of their owners' hypoglycemia, opens an intriguing clinical scenario for management of diabetes. The skill seems attributable to the ability of dogs to identify patterns in skin and breath odors as well as to understand and interpret visual cues from humans during hypoglycemia. Provided that further trials can confirm the findings, the use of diabetes alert dogs that are trained to detect the onset of hypoglycemia can be regarded as a fast, versatile, reliable, and cost-effective approach for safeguarding the health of individuals with diabetes.

Fish Intake and Venous Thromboembolism: A Systematic Literature Review.

Diet plays an important role in modulating the risk of arterial and venous thrombosis. Several lines of evidence attest that consumption of fish and its compounds, especially omega-3 fatty acids, may be effective to decrease the cardiovascular risk. Since the pathogenesis of arterial and venous thrombosis share some common aspects, we performed a systematic review of published clinical studies that investigated the association between fish intake and venous thrombosis. An electronic search was carried out in Medline, Scopus, and ISI Web of Science using the key words "fish" OR "seafood" AND "venous thromboembolism" OR "deep vein thrombosis" OR "pulmonary embolism", with no language or date restriction. Overall, 6 studies (5 prospective and 1 case-control) were finally identified. In only 1 small case-control study, a larger intake of total fish was found to be negatively associated with the risk of venous thromboembolism. No association was found in 4 large prospective studies, whereas a positive association was observed in the remaining. No substantial difference was also noticed between intake of fatty or lean fish. Taken together, the current epidemiological evidence does not support the existence of a significant effect of total fish consumption on the risk of venous thromboembolism.

The burden of vitamin D deficiency in a mediterranean country without a policy of food fortification.

BACKGROUND: Vitamin D deficiency is a public healthcare issue and its correction is increasingly regarded as a cornerstone of preventive medicine. METHODS: We designed a retrospective observational study to clearly define the burden of total vitamin D (25-hydroxyvitamin D) deficiency in a supposedly healthy population of outpatients residing in two regions (Emilia Romagna and Veneto) of Northern Italy. RESULTS: 25-hydroxyvitamin D results were available for a total number of 5,096 outpatients in the two centers. The median value of 25-hydroxyvitamin D was 60 nmol/L, and was higher in women than in men (62 nmol/L versus 56 nmol/L; p<0.001). The rate of 25-hydroxyvitamin D deficiency was 36%, and was marginally but significantly higher in men than in women (40% versus 35%; p=0.003). A significant variation in the rate of 25-hydroxyvitamin D deficiency was found throughout different age ranges, exhibiting a significant increase in the elderly. CONCLUSIONS: The results of this large observational study show that the burden of 25-hydroxyvitamin D deficiency in two regions of a Mediterranean country without a policy of food fortification is as high as 36%, and this evidence represents a background for healthcare preventive measures aimed at reducing the prevalence of this condition in the general population. (www.actabiomedica.it).

Serum potassium levels inversely correlate with D-dimer in patients with acute-onset atrial fibrillation.

BACKGROUND: D-dimer values are frequently increased in patients with atrial fibrillation (AF) compared to subjects in sinus rhythm. Hypokalemia plays a role in several cardiovascular diseases, but little is known about the association with AF. OBJECTIVE: D-dimer values are frequently increased in patients with atrial fibrillation (AF) compared with subjects in sinus rhythm. Hypokalemia plays a role in several cardiovascular diseases, but little is known about the association with AF. The aim of this study was to investigate correlations between D-dimer and serum potassium in acute-onset AF (AAF). METHODS: To investigate the potential correlation between the values of serum potassium and D-dimer in patients with AAF, we retrospectively reviewed clinical and laboratory data of all emergency department visits for AAF in 2013. RESULTS: Among 271 consecutive AAF patients with D-dimer assessments, those with hypokalemia (n = 98) had significantly higher D-dimer values than normokalemic patients (139 versus 114 ng/mL, p = 0.004). The rate of patients with D-dimer values exceeding the diagnostic cut-off was higher in the group of patients with hypokalemia than in those with normal serum potassium (26.5% versus 16.2%; p = 0.029). An inverse and highly significant correlation was found between serum potassium and D-dimer (r = -0.21; p < 0.001), even after adjustments for age and sex (beta coefficient -94.8; p = 0.001). The relative risk for a positive D-dimer value attributed to hypokalemia was 1.64 (95% CI, 1.02 to 2.63; p = 0.040). The correlation remained statistically significant in patients free from antihypertensive drugs (r = -0.25; p = 0.018), but not in those taking angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, or diuretics. CONCLUSIONS: The inverse correlation between values of potassium and D-dimer in patients with AAF provides important and complementary information about the thromboembolic risk of these patients.