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Objective: To gain insights into how proteases signal to connective tissues cells in the periodontium. Background: The connective tissue degradation observed in periodontitis is largely due to matrix metalloproteinase (MMP) release by gingival fibroblasts. Granzyme B (GzmB) is a serine protease whose role in periodontitis is undefined. Methods: Human gingival crevicular fluid (GCF) samples were obtained from sites with periodontal disease and healthy control sites. GzmB was quantified in the GCF ([GzmB]GCF) by ELISA. Gingival fibroblasts (GF) were cultured in the presence or absence of recombinant GzmB. Culture supernatants were analyzed by ELISA to quantify GzmB‐induced release of interstitial collagenase (MMP‐1). In some experiments, cells were pre‐treated with the inhibitor PD98059 to block MEK/ERK signaling. The protease‐activated receptor‐1 (PAR‐1) was blocked with ATAP‐2 neutralizing antibody prior to GzmB stimulation. Systemic MMP‐1 levels were measured in plasma from wild‐type (WT) and granzyme‐B‐knockout (GzmB−/−) mice. Results: The [GzmB]GCF in human samples was ~4–5 fold higher at sites of periodontal disease (gingivitis/periodontitis) compared to healthy control sites, suggesting an association between GzmB and localized matrix degradation. GzmB induced a ~4–5‐fold increase in MMP‐1 secretion by cultured fibroblasts. GzmB induced phosphorylation of Erk1/2, which was abrogated by PD98059. GzmB‐induced upregulation of MMP‐1 secretion was also reduced by PD98059. Blockade of PAR‐1 function by ATAP‐2 abrogated the increase in MMP‐1 secretion by GF. Circulating MMP‐1 was similar in WT and GzmB−/− mice, suggesting that GzmB's effects on MMP‐1 release are not reflected systemically. Conclusion: These data point to a novel GzmB‐driven signaling pathway in fibroblasts in which MMP‐1 secretion is upregulated in a PAR1‐ and Erk1/2‐dependent manner. [ABSTRACT FROM AUTHOR]

Background: Despite the widespread use of medical cannabis, little is known regarding the safety, efficacy, and dosing of cannabis products in children with cancer. The objective of this study was to systematically appraise the existing published literature for the use of cannabis products in children with cancer. Methods: This systematic review, registered with the International Prospective Register of Systematic Reviews (CRD42020187433), searched four databases: MEDLINE, Embase, PsycINFO, and the Cochrane Library. Abstracts and full texts were screened in duplicate. Data on types of cannabis products, doses, formulations, frequencies, routes of administration, indications, and clinical and demographic details as well as reported efficacy outcomes were extracted. Data on cannabinoid‐related adverse events were also summarized. Results: Out of 34,611 identified citations, 19 unique studies with a total of 1927 participants with cancer were included: eight retrospective chart reviews, seven randomized controlled trials, two open‐label studies, and two case reports. The included studies reported the use of various cannabis products for the management of symptoms. Cannabinoids were commonly used for the management of chemotherapy‐induced nausea and vomiting (11 of 19 [58%]). In controlled studies, somnolence, dizziness, dry mouth, and withdrawal due to adverse events were more commonly associated with the use of cannabinoids. Across all included studies, no serious cannabis‐related adverse events were reported. Conclusions: Although there is evidence to support the use of cannabis for symptom management, in children with cancer, there is a lack of rigorous evidence to inform the dosing, safety, and efficacy of cannabinoids. Because of the increasing interest in using cannabis, there is an urgent need for more research on medical cannabis in children with cancer. In the last 10 years, there has been an increase in the use of cannabis‐based products (both natural and synthetic cannabinoids) to help children with cancer‐related symptoms. This systematic review summarizes 19 studies related to the use of cannabinoids for the management of cancer‐related symptoms in children. The most common indication for the use of cannabinoids in the included studies was chemotherapy‐induced nausea and vomiting. A variety of cannabinoids were used: nabilone, Δ‐9‐tetrahydrocannabinol, dronabinol, and cannabidiol. The most common route of administration was oral with capsules as a formulation. [ABSTRACT FROM AUTHOR]

Metformin pharmacokinetics are highly dependent upon organic cationic transporters. There is evidence of a change in its renal clearance in hyperlipidemic obese patients, and no information on its metabolic fate. To study some of these aspects, the influence of poloxamer 407 (P407)-induced hyperlipidemia on metformin pharmacokinetics was assessed. Control and P407-treated adult male rats were administered 30 mg/kg metformin intravenously (i.v.). The pharmacokinetic assessments were performed at 2 time points, 36 and 108 h, following the intraperitoneal dose of P407 (1 g/kg). mRNA and protein expressions of cationic drug transporters were also measured. There was no evidence of a change in metformin pharmacokinetics after i.v. doses as a consequence of short-term hyperlipidemia, and a change in transporter mRNA but not protein expression was observed in the P407treated rats 108 h after P407 injection. Urinary recovery of unchanged drug was high (>90%) but incomplete. Presumed metabolite peaks were detected in chromatograms of hepatocytes and microsomal protein spiked with metformin. Comparative chromatographic elution times and mass spectra suggested that one of the predominant metabolites was guanylurea. Hyperlipidemia by itself did not affect the pharmacokinetics of metformin. Guanylurea is a putative metabolite of metformin in rats. Key words: poloxamer 407, biguanides, organic cation transporters, mass spectroscopy. Les proprietes pharmacocinetiques de la metformine dependent dans une tres grande mesure des transporteurs cationiques organiques. Des indices laissent voir des variations dans sa clairance renale chez les patients obeses presentant une hyperlipidemie, mais aucune information quant son devenir metabolique. En vue d'etudier certains de ces aspects, nous avons evalue l'influence de l'hyperlipidemie provoquee par le poloxamere 407 (P407) sur les proprietes pharmacocinetiques de la metformine. Nous avons administre de la metformine ;a 30 mg/kg par voie intraveineuse (i.v.) chez des rats males adultes temoins et exposes au P407. Nous avons procede aux evaluations de la pharmacocinetique deux jalons temporels (36 et 108 h) apres l'administration de P407 1 g/kg par voie intraperitoneale. Nous avons aussi mesure l'expression de l'ARNm et des proteines des transporteurs cationiques de medicaments. Nous n'avons observe aucun indice de variation des proprietes pharmacocinetiques de la metformine apres des doses i.v. en tant que consequence d'une hyperlipidemie court terme. Nous avons observe que 108 h apres l'exposition au P407, les taux d'ARNm du transporteur variaient, mais pas l'expression proteique. Par ailleurs, la recuperation urinaire de medicament inchange etait elevee (>90 %), mais incomplete. Nous avons detecte des sommets metaboliques presumes dans les chromatogrammes d'hepatocytes, et les proteines microsomiales presentaient des sommets coordonnes avec ceux de la metformine. Les temps d'elution chromatographiques et les spectres de masse comparatifs laissaient entendre que l'un des metabolites predominants serait la guanyluree. En elle-meme, l'hyperlipidemie n'affecte pas les proprietes pharmacocinetiques de la metformine. Il est possible que la guanyluree soit un metabolite de la metformine chez le rat. [Traduit par la Redaction] Mots-cles : poloxamere 407, biguanides, transporteurs cationiques organiques, spectroscopie de masse., Introduction Lipoproteins are involved in the movement and mobilization of lipids (triglycerides, cholesterol, and phospholipids) between tissues and the blood, which serves as a conduit (Wasan et al. 2008). Hyperlipidemia [...]

In-vitro studies were performed to shed light on previous findings that showed increased uptake of cyclosporine A in the kidneys and liver of hyperlipidemic rats, and increased signs of kidney toxicity. Hepatocytes were obtained from rats, cultured, and exposed to a diluted serum from hyperlipidemic rats. Some cells were also exposed to lipid-lowering drugs. After washing out the rat serum or lipid-lowering drugs, cells were exposed to cyclosporine A embedded in serum lipoproteins. Pretreatment with hyperlipidemic serum and lipid-lowering drugs was associated with an increased uptake of cyclosporine A. As expected, atorvastatin caused an increase in low density lipoprotein receptor and a decrease in MDR1A mRNA in the hepatocytes. A decrease in NRK-52E rat renal tubular cellular viability caused by cyclosporine A was noted when cells were preincubated with diluted hyperlipidemic serum. This was matched with evidence of hyperlipidemic-serum-associated increases in the NRK-52E cellular uptake of cyclosporine A and rhodamine-123. The findings of these experiments suggested that in hyperlipidemia the expression and (or) the functional activity of P-glycoprotein was diminished, leading to greater hepatic and renal uptake of cyclosporine A, and renal cellular toxicity. Key words: hepatocytes, hyperlipidemia, lipoprotein receptors, NRK-52E cells, P-glycoprotein. Des etudes in vitro ont ete realisees afin de faire la lumiere sur des resultats obtenus precedemment, qui ont revele une captation accrue de cyclosporine A dans les reins et le foie de rats hyperlipidemiques ainsi que des signes accrus de toxicite renale. Des hepatocytes de rats ont ete isoles, cultives et exposes a du serum de rat hyperlipidemique dilue. Certaines cellules ont aussi ete exposees a des hypolipidemiants. Apres avoir rince les cellules du serum de rat ou des hypolipidemiants, elles ont ete exposees a la cyclosporine A enrobee dans des lipoproteines seriques. Le pretraitement au serum hyperlipidemique et aux hypolipidemiants etait associe a une captation accrue de cyclosporine A. Comme attendu, l'atorvastatine induisait une augmentation de l'expression du recepteur des lipoproteines de faible densite ainsi qu'une diminution de l'expression de l'ARNm de MDR1A dans les hepatocytes. Une diminution la viabilite des cellules de tubules renaux de rats NRK-52E induite par la cyclosporine A a ete notee lorsque les cellules etaient preincubees avec le serum hyperlipidemique dilue. Cela coincidait avec l'augmentation de la captation de cyclosporine A et de rhodamine-123 associee au serum hyperlipidemique dans les cellules NRK-52E. Les resultats de ces experiences suggerent qu'en situation d'hyperlipidemie, l'expression et (ou) l'activite fonctionnelle de la P-glycoproteine etait diminuee, conduisant a une captation accrue de clyclosporine A par le foie et les reins, ainsi qu'a une toxicite cellulaire renale. [Traduit par la Redaction] Mots-cles: hepatocytes, hyperlipidemie, recepteurs de lipoproteines, cellules NRK-52E, P-glycoproteine., Introduction In rats, experimental hyperlipidemia (HL) is associated with increased concentrations of the immunosuppressive agent, cyclosporine A (CyA) in the kidneys and liver (Aliabadi et al. 2006). This finding has [...]

The relationship between 25-hydroxyvitamin D3 (25(OH)D), the surrogate marker for vitamin D3, serum concentration and COVID-19 has come to the forefront as a potential pathway to improve COVID-19 outcomes. The current evidence remains unclear on the impact of vitamin D status on the severity and outcomes of COVID-19 infection. To explore possible association between low 25(OH)D levels and risk of developing severe COVID-19 (i.e. need for invasive mechanical ventilation, the length of hospital stay, total deaths). We also aimed to understand the relationship between vitamin D insufficiency and elevated inflammatory and cardiac biomarkers. We conducted a comprehensive electronic literature search for any original research study published up to March 30, 2021. For the purpose of this review, low vitamin D status was defined as a range of serum total 25(OH)D levels of <10 to <30 ng/ml. Two independent investigators assessed study eligibility, synthesized evidence, analyzed, critically examined, and interpreted herein. Twenty-four observational studies containing 3637 participants were included in the meta-analysis. The mean age of the patients was 61.1 years old; 56% were male. Low vitamin D status was statistically associated with higher risk of death (RR, 1.60 (95% CI, 1.10–2.32), higher risk of developing severe COVID-19 pneumonia (RR: 1.50; 95% CI, 1.10–2.05). COVID-19 patients with low vitamin D levels had a greater prevalence of hypertension and cardiovascular diseases, abnormally high serum troponin and peak D-dimer levels, as well as elevated interleukin-6 and C-reactive protein than those with serum 25(OH)D levels ≥30 ng/ml. In this meta-analysis, we found a potential increased risk of developing severe COVID-19 infection among patients with low vitamin D levels. There are plausible biological mechanisms supporting the role of vitamin D in COVID-19 severity. Randomized controlled trials are needed to test for potential beneficial effects of vitamin D in COVID-19 outcomes. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPIs) are one of the most used classes of drugs. For most indications, PPIs are only recommended up to 8 weeks duration. However, PPI use continues to expand. Regular and prolonged use of PPIs should be avoided because of the risk of adverse events., Objectives: The main objective of this study was to (1) investigate the extent of PPI usage in people aged 65 or older in the province of British Columbia (BC), Canada, (2) provide an overview of the harms associated with the long-term use of PPIs., Methods: We examined utilization trends of the PPIs in BC since the year 2009 using PharmaNet, BC's medication dispensing database where the information is accessible to community pharmacists. We performed a comprehensive literature search for relevant reviews reporting harms associated with long-term use of PPIs. A search was conducted from January 2014 to June 2022., Results: Between 2000 and 2018 BC's population grew by 20%, but the use of PPIs escalated to 257%. Of these older British Columbians, 62% had a cumulative exposure exceeding 2 years and 42% exceeded 5 years. This is alarming because the recommended treatment duration is 4-12 weeks for common indications including reflux esophagitis, and duodenal and gastric ulcers. Only 13.5% were dispensed PPIs for 90 days or less. Patients on long-term PPI therapy should be reassessed. Adverse events of PPI use are common among older adults. We identified over 217 systematic reviews published during the last 8 years of specific harms associated with long-term daily usage of PPIs. These harms include increased risks of death, cardiovascular disease, acute renal injury, chronic kidney disease, dementia, fractures, hypomagnesemia, iron deficiency, vitamin B12 deficiency, enteric infection (including C. difficile ), pneumonia, and neoplasia (gastric cancer, carcinoids, and colon cancer), and drug interactions., Conclusion: This study revealed a high prevalence of PPI use among elderly populations in BC, Canada. The overutilization of PPIs is often a result of failure to re-evaluate the need for continuation of therapy. Published studies identified signals of serious harm from long-term PPI exposure. Healthcare providers with patients can reverse the relentless expansion of long-term PPI exposure by discussing the expected benefits and potential harms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 , commonly known as calcitriol), the most active metabolite of vitamin D 3 , and ginsenoside Rh2 can regulate cellular differentiation and proliferation proteins. The purpose of the present study was to assess the effect of 1,25(OH) 2 D 3 on the anticancer activities of Rh2 in human prostate cancer cells such as androgen-dependent LNCaP and androgen-independent C4-2 in vitro. The effects of treatment with 1,25(OH) 2 D 3 or Rh2, either alone or in combination, on prostate cancer cells were evaluated through tetrazolium-based cell viability assay, BrdU cell proliferation rate estimation assay, and Western blot protein expression analyses of nuclear receptors (androgen receptor and vitamin D receptors) and apoptotic proteins (Bcl-2, Bax, and Caspase 3). The Combination Indices (CI) and Dose Reduction Indices (DRI) of 1,25(OH) 2 D 3 and Rh2 were calculated to determine synergistic anticancer activity using Calcusyn software (Biosoft, Cambridge, UK). The cell viability assay data indicate that Rh2 treatment alone inhibited cell viability in a concentration-dependent manner and the addition of 10 nM 1,25(OH) 2 D 3 to Rh2 significantly enhanced its ability to reduce cell viability up to 80 % in both the cell lines. Similarly, addition of 10 nM 1,25(OH) 2 D 3 to Rh2 significantly lowered its IC 50 values for cell proliferation from the range of 32-65 μM to 14-8 μM in LNCaP and C4-2 cells. In addition, protein expression analyses indicated that the combined treatment with Rh2 and 1,25(OH) 2 D 3 led to greater downregulation of androgen receptor expression compared to single agent exposure. Similarly, the presence of 1,25(OH) 2 D 3 synergistically increased the pro-apoptotic actions of Rh2 in both the cell lines. Overall, 1,25(OH) 2 D 3 augments the Rh2-mediated anticancer effects through stimulating apoptosis and reduced cell proliferation which suggests that synergism of this combination may lead to potential lower need of the active vitamin D 3 and limited toxicity from it., (Copyright © 2021 Elsevier Ltd. All rights reserved.)