Opuntia monacantha: Validation of the anti-inflammatory and anti-arthritic activity of its polyphenolic rich extract in silico and in vivo via assessment of pro- and anti-inflammatory cytokines.

ETHNOPHARMACOLOGICAL RELEVANCE: Opuntia monacantha belongs to the cactus family Cactaceae and is also known by cochineal prickly pear, Barbary fig or drooping prickly pear. It was traditionally used to treat pain and inflammation. O. monacantha cladodes showed pharmacological effects such as antioxidant potential owing to the presence of certain polysaccharides, flavonoids, and phenols. AIM OF THE STUDY: This research aimed to evaluate the anti-inflammatory as well as the anti-arthritic potential of ethanol extract of Opuntia monacantha (E-OM). MATERIALS AND METHODS: In vivo edema in rat paw was triggered by carrageenan and used to evaluate anti-inflammatory activity, while induction of arthritis by Complete Freund's Adjuvant (CFA) rat model was done to measure anti-arthritic potential. In silico studies of the previously High performance liquid chromatography (HPLC) characterized metabolites of ethanol extract was performed by using Discovery Studio 4.5 (Accelrys Inc., San Diego, CA, USA) within active pocket of glutaminase 1 (GLS1) (PDB code: 3VP1; 2.30 Å). RESULTS: EOM, particularly at 750 mg/kg, caused a reduction in the paw edema significantly and decreased arthritic score by 80.58% compared to the diseased group. It revealed significant results when histopathology of ankle joint was examined at 28th day as it reduced inflammation by 18.06%, bone erosion by 15.50%, and pannus formation by 24.65% with respect to the diseased group. It restored the altered blood parameters by 7.56%, 18.47%, and 3.37% for hemoglobin (Hb), white blood count (WBC), and platelets, respectively. It also reduced rheumatoid factor RF by 13.70% with concomitant amelioration in catalase (CAT) and superoxide dismutase (SOD) levels by 19%, and 34.16%, respectively, in comparison to the diseased group. It notably decreased mRNA expression levels of COX-2, IL-6, TNF-α, IL-1, NF-κß and augmented the levels of IL-4 and IL-10 in real time PCR with respect to the diseased group and piroxicam. HPLC analysis previously performed showed that phenolic acids and flavonoids are present in E-OM. Molecular docking studies displayed pronounced inhibitory potential of these compounds towards glutaminase 1 (GLS1), approaching and even exceeding piroxicam. CONCLUSIONS: Thus, Opuntia monacantha could be a promising agent to manage inflammation and arthritis and could be incorporated into pharmaceuticals.

Design, QSAR Methodology, Synthesis and Assessment of Some Structurally Different Xanthone Derivatives as Selective Cox-2 Inhibitors for their Anti-inflammatory Properties.

INTRODUCTION: Inflammation can be defined as a complex biological response that is produced by body tissues to harmful agents like pathogens, irritants, and damaged cells and thereby acts as a protective response incorporating immune cells, blood vessels, and molecular mediators. Histamine, serotonin, bradykinin, leukotrienes (LTB4), prostaglandins (PGE2), prostacyclins, reactive oxygen species, proinflammatory cytokines like IL-1, IL-11, TNF- anti-inflammatory cytokines like IL-4, IL-10, IL-11, IL-6 and IL-13, etc. all have different effects on both pro and anti-inflammatory mediators. Incorporation of combinatorial chemistry and computational studies have helped the researchers to design xanthones moieties with high selectivity that can serve as a lead compound and help develop potential compounds that can act as effective COX-2 inhibitors. The study aims to design and develop different series of substituted hydroxyxanthone derivatives with anti-inflammatory potential. METHODS: The partially purified synthetic xanthone derivatives were orally administered to the carrageenan induced paw oedemic rat models at the dose of 100 mg/kg, and their effect in controlling the degree of inflammation was measured at the time interval of 30 min, 1, 2, 3, 4 and 6 hrs. respectively. Further, these compounds were also subjected to modern analytical studies like UV, IR, NMR and mass spectrometry or their characterization. RESULTS: The results drawn out of the in silico, in vitro, in vivo and analytical studies concluded that the hydroxyxanthone derivatives can obstruct the enzyme COX-2 and produce anti-inflammatory action potentially. CONCLUSION: With the aim to evaluate the compounds for their anti-inflammatory activity, it was observed that the newly designed xanthonic compounds also possess a safe toxicity margin and hence can be utilized by the researchers to develop hybrid xanthonic moieties that can specifically target the enzyme COX-2.

In Vitro Assessment of Anti-Adipogenic and Anti-Inflammatory Properties of Black Cumin (Nigella sativa L.) Seeds Extract on 3T3-L1 Adipocytes and Raw264.7 Macrophages.

Background and Objectives: This study evaluated the in vitro anti-adipogenic and anti-inflammatory properties of black cumin (Nigella sativa L.) seed extract (BCS extract) as a potential candidate for developing herbal formulations targeting metabolic disorders. Materials and Methods: We evaluated the BCS extract by assessing its 2,2-diphenyl-1-picrohydrazyl (DPPH) radical scavenging activity, levels of prostaglandin E2 (PGE2) and nitric oxide (NO), and mRNA expression levels of key pro-inflammatory mediators. We also quantified the phosphorylation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPK) signaling molecules. To assess anti-adipogenic effects, we used differentiated 3T3-L1 cells and BCS extract in doses from 10 to 100 µg/mL. We also determined mRNA levels of key adipogenic genes, including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/BEPα), adipocyte protein 2 (aP2), lipoprotein lipase (LPL), fatty acid synthase (FAS), and sterol-regulated element-binding protein 1c (SREBP-1c) using real-time quantitative polymerase chain reaction (qPCR). Results: This study showed a concentration-dependent DPPH radical scavenging activity and no toxicity at concentrations up to 30 µg/mL in Raw264.7 cells. BCS extract showed an IC50 of 328.77 ± 20.52 µg/mL. Notably, pre-treatment with BCS extract (30 µg/mL) significantly enhanced cell viability in lipopolysaccharide (LPS)-treated Raw264.7 cells. BCS extract treatment effectively inhibited LPS-induced production of PGE2 and NO, as well as the expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), interleukin (IL)-1ß and IL-6, possibly by limiting the phosphorylation of p38, p65, inhibitory κBα (I-κBα), and c-Jun N-terminal kinase (JNK). It also significantly attenuated lipid accumulation and key adipogenic genes in 3T3-L1 cells. Conclusions: This study highlights the in vitro anti-adipogenic and anti-inflammatory potential of BCS extract, underscoring its potential as a promising candidate for managing metabolic disorders.

MANAGEMENT OF RISKS OF ADVERSE DRUG REACTIONS ACCORDING TO ADR REPORT FORM DATA FROM LVIV REGION HEALTHCARE FACILITIES IN 2022.

The study aimed to analyse the adverse drug reactions report form data received by the State Expert Center of the Ministry of Health of Ukraine from healthcare professionals in the Lviv region in 2022. Regarding specific types of medicines, the ones with proven cause-and-effect relationships that caused the highest frequency of adverse drug reactions incidents were chemotherapeutic agents (35.5%), medicines affecting the cardiovascular system (20.3%), and non-steroidal anti-inflammatory drugs (8%). Within the penicillin class, amoxicillin potentiated by clavulanate (67%) and amoxicillin (29%) were the dominant drugs showing the highest incidence rate of adverse reactions. Among cephalosporins, ceftriaxone (46%) and cefixime (15%) were found to take the lead in terms of adverse reaction frequency. The highest proportion among all adverse drug reactions caused by penicillins and cephalosporins was attributed to allergic reactions. To confirm or rule out immediate or delayed type allergies in patients, as well as in patients with a history of immediate-type allergic reactions to ß-lactams and planned administration of another ß-lactam, it is necessary to conduct skin testing (skin prick test, or, in the case of parenteral administration, intradermal test) with the planned ß-lactam antibiotic. The second highest proportion of induced adverse drug reactions was attributed to drugs affecting the cardiovascular system (20.3%). The leading medications in the angiotensin-converting enzyme inhibitors category were enalapril (47%) and the combination of lisinopril with hydrochlorothiazide (24%). In the angiotensin II receptor blockers category of medications, valsartan (30%) and telmisartan-hydrochlorothiazide combination (20%) ranked highest. In the category of CCB drugs, amlodipine (66%) and nifedipine (20%) held the leading positions. among angiotensin-converting enzyme inhibitors, enalapril caused the most prevalent and predicted adverse reaction, that of cough, affecting 10.5% of patients, whereas, with the combination therapy of lisinopril and hydrochlorothiazide, the cough was observed in only 5.2% of patients. Angiotensin II receptor blockers have a better safety profile, particularly concerning cough. Analysis of adverse drug reactions reports for angiotensin II receptor blockers showed no cases of cough with valsartan and telmisartan-hydrochlorothiazide combination. Among calcium channel blocker medications, amlodipine emerged to rank highest, causing one of the predicted adverse drug reactions, that of lower extremity oedema in 64% of patients. The second position was taken by the combination of amlodipine with valsartan, which showed a statistically significant reduction of 14.3% (p≤0.05) in the incidence of oedema. Using amlodipine at a dose of 5 mg in combination with sartan medicines as angiotensin receptor blockers is an effective therapeutic alternative not only for enhancing blood pressure control in hypertensive patients but also for improving the safety profile of amlodipine. Among all the non-steroidal anti-inflammatory drugs prescribed to patients in the Lviv region in 2022, the highest number of adverse reactions was associated with the administration of diclofenac, ibuprofen, paracetamol, and nimesulide, causing adverse drug reactions in 22%, 19%, 17%, and 10% of cases, respectively. The most common systemic manifestations of adverse reactions with these non-steroidal anti-inflammatory drugs were allergic reactions (63.4%) and gastrointestinal disorders (26.8%). From an evidence-based medicine perspective, the most justified approach for primary and secondary prevention of gastrointestinal complications is the use of proton pump inhibitors.

American College of Allergy, Asthma and Immunology members' preferred steps 1 to 3 asthma maintenance and reliever therapy and incomplete insurance coverage indicated as main practice hurdle.

BACKGROUND: New asthma guidelines (GINA, 2022; NAEPP EPR-4, 2020) include considerable changes in treatment recommendations, specifically regarding anti-inflammatory rescue and Single MAintenance and Reliever Therapy (SMART). OBJECTIVE: To explore American College of Allergy, Asthma and Immunology members' preferred treatment and perceived hurdles. METHODS: A survey (SurveyMonkey) regarding steps 1 to 3 asthma therapy was e-mailed to American College of Allergy, Asthma and Immunology members. RESULTS: The allergists completed 147 surveys (46% with >20 years of experience; 98% from United States; 29% academic, 75% [also] private practice). In addition, 69% follow the National Asthma Education and Prevention Program and 81% the Global Initiative for Asthma recommendations. Of 147 allergists, 117 (80%) indicated correctly what SMART strategy is; 21%/36%/50%/39% would use SMART in step 3 treatment of a below 5-year-old/5- to 11-year-old/12- to 65-year-old/above 65-year-old patient, respectively. In this group, 11% to 14% incorrectly chose inhaled corticosteroid (ICS) plus salmeterol and 9% ICS plus vilanterol for SMART. In a 4-year-old needing step 1 therapy (N = 129), 55% of the respondents would add anti-inflammatory therapy; for step 2 treatment, most would prescribe ICS 100 to 200 µg budesonide equivalent daily; in step 3, 49% would prescribe ICS plus long-acting beta-agonist (LABA). In a 7-year-old needing step 1 treatment (N = 134), 40% would prescribe only short-acting beta-agonist; in step 3, 45% would institute SMART strategy, but only 8 of 135 (6%) chose very-low dose ICS plus formoterol (as recommended in Global Initiative for Asthma); most (39%) use low-dose ICS plus formoterol. As for rescue therapy, 59% is now instituting some form of anti-inflammatory rescue. Finally, in a 25-year-old patient (N = 144): in step 1, 39% would prescribe exclusively short-acting beta-agonist; in step 2, 4% only anti-inflammatory rescue and the rest prescribes ICS maintenance; one-third begins SMART strategy at step 2 and 50% in step 3. Major hurdles for prescribing one's preferred strategy included incomplete insurance coverage, insurance not approving more than one canister of ICS-formoterol per month, and cost. CONCLUSION: Asthma therapy varies among physicians, with respondents suggesting underutilization of the recommended anti-inflammatory rescue and SMART therapy. A major hurdle is lack of insurance coverage of medication in line with the guidelines.

Tobacco Alkaloid Assessment in a DSS-Induced Colitis Mouse Model with a Fully Humanized Immune System.

Inflammatory bowel disease (IBD) refers to chronic intestinal immune-mediated diseases including two main disease manifestations: ulcerative colitis (UC) and Crohn's disease (CD). Epidemiological, clinical, and preclinical evidence has highlighted the potential anti-inflammatory properties of naturally occurring alkaloids. In the present study, we investigated the potential anti-inflammatory activities of the tobacco alkaloids nicotine and anatabine in a dextran sulfate sodium (DSS)-induced UC mouse model with a fully humanized immune system. Our results show that nicotine significantly reduced all acute colitis symptoms and improved colitis-specific endpoints, including histopathologically assessed colon inflammation, tissue damage, and mononuclear cell infiltration. The tobacco alkaloid anatabine showed similar effectiveness trends, although they were generally weaker or not significant. Gene expression analysis in the context of biological network models of IBD further pinpointed a possible mechanism by which nicotine attenuated DSS-induced colitis in humanized mice. The current study enables further investigation of possible molecular mechanisms by which tobacco alkaloids attenuate UC symptoms.

Assessment of hypolipidemic and anti-inflammatory properties of walnut (Juglans regia) seed coat extract and modulates some metabolic enzymes activity in triton WR-1339-induced hyperlipidemia in rat kidney, liver, and heart.

Atherosclerosis and cognitive impairment are both influenced by hyperlipidemia. Due to their high margin of safety and low cost, natural chemicals have recently attracted particular attention in the context of the treatment of disease. Hence, the purpose of this study was to investigate the possible amendatory impact of ethanol extract walnut (Juglans regia) seed coat (E-WSC) on some metabolic enzymes (glutathione reductase (GR), paraoxonase-1 (PON1), aldose reductase (AR), sorbitol dehydrogenase (SDH), acetylcholinesterase (AChE), glutathione S-transferase (GST), and butyrylcholinesterase (BChE)) activity in the liver, kidney, and heart of rats with Triton WR-1339-induced hyperlipidemia. Rats were divided into five groups: control group, HL-Control group (Triton WR-1339 400 mg/kg, i.p administered group), E- WSC + 150 (150 mg/kg,o.d given group), E- WSC + 300 (E- WSC 300 mg/kg, o.d given group) and HL+ E-WSC + 300 (Group receiving E- WSC 300 mg/kg, o.d 30 min prior to administration of Triton WR-1339 400 mg/kg, i.p). In HL-Control, AR, SDH, and BChE enzyme activity was significantly increased in all tissues compared to the control, while the activity of other studied enzymes was significantly decreased. The effects of hyperlipidemia on balance were improved and alterations in the activity of the investigated metabolic enzymes were prevented by E-WSC. As a result, promising natural compounds that can be used as adjuvant therapy in the treatment of cognitive disorders and hyperlipidemia may be found in E-WSC powder.

Two for the price of one: itaconate and its derivatives as an anti-infective and anti-inflammatory immunometabolite.

The metabolite itaconate (ITA) and its derivatives, both chemically synthesized and endogenous, have emerged as immunoregulators, with roles in limiting inflammation but also having effects on bacterial and viral infection. Some members of the ITA family have been shown to target and inhibit multiple processes in macrophages with recently identified targets, including NLRP3, JAK1, ten-eleven translocation-2 dioxygenases, and TFEB, a key transcription factor for lysosomal biogenesis. They have also been shown to target multiple bacteria, inhibiting their replication, as well as having antiviral effects against viruses such as SARS-CoV2, Zika virus, and Influenza virus. The importance of ITA is highlighted by the fact that several pathogens have developed mechanisms to evade ITA and can manipulate ITA for their own gain. Two newly discovered isomers of ITA, mesaconate and citraconate, are also discussed, which also have immunomodulatory effects. ITA continues to be a fascination, both in terms of inflammation but also as an antibacterial and antiviral agent, with therapeutic potential in immune and inflammatory diseases.

Assessment of the Anti-inflammatory Effects of NORFLO® ORO in Acute Relapses of HLA-B27-associated Autoimmune Uveitis: A Multicenter, Randomized, Placebo-controlled, Double-blind Clinical Study.

BACKGROUND: An effective therapy to reduce the number and severity of HLA-B27-related acute anterior uveitis (AAU) recurrences represents a clinical need. Curcumin is a promising therapeutic option in various inflammatory eye diseases. To enhance its absorption and eye tissue selectivity, a phospholipidic-curcumin complex (PHBC) has been formulated (Iphytoone®, Eye Pharma S.p.A.). AIMS: This study investigates if PHBC is effective and safe to decrease the number and intensity of HLA-B27-related AAU relapses. METHODS: HLA-B27-related AAU patients were randomly divided to receive PHBC or placebo for 12 months (NCT03584724). RESULTS: Compared with the previous year, the number of relapses decreased in both groups. The proportion of responders was significantly higher in the PBHC group. The severity of attacks was comparable. The study drug was well tolerated. CONCLUSIONS: A beneficial effect of PHBC treatment is suggested because the proportion of responders was significantly higher in this group of patients.

Assessment of Efficacy and Safety Using PPAR-γ Agonist-Loaded Nanocarriers for Inflammatory Eye Diseases.

Drug-loaded nanocarriers (NCs) are new systems that can greatly improve the delivery and targeting of drugs to specific tissues and organs. In our work, a PPAR-γ agonist loaded into polymeric NCs was prepared, stabilized by spray-drying, and tested in vitro, ex vivo, and in vivo (animal models) to provide a safe formulation for optical anti-inflammatory treatments. The NCs were shown to be well tolerated, and no signs of irritancy or alterations of the eye properties were detected by the in vitro HET-CAM test and in vivo Draize test. Furthermore, no signs of cytotoxicity were found in the NC formulations on retinoblastoma cells (Y-79) analyzed using the alamarBlue assay, and the transmittance experiments evidenced good corneal transparency with the formulations tested. The ocular anti-inflammatory study confirmed the significant prevention efficacy using the NCs, and these systems did not affect the corneal tissue structure. Moreover, the animal corneal structure treated with the NCs was analyzed using X-ray diffraction using synchrotron light. Small-angle X-ray scattering (SAXS) analysis did not show a significant difference in corneal collagen interfibrillar spacing after the treatment with freshly prepared NCs or NCs after the drying process compared to the corresponding negative control when inflammation was induced. Considering these results, the PPAR-γ agonist NCs could be a safe and effective alternative for the treatment of inflammatory ocular processes.

The economic burden of low back pain in KwaZulu-Natal, South Africa: A prevalence-based cost-of-illness analysis from the healthcare provider's perspective.

BACKGROUND: Low back pain (LBP) is a multifactorial and the most prevalent musculoskeletal disorder, whose economic burden is of global concern. Evidence suggests that the burden of LBP in increasing and will continue rising with the greatest burden occurring in low-and-middle-income-countries (LMICs). This study sought to determine the economic burden of LBP in KwaZulu-Natal, South Africa from the providers perspective. METHODS: We used a retrospective prevalence-based cost-of-illness methodology to estimate the direct medical cost of LBP. Direct medical costs constituted costs associated with healthcare utilisation in inpatient care, outpatient care, investigations, consultations, and cost of auxiliary devices. We used diagnostic-specific data obtained from hospital clinical reports. All identifiable direct medical costs were estimated using a top-down approach for costs associated with healthcare and a bottom-up approach for costs associated with inpatient and outpatient care. RESULTS: The prevalence of chronic low back pain CLBP was 24.3% (95% CI: 23.5-25.1). The total annual average direct medical costs associated with LBP was US$5.4 million. Acute low back pain (ALBP) and CLBP contributed 17% (US$0.92 million) and 83% (US$4.48 million) of the total cost, respectively. The per patient total annual average direct medical cost for ALBP and CLBP were US$99.43 and US$1,516.67, respectively. The outpatient care costs contributed the largest share (38.9%, US$2.10 million) of the total annual average direct medical cost, 54.9% (US$1.15 million) of which was attributed to nonsteroidal-anti-inflammatory drugs (NSAIDs). The total average cost of diagnostic investigations was estimated at US$831,595.40, which formed 15.4% of the average total cost. CONCLUSION: The economic burden of LBP is high in South Africa. Majority of costs were attributed to CLBP. The outpatient care costs contributed the largest share percent of the total cost. Pain medication was the main intervention strategy, contributing more than half of the total outpatient costs. Measures should be taken to ensure guideline adherence. Focus should also be placed towards development of prevention measures to minimise the cost.

Switching from adalimumab originator to biosimilars in hidradenitis suppurativa: What's beyond cost-effectiveness?

In the last years, adalimumab biosimilars have represented a commonly used alternative to the originator agent in the treatment of moderate to severe hidradenitis suppurativa. As of today, studies investigating the switch from adalimumab originator to biosimilar, following pharmacoeconomic policies, are lacking. Herein we present a real-life setting retrospective study aimed at assessing the safety and efficacy of this switch in 37 patients, evaluated for 12 months in terms of IHS4 (International Hidradenitis Suppurativa Severity Score System) and HiSCR (Hidradenitis Suppurativa Clinical Response). Overall, no significant differences emerge between adalimumab originator and biosimilar in terms of clinical response following non-medical switch. High discontinuation rates (43.2%) raise questions on patients' compliance to the new drug regimen, as severe pain at the injection site represents a substantial cause of biosimilar discontinuation (i.e., 31.5% of the cases). In selected cases, rechallenge with adalimumab originator may represent a valid option, as 66.6% (n = 8) of the patients who switched back to the former agent have benefited in terms of tolerability and efficacy. Carefully integrating pharmacoeconomic policies with a thorough assessment regarding the benefit-risk ratio of a nonmedical switch from originator to biosimilars remains essential to provide each HS patient with the best therapeutic option.

Research progress on natural ß-glucan in intestinal diseases.

ß-Glucan, an essential natural polysaccharide widely distributed in cereals and microorganisms, exhibits extensive biological activities, including immunoregulation, anti-inflammatory, antioxidant, antitumor properties, and flora regulation. Recently, increasing evidence has shown that ß-glucan has activities that may be useful for treating intestinal diseases, such as inflammatory bowel disease (IBD), and colorectal cancer. The advantages of ß-glucan, which include its multiple roles, safety, abundant sources, good encapsulation capacity, economic development costs, and clinical evidence, indicate that ß-glucan is a promising polysaccharide that could be developed as a health product or medicine for the treatment of intestinal disease. Unfortunately, few reports have summarized the progress of studies investigating natural ß-glucan in intestinal diseases. This review comprehensively summarizes the structure-activity relationship of ß-glucan, its pharmacological mechanism in IBD and colorectal cancer, its absorption and transportation mechanisms, and its application in food, medicine, and drug delivery, which will be beneficial to further understand the role of ß-glucan in intestinal diseases.

Mechanistic efficacy assessment of selected novel methanimine derivatives against vincristine induced Neuropathy: In-vivo, Ex-vivo and In-silico correlates.

Vincristine induced peripheral neuropathy (VIPN) is a serious untoward side effect suffered by cancer patients, which still lacks an adequate therapeutic approach. This study examined the alleviating potential of novel methanimine derivatives i.e. (E)-N-(4-nitrobenzylidene)-4-chloro-2-iodobenzamine (KB 9) and (E)-N-(2-methylbenzylidene)-4-chloro-2-iodobenzamine (KB 10) in VIPN. Vincristine was injected in BALB/c mice for 10 days to instigate nociceptive neuropathy. Dynamic and static allodynia, thermal (hot and cold) hyperalgesia were evaluated at 0, 5, 10 and 14 days using cotton brush, Von Frey filament application, hot plate test, acetone drop and cold water respectively. Tumour necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), lipid peroxide (LPO), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and reactive oxygen species (ROS) assays were performed to assess the efficacy of KB9 and KB10 against neuroinflammation and oxidative stress utilizing ELISA, immunohistochemistry and western blot analysis in brain and sciatic nerve tissues. Computational studies were executed to determine the stable binding conformation of both compounds with respect to COX-2 and NF-κB. Interestingly, both compounds substantially reduced protein expression related to neuroinflammation, oxidative stress (LPO, GST, SOD, CAT) and pain (NF-κB, COX-2, IL-1ß and TNF-α). This molecular analysis suggested that the neuroprotective effect of KB9 and KB10 was mediated via regulation of inflammatory signaling pathways. Overall, this study demonstrated that KB9 and KB10 ameliorated vincristine induced neuropathy, through anti-inflammatory, anti-nociceptive and antioxidant mechanisms.

In vitro assessment of the anti-inflammatory and skin-moisturizing effects of Filipendula palmata (Pall.) Maxim. On human keratinocytes and identification of its bioactive phytochemicals.

ETHNOPHARMACOLOGICAL RELEVANCE: The meadowsweet family (genus Filipendula) includes about 30 species, which have been traditionally used in folk medicine to treat various inflammatory diseases. Particularily, F. palmata (Pall.) Maxim. (Siberian meadowsweet) were traditionally and widely used as an ethnic herb in the Oroqen application. AIM OF THE STUDY: Limited studies have been documented on most species, except for two main species, F. ulmaria (L.) Maxim. and F. vulgaris Moench. Thus, this study aimed to investigate the anti-inflammatory and skin-moisturizing effects of 70% ethanolic extract (FPE) of F. palmata on human epidermal keratinocytes. MATERIALS AND METHODS: HaCaT keratinocytes were treated with FPE under different conditions. Quantitative real time-PCR, enzyme-linked immunosorbent assay, western blotting methods were used to evaluate the effect and molecular mechanism of the cells treated with FPE. The bioactive compounds in FPE, which are responsible for biological activities, was explored using mass spectrometric analysis. RESULTS: FPE did not show a cytotoxic effect on the cells at concentrations below 200 µg/mL. FPE significantly suppressed the intracellular reactive oxygen species and mitochondrial superoxide of inflamed HaCaT cells induced by tumor necrosis factor-α and interferon-γ (T + I) and inflammatory chemokine genes and proteins, such as CC chemokine ligands (CCL5, CCL17, and CCL27) and CXC chemokine ligand (CXCL8). These anti-inflammatory activities of FPE were mediated by the downregulation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. In normal HaCaT cells, FPE significantly promoted the production of hyaluronic acid (HA) via the downregulation of hyaluronidase (HYAL1 and HYAL2) and upregulation of hyaluronic acid synthase (HAS1, HAS2, and HAS3) genes, and these effects seemed to be associated with the PI3K/Akt/NF-κB signaling. Ultraperformance liquid chromatography-tandem mass spectrometry indicated that FPE contains four flavonoids, including (+)-catechin, miquelianin, scutellarin, and quercitrin, as its major phytochemicals. Finally, we demonstrated that miquelianin and quercitrin contribute partially to the anti-inflammatory and HA-producing activity of FPE without cytotoxic effects on HaCaT cells. CONCLUSIONS: Our findings suggest that topical applications of FPE can be utilized as an alternative therapy for treating skin inflammation. Additionally, our findings serve as a reference in applying FPE as a functional ingredient to treat inflammatory skin diseases and promote skin health.

Avaliação in silico da afinidade de drogas ao receptor TRPA1 como preditor para o manejo farmacológico da sensibilidade provocada pelo clareamento dentário / In silico assessment of drug affinity to the TRPA1 receptor as a predictor for the pharmacological management of sensitivity caused by tooth whitening

Introdução: Reduzir a sensibilidade do clareamento dental em consultório representa um desafio para os profissionais. Pesquisadores associaram o bloqueio do receptor de dor TRPA1 com a redução da sensibilidade ao clareamento. No entanto, a afinidade química dos analgésicos/anti-inflamatórios para o TRPA1 ainda precisa ser averiguada. Objetivo: Realizar uma triagem virtual de múltiplos medicamentos (analgésicos e antiinflamatórios) para verificar a afinidade química pelo receptor TRPA1. Metodologia: A estrutura cristalina das proteínas do receptor TRPA1 foi recuperada do Protein Data Bank. Os códigos SMILES dos ligantes foram extraídos do PubChem. A energia de ligação do complexo foi obtida em ∆G - kcal/mol pelo AutoDock Vina© e replicada nos servidores SwissDock©, Dockthor© e CbDock©. LigPlus© confirmou os sítios de ligação. Resultados: Apesar dos antagonistas dos receptores analisados apresentarem alta afinidade, codeína e dexametasona apresentaram regularidade em todos os servidores, mesmo apresentando valores de energia de ligação de -7,9 kcal/mol para codeína e -8,1 kcal/mol para dexametasona. Conclusão: A codeína e a dexametasona podem ser drogas potenciais para controlar a sensibilidade ao clareamento dental caso atinjam o receptor TRPA1 da polpa dentária (AU).

Introduction: Reducing in-office tooth bleaching sensitivity represents a challenge for professionals. Researchers have associated the block of the pain receptor TRPA1 with reducing bleaching sensitivity. However, the chemical affinity of analgesic/antiinflammatory drugs to the TRPA1 needs to be verified. Objective: To perform a virtual screening of multiple drugs (analgesic and anti-inflammatory drugs) to verify chemical affinity for the TRPA1 receptor. Methodology: The crystal structure of the TRPA1 receptor proteins was retrieved from the Protein Data Bank. The SMILES codes of the ligands were extracted from PubChem. The binding energy of the complex was obtained in ∆G - kcal/mol by AutoDock Vina© and replicated in the webservers SwissDock©, Dockthor©, and CbDock©. LigPlus© confirmed the binding sites. Results: Although the receptor antagonists analyzed showed high affinity, codeine and dexamethasone showed regularity among all servers, even showing binding energy values of -7.9 kcal/mol for codeine and -8.1 kcal/mol for dexamethasone. Conclusion: Codeine and dexamethasone may be potential drugs to manage tooth bleaching sensitivity if they reach the dental pulp TRPA1 receptor (AU).

Assessment of anti-inflammatory and antioxidant activity of quercetin-rutin blend (SophorOx™) - an invitro cell based assay.

OBJECTIVES: Quercetin & Rutin, are bioactive compounds that are widely used for various therapeutic properties. There's been growing interest in the biological activities of these polyphenols belonging to the class of flavonoids known to have various health benefits. Quercetin is now popularly recognized as a phytochemical remedy for a plethora of disease groups such as metabolic syndrome (more specifically diabetes), obesity/weight management and mood disorders. Due to its unique chemical structure, the most prominent property of Quercetin is probably its antioxidant capability. It acts as a free radical scavenger to form resonance-stabilized phenoxyl radicals. Certain in vitro studies have also shown quercetin to have anti-viral, anti-carcinogenic and platelet aggregation properties. Rutin has also been shown to exert diverse biological effects such as anti-tumor activities, reduction of inflammatory cytokines and antimicrobial activities. The current study was designed to further confirm the antioxidant and anti-inflammatory property of a Quercetin-Rutin blend (SophorOx™). METHODS: The analysis was performed in a cell-based assay using RAW 264.7 macrophage cell line. SophorOx™ was screened for cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) to obtain optimum concentrations for experimental assays. SophorOx™ was measured for pro-inflammatory cytokine levels (TNF-α & IL-6) and nitric oxide (NO) levels. Additionally, ROS (reactive oxygen species) levels in RAW cells were estimated using a cell-permeant reagent 2'7'-dichlorofluorescein diacetate (DCFH-DA). RESULTS: SophorOx™ at 10 µM concentration, exhibited an anti-inflammatory property with significant inhibitory levels of TNF-α (∼28.25%) and IL-6 (∼32.25%). SophorOx™ at similar concentrations reduced nitric oxide levels to 70.55% in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Raw 264.7 cells stimulated with LPS exhibited a significant increase in intracellular ROS and this was significantly reduced (78.2% reduction) at lower concentrations (0.3 µM) of SophorOx™. CONCLUSIONS: The anti-inflammatory effects of SophorOx™ were investigated in LPS stimulated RAW 264.7 macrophages. Data suggests, that SophorOx™ reduced levels of nitric oxide, intracellular ROS and pro-inflammatory cytokines (TNF-α & IL-6) at low concentrations without affecting the viability of RAW cells. Present invitro trial suggests that SophorOx™ is a potent antioxidant and anti-inflammatory agent and displays a prominent ability to block mediators of oxidative stress and inflammation.

Cost-effectiveness of Physical Therapy vs Intra-articular Glucocorticoid Injection for Knee Osteoarthritis: A Secondary Analysis From a Randomized Clinical Trial.

Importance: Physical therapy and glucocorticoid injections are initial treatment options for knee osteoarthritis, but available data indicate that most patients receive one or the other, suggesting they may be competing interventions. The initial cost difference for treatment can be substantial, with physical therapy often being more expensive at the outset, and cost-effectiveness analysis can aid patients and clinicians in making decisions. Objective: To investigate the incremental cost-effectiveness between physical therapy and intra-articular glucocorticoid injection as initial treatment strategies for knee osteoarthritis. Design, Setting, and Participants: This economic evaluation is a secondary analysis of a randomized clinical trial performed from October 1, 2012, to May 4, 2017. Health economists were blinded to study outcomes and treatment allocation. A randomized sample of patients seen in primary care and physical therapy clinics with a radiographically confirmed diagnosis of knee osteoarthritis were evaluated from the clinical trial with 96.2% follow-up at 1 year. Interventions: Physical therapy or glucocorticoid injection. Main Outcomes and Measures: The main outcome was incremental cost-effectiveness between 2 alternative treatments. Acceptability curves of bootstrapped incremental cost-effectiveness ratios (ICERs) were used to identify the proportion of ICERs under the specific willingness-to-pay level ($50 000-$100 000). Health care system costs (total and knee related) and health-related quality-of-life based on quality-adjusted life-years (QALYs) were obtained. Results: A total of 156 participants (mean [SD] age, 56.1 [8.7] years; 81 [51.9%] male) were randomized 1:1 and followed up for 1 year. Mean (SD) 1-year knee-related medical costs were $2113 ($4224) in the glucocorticoid injection group and $2131 ($1015) in the physical therapy group. The mean difference in QALY significantly favored physical therapy at 1 year (0.076; 95% CI, 0.02-0.126; P = .003). Physical therapy was the more cost-effective intervention, with an ICER of $8103 for knee-related medical costs, with a 99.2% probability that results fall below the willingness-to-pay threshold of $100 000. Conclusions and Relevance: A course of physical therapy was cost-effective compared with a course of glucocorticoid injections for patients with knee osteoarthritis. These results suggest that, although the initial cost of delivering physical therapy may be higher than an initial course of glucocorticoid injections, 1-year total knee-related costs are equivalent, and greater improvement in QALYs may justify the initial higher costs. Trial Registration: ClinicalTrials.gov Identifier: NCT01427153.

Model-based cost-effectiveness analyses comparing combinations of urate lowering therapy and anti-inflammatory treatment in gout patients.

OBJECTIVES: To assess the cost-effectiveness of various combinations of urate lowering therapy (ULT) and anti-inflammatory treatment in the management of newly diagnosed gout patients, from the Dutch societal perspective. METHODS: A probabilistic patient-level simulation estimating costs and quality-adjusted life years (QALYs) comparing gout and hyperuricemia treatment strategies was performed. ULT options febuxostat, allopurinol and no ULT were considered. Flare treatments naproxen, colchicine, prednisone, and anakinra were considered. A Markov Model was constructed to simulate gout disease. Health states were no flare, and severe pain, mild pain, moderate pain, or no pain in the presence of a flare. Model input was derived from patient level clinical trial data, meta-analyses or from previously published health-economic evaluations. The results of probabilistic sensitivity analyses were presented using incremental cost-effectiveness ratios (ICERs), and summarized using cost-effectiveness acceptability curves (CEACs). Scenario analyses were performed. RESULTS: The ICER for allopurinol versus no ULT was €1,381, when combined with naproxen. Febuxostat yielded the highest utility, but also the highest costs (€4,385 vs. €4,063 for allopurinol), resulting in an ICER of €25,173 when compared to allopurinol. No ULT was not cost-effective, yielding the lowest utility. For the gout flare medications, comparable effects on utility were achieved. Combined with febuxostat, naproxen was the cheapest option (€4,404), and anakinra the most expensive (€4,651). The ICER of anakinra compared to naproxen was €818,504. Colchicine and prednisone were dominated by naproxen. CONCLUSION: Allopurinol and febuxostat were both cost-effective compared to No ULT. Febuxostat was cost-effective in comparison with allopurinol at higher willingness-to-pay thresholds. For treating gout flares, colchicine, naproxen and prednisone offered comparable health economic implications, although naproxen was the favoured option.