J Pharmacol Exp Ther. 2022 Apr 5:JPET-AR-2021-001019. doi: 10.1124/jpet.121.001019. Online ahead of print.

ABSTRACT

Acute lung injury (ALI) is a serious inflammatory lung disease. Imbalances in the polarization of classically activated (M1) and alternatively activated (M2) macrophages are closely related to ALI. Anisodamine has a promising therapeutic effect for septic shock. Nevertheless, the role of Anisodamine in progression of ALI remains to be investigated. Our results showed that Anisodamine significantly reduced lung damage, myeloperoxidase (MPO) activity, lung wet/dry ratio, total cell number and protein concentrations in bronchoalveolar lavage fluid (BALF), and decreased IL-6 level and the levels of M1 phenotypic markers, while increased IL-10 level and the levels of M2 phenotypic markers in mice with a nasal instillation of lipopolysaccharide (LPS). Bone marrow-derived macrophages (BMDMs) were stimulated or transfected with LPS plus Anisodamine or LPS plus G9a shRNA. Anisodamine and downregulation of G9a both promoted BMDM M2 polarization caused by IL-4 treatment and inhibited M1 polarization resulted from LPS treatment. ChIP assay revealed that Anisodamine inhibited G9a-mediated methylation and expression suppression on IRF4. Overexpression of G9a or silence of IRF4 reversed the improvement effect of Anisodamine on lung tissue injury, evidencing by an increase of MPO activity and the restoration of LPS-induced alterations of M1 and M2 polarization. In conclusion, Anisodamine protected against LPS-induced ALI, during which Anisodamine suppressed the LPS-stimulated alterations of macrophage M1 and M2 polarization through inhibiting G9a mediated methylation of IRF4, suggesting that Anisodamine was a potential therapeutic drug to alleviate ALI. Significance Statement Anisodamine treatment was able to attenuate lung injury and pulmonary edema after the stimulation of LPS, and the specific mechanism was through reversing the LPS-induced alterations of M1 and M2 polarization by inhibiting G9a mediated silencing of IRF4, which suggests the Anisodamine has the potential to alleviate ALI.

PMID:35383125 | DOI:10.1124/jpet.121.001019

J Cancer Res Ther. 2022 Jan-Mar;18(1):109-118. doi: 10.4103/jcrt.JCRT_925_20.

ABSTRACT

PURPOSE: Lung cancer mostly diagnosed at advanced inoperable stages; thereby, the chemo-, radiation-, targeted or immune-therapy alone or in combination remains the treatment of choice. In chemotherapy, platinum-based compounds such as cisplatin and carboplatin and third-generation drugs such as docetaxel, paclitaxel, gemcitabine, and vinorelbine are widely used. The beneficial therapeutic outcome of the chemotherapy alone or in combination with radiation (chemoradiation) and/or development of drug resistance depends on the inter-individual genetic differences. Hence, this study was carried out to find gene biomarker that could be useful in the diagnosis of the disease and to predict the outcome of chemo/chemoradiation therapy in ethnic North Indian population.

MATERIALS AND METHODS: In this clinical study, lung cancer (n = 52) patients from North Indian population were recruited. All the patients were treated with carboplatin target area under curve-5 in combination with third-generation drugs (gemcitabine 1.2 mg/m2; paclitaxel 175 mg/m2; and etopside 100 mg/m2) and radiation therapy. The genomic DNA was isolated from the blood sample and performed polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism.

RESULTS: We found hazard ratio to be significantly higher for XPDLys751Gln (hazard ratio [HR] =2.11, 95% confidence interval [CI]: 0.98-4.53, P = 0.056) and IL1 β511C/T (HR = 9.9, 95% CI: 2.55-38.40, P = 0.001). GSTT1 null (HR = 0.39, 95%CI: 0.18-0.84, P = 0.017) genotype has better response to chemotherapy. Generalized multidimensional reduction model suggested that IL1RN (cross-validation consistency [CVC] =10/10, P = 0.054) and XRCC1399Gln, GSTM1 (CVC = 10/10, P = 0.001) as best predicted model in lung cancer patients to the treatment response.

CONCLUSION: Genetic polymorphisms and single nucleotide polymorphisms in DNA repair gene (XRCC1, XPD) and drug-metabolizing gene (GSTM1 and GSTT1) could serve as genetic biomarkers in lung cancer patients treated with the above indicated chemotherapy. Based on genotype and chemotherapy treatments, the toxicity effects can be minimized, this will help in the development of personalized medicine in future with better efficacy.

PMID:35381771 | DOI:10.4103/jcrt.JCRT_925_20

Pharmacogenomics. 2022 Apr 5. doi: 10.2217/pgs-2022-0032. Online ahead of print.

NO ABSTRACT

PMID:35380470 | DOI:10.2217/pgs-2022-0032

Pharmacogenomics. 2022 Apr 5. doi: 10.2217/pgs-2021-0158. Online ahead of print.

ABSTRACT

Pharmacogenetics (PGx) is the relationship between an individual's genetic variations and the response to pharmacological treatment. We chose to perform an overview of reviews on PGx testing-guided treatment for cardiovascular diseases, based on clinically relevant gene-drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. The most studied gene-drug pairs were clopidogrel and warfarin associated with cytochrome p450 and vitamin K epoxide reductase complex subunit 1 genes (CYP2C19, CYP2C9 and VKORC1), classified as critically low quality. There is a need for more quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of PGx testing for cardiovascular diseases.

PMID:35380455 | DOI:10.2217/pgs-2021-0158

J Investig Med. 2022 Apr 4:jim-2022-002339. doi: 10.1136/jim-2022-002339. Online ahead of print.

ABSTRACT

This study aimed to explore the clinical adverse effects of anthracyclines on patients undergoing chemotherapy after breast cancer surgery. A total of 118 patients who received anthracycline chemotherapy after breast cancer surgery were selected as the research object, and the changes of echocardiogram, ECG, myocardial enzymes and blood biochemical indices before, during and after chemotherapy were studied. SPSS V.20 was used to conduct statistical analysis. The differences in heart rate, ST-segment abnormalities, creatine kinase, lactate dehydrogenase, hemoglobin, albumin, triglycerides and high-density lipoprotein were statistically significant. Heart rate and triglycerides increased significantly in the early stage of chemotherapy; ST-segment abnormality increased during the entire chemotherapy period; creatine kinase and lactate dehydrogenase increased significantly in the late stage of chemotherapy; hemoglobin and albumin decreased in the early stage of chemotherapy. The magnitude is large; high-density lipoprotein decreases throughout the chemotherapy period. In anthracycline chemotherapy regimens, bone marrow suppression and dyslipidemia occur in the early stage of chemotherapy, and the risk of cardiotoxicity is higher in the late stage of chemotherapy.

PMID:35379700 | DOI:10.1136/jim-2022-002339

Farm Hosp. 2021 Dec 23;45(7):102-108.

ABSTRACT

OBJECTIVE: The goal of this article is to analyze the situation of harmacokinetics and pharmacogenetics units in the pharmacy departments of Spanish hospitals, evaluate their development both in the clinical and educational areas, and draw up a map reflecting their current status. Method: A 29-item survey structured in five blocks was designed with general questions about the respondents' hospital and the clinical and educational activities carried out by their pharmacy department, in the fields of both pharmacokinetics and pharmacogenetics.

RESULTS: Sixty-nine hospitals answered the survey. The highest response rates corresponded to Catalonia, the Valencia region and Andalusia. The drug families subject to closest monitoring were classic antibiotics (93%), digoxin (57%), classic antiepileptics (51%) and biologicals (43%). The most frequently used computer programs included PKS and NONMEM (93% and 22% of hospitals, respectively). Regarding training in pharmacokinetics, second year residents were those who most frequently rotated through the pharmacokinetics unit (40%), while 44% of those units allowed external residents. As far as pharmacogenetics is concerned, in 42% of hospitals that engaged in pharmacogenetic work, the department in charge was pharmacy. The most frequent specialties covered were hemato-oncology (72%) and psychiatry (15%). Twenty-four percent of hospitals offered rotations through their pharmacogenetics unit but only seven of them allowed external residents.

CONCLUSIONS: The results of the survey showed an increase in the erformance of pharmacokinetic and pharmacogenetic activities by Spanish hospital pharmacies as compared with the data from a 2009 baseline survey, with many hospitals introducing the performance of therapeutic drug monitoring of non-classical antibiotics, immunosuppressants and biologics. However, the percentage of hospitals that follow the ideal model based on analytical determinations and pharmacokinetic reporting has decreased the data obtained served as a basis to create an updated map of the harmacokinetics and pharmacogenetics units operating in Spanish hospital pharmacy departments. This map, available at http://bit.ly/mapaPKGen, will be very useful to facilitate the training of residents in these disciplines and will help promote the development of pharmacokinetic and pharmacogenetic activities among hospital pharmacists.

PMID:35379116

Farm Hosp. 2021 Dec 22;45(7):84-93.

ABSTRACT

OBJECTIVE: Neuropsychiatrists often resort to drugs with broad interindividual pharmacokinetic variability metabolized by highly polymorphic enzymes such as CYP2D6 and CYP2C19. Pharmacokinetics and pharmacogenetics offer considerable promise as techniques capable to allow individualized adjustments in treatments with psychoactive drugs. The purpose of this study was to review the existing evidence for the application of pharmacokinetics and pharmacodynamics to the dosing of drugs used in neuropsychiatry.

METHOD: A literature search was conducted in PubMed and Embase to find prospective studies published between January 2000 and April 2021 that used determination of psychotropic drug plasma levels or genotyping to improve response to treatment or minimize adverse events in adult patients with psychiatric conditions. MeSH terms and free search terms were used. Each article was reviewed by two independent reviewers to ensure that they met the inclusion criteria. A quantitative method was established to assess the quality of the articles selected. Results: A total of 27 articles met the inclusion criteria of which 16 used pharmacokinetic and 11 pharmacogenetic techniques. Fifty percent of pharmacokinetic studies met the five predefined quality criteria. Eight of the 16 papers were on antidepressants; the remainder were on antipsychotics. Two of the latter did not find an association with efficacy or safety. None of the pharmacogenetic studies met the five quality criteria. Only one of the two studies on antipsychotics found fewer adverse events with genetics-guided dosing in patients on CYP2D6 substrate antipsychotics. Six of the nine studies on antidepressants found that pharmacogeneticsbased dosing improved efficacy.

CONCLUSIONS: The evidence available on pharmacokinetics and harmacodynamics- based personalization of treatment with psychoactive drugs is scarce. Many existing studies analyze associations between genotypes and response or toxicity but provide few data on the efficacy of treatment individualization. The results obtained suggest the existence of significant differences in pharmacokinetic parameters between responding and nonresponding patients, particularly in the treatment of depression. Given that the availability of pharmacogenetic information may be useful at the beginning of treatment, combining both techniques could help optimize pharmacotherapy. However, clinical trials are needed to establish their benefits with greater accuracy.

PMID:35379114

Farm Hosp. 2021 Dec 22;45(7):56-63.

ABSTRACT

OBJECTIVE: The rise in the development of monoclonal antibodies has brought about a revolution in the pharmacotherapy of inflammatory bowel disease (Crohn's disease and ulcerative colitis). Systematic plasma concentrations monitoring of these biological drugs in anticipation of potential clinical failures of treatment is known as proactive therapeutic drug monitoring. New pharmacogenetic analysis techniques have recently been developed that can predict response to these treatments even before they are administered. The goal of this systematic review is to analyze the potential benefits of proactive therapeutic drug monitoring and of the harmacogenetic analysis of biological drugs in inflammatory bowel disease patients in terms of clinical remission.

METHOD: A systematic search was performed in the MEDLINE/Pubmed, Embase and Cochrane Library databases using the escriptors proactive drug monitoring, biological drugs, inflammatory bowel disease and pharmacogenetics. Only randomized clinical trials published between January 2015 and May 2021 were included; all articles whose main topic was not related to the topic were excluded by hand. The quality of the articles was assessed using the Jadad scale and risk of bias was assessed using the Cochrane Collaboration tool.

RESULTS: After applying inclusion and exclusion criteria, seven of the 228 retrieved articles were selected for review. Almost all the studies measured the same clinical variables (Harvey-Bradshaw index for Crohn's disease and Mayo score for ulcerative colitis). Only in two of the included studies was proactive therapeutic drug monitoring superior to reactive monitoring- or no level-guided dose adjustments. No pharmacogenetic analyses were found that met the criteria defined. Conclusions: This review shows that the data supporting the use of proactive therapeutic drug monitoring in inflammatory bowel disease is limited and of low quality. Although pharmacogenetic analysis can be a useful tool for personalizing treatment, further and better designed randomized clinical trials are needed to determine the role of proactive drug monitoring strategies in clinical practice.

PMID:35379111

Farm Hosp. 2021 Dec 22;45(7):11-37.

ABSTRACT

OBJECTIVE: As more genes are incorporated into pharmacogenomic care processes and more importance is given to rare variants, the use of targeted capture sequencing panels has been proposed as a very efficient alternative due to their affordability, high throughput, and deep coverage, all of them characteristics of high-quality next-generation sequencing data. The purpose of this study is to describe the prevalence of clinically actionable pharmacogenetic variants previously described in the scientific literature, as well as that of new variants identified by next-generation sequencing technologies, and to evaluate the drugs potentially affected by such variants.

METHOD: A panel of 18 clinically actionable pharmacogenomics-related genes was evaluated in 41 subjects diagnosed with breast cancer undergoing neoadjuvant treatment. The prevalence of previously descri- bed clinically actionable variants as well as of phenotypes classified according to current interpretation standards was studied. The pharmacological treatments potentially affected by the identified variants were also evaluated. An estimation was made of the prevalence of not previously described, possibly deleterious, variants selected using bioinformatics criteria.

RESULTS: All subjects carried clinically actionable variants, with a mean of 4.02 genes affected by each variant per individual. VKORC1, CYP4F2, CYP2C19, CYP2D6 and CYP2B6 were the most polymorphic genes and were present with actionable phenotypes in more than 50% of patients; 15-50% had actionable phonotypes in UGT1A1, SLCO1B1, CYP2C9 and TPMT and 2-15% in HLA-B, CYP3A5, HLA-A and DPYD. No actionable variants were identified in RYR1, CACNA1S, G6PD, F5 and NUDT15. These variants had the potential to affect response to 84% of the drugs described in the leading pharmacogenetic guidelines. Possibly deleterious variants not previously described accounted for 11.4% of all clinically actionable variants and were present in 12.2% of patients.

CONCLUSIONS: The results obtained show a high prevalence of clinically actionable variants, both common, i.e., previously described in the literature, and rare, i.e., not previously studied with conventional technological approaches. The latter are candidates for a more exhaustive molecular and/or clinical characterization.

PMID:35379108

Farm Hosp. 2021 Dec 21;45(7):5-10.

ABSTRACT

OBJECTIVE: To determine the prevalence of loss-of-function variants in the dihydropyrimidine dehydrogenase gene in patients with gastrointestinal neoplasms, assess their clinical relevance, and evaluate the implementation of a multidisciplinary circuit at three months from its implementation.

METHOD: This is a descriptive, observational and retrospective study, which included adult patients with gastrointestinal cancer treated at a tertiary university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020. The variables collected were sex, age, type of cancer, location, stage, treatment received, indication of treatment and degree of toxicity developed during the first three cycles. The genotyped variants were rs3918290 (c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798 (c.2846A>T) and rs75017182 (c.1129-5923C>G).

RESULTS: A total of 115 patients were included. The frequency of heterozygous dihydropyrimidine dehydrogenase variant carriers was 9.6% (11 patients). The most frequently identified variant was rs75017182 (6 patients). The second most common variant was rs67376798 (3 patients), followed by rs3918290 (2 patients). No patients presented with the rs55886062 variant. Two of the dihydropyrimidine dehydrogenase carriers developed grade 3-5 toxicity after the first cycle of a regimen that included fluoropyrimidines. Both received full doses of fluoropyrimidine, since their dihydropyrimidine dehydrogenase genotype was unknown before treatment initiation. None of the dihydropyrimidine dehydrogenase carriers who began treatment with a reduced dose of fluoropyrimidine experienced grade 3-5 toxicity. Since the creation in October 2020 of a multidisciplinary team, with the active participation of hospital pharmacists, the monthly average of dihydropyrimidine dehydrogenase genotyping studies has increased from 6.4 (January-October) to 17.5 (November-December).

CONCLUSIONS: The present study shows a relatively high prevalence of loss-of- function variants in the dihydropyrimidine dehydrogenase gene as well as the importance of genotyping such variants before starting a treatment with fluoropyrimidines. Hospital pharmacists can contribute to the implementation of pharmacogenetics in daily clinical practice in a tertiary hospital.

PMID:35379107

Clin Pharmacol Ther. 2022 Apr 3. doi: 10.1002/cpt.2598. Online ahead of print.

ABSTRACT

The combined use of diagnostic and therapeutic radioligands with the same molecular target, also known as theranostics, enables accurate patient selection, targeted therapy and prediction of treatment response. Radioiodine, bone-seeking radioligands and norepinephrine analogues have been used for many years for diagnostic imaging and radioligand therapy of thyroid carcinoma, bone metastases, pheochromocytoma, paraganglioma and neuroblastoma, respectively. In recent years, radiolabeled somatostatin analogues and prostate-specific membrane antigen ligands have shown clinical efficacy in the treatment of neuroendocrine tumors and prostate cancer, respectively. Several candidate compounds are targeting novel theranostic targets such as fibroblast activation protein, C-X-C chemokine receptor 4 and gastrin-releasing peptide receptor. In addition, several strategies to improve efficacy of radioligand therapy are being evaluated, including dosimetry-based dose optimization, multi-receptor targeting, upregulation of target receptors, radiosensitization, pharmacogenomics and radiation genomics. Design and evaluation of novel radioligands and optimization of dose and dose schedules, within the complex context of individualized multimodal cancer treatment, requires a multidisciplinary approach including clinical pharmacology. Significant increases in the use of these radiopharmaceuticals in routine oncological practice can be expected, which will have major impact on patient care as well as (radio)pharmacy utilization.

PMID:35373336 | DOI:10.1002/cpt.2598

HGG Adv. 2022 Mar 16;3(2):100100. doi: 10.1016/j.xhgg.2022.100100. eCollection 2022 Apr 14.

ABSTRACT

The origins of pharmacogenetics date back to the 1950s, when it was established that inter-individual differences in drug response are partially determined by genetic factors. Since then, pharmacogenetics has grown into its own field, motivated by the translation of identified gene-drug interactions into therapeutic applications. Despite numerous challenges ahead, our understanding of the human pharmacogenetic landscape has greatly improved thanks to the integration of tools originating from disciplines as diverse as biochemistry, molecular biology, statistics, and computer sciences. In this review, we discuss past, present, and future developments of pharmacogenetics methodology, focusing on three milestones: how early research established the genetic basis of drug responses, how technological progress made it possible to assess the full extent of pharmacological variants, and how multi-dimensional omics datasets can improve the identification, functional validation, and mechanistic understanding of the interplay between genes and drugs. We outline novel strategies to repurpose and integrate molecular and clinical data originating from biobanks to gain insights analogous to those obtained from randomized controlled trials. Emphasizing the importance of increased diversity, we envision future directions for the field that should pave the way to the clinical implementation of pharmacogenetics.

PMID:35373152 | PMC:PMC8971318 | DOI:10.1016/j.xhgg.2022.100100

Kidney360. 2022 Feb 24;3(2):204-207. doi: 10.34067/KID.0007792021. eCollection 2022 Feb 24.

NO ABSTRACT

PMID:35373121 | PMC:PMC8967644 | DOI:10.34067/KID.0007792021

Front Mol Biosci. 2022 Mar 15;9:822188. doi: 10.3389/fmolb.2022.822188. eCollection 2022.

NO ABSTRACT

PMID:35372509 | PMC:PMC8964776 | DOI:10.3389/fmolb.2022.822188

Front Oncol. 2022 Mar 15;12:824511. doi: 10.3389/fonc.2022.824511. eCollection 2022.

ABSTRACT

Immune checkpoint inhibitors (ICIs) are widely used improving clinical outcomes in many cancer patients. However, they can induce serious consequences, like neurological immune-related adverse drug reactions (NirADRs). Although these are rare complications, they can be serious with important impact on patients' quality of life. Our purpose is to describe these adverse events observed in the European clinical practice context. We carried out a descriptive analysis of individual case safety reports (ICSRs) related to ICIs collected until February 7, 2020, in the European spontaneous reporting database, EudraVigilance, and reported nervous disorders as suspect adverse drug reactions (ADRs). NirADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA). In order to identify a hypothetical different reporting probability of the NirADR types between the ICI classes, we carried out a disproportionality analysis. The reporting odds ratio (ROR) with 95% CI was computed comparing the different ICI classes to each other based on their pharmacological target [the cytotoxic T-lymphocyte antigen-4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1)]. Finally, we researched in the literature the hypothesized mechanisms, which could explain the onset of these ICI-related neurological complications. Overall, we found 4,875 cases describing 6,429 ICI-related suspected NirADRs. ICI-related neurotoxicities include a wide range of central and peripheral events. These were mainly related to anti-PD-1 agents and occurred in male patients (59%). Our analysis confirmed a gender difference of NirADRs. Twenty-three percent of the events (comprising myasthenia gravis, neuropathy peripheral, and cerebral infarction) had unfavorable fallouts, including fatal outcome (7%). Majority of the NirADRs were categorized as "Neurological disorders NEC" HLGTs MedDRA (2,076; 32%). In 1,094 cases (22%), more NirADRs overlapped with other neurologic complications. An interesting overlapping of myasthenia gravis with myositis or myocarditis emerged. From our disproportionality analysis, an increased reporting probability of peripheral neuropathies and headaches emerged with ipilimumab when compared to anti-PD-1 and anti-PD-L1 agents. However, neuromuscular disorders were more probably reported with anti-PD-1. Several pathogenic mechanisms, including neuronal damage by T cells and autoantibodies and/or cytokine-mediated inflammation processes, have been hypothesized. However, the pathogenesis of these ICI-related complications is not completely understood. Considering the recent marketing authorizations of ICIs, further studies are strongly needed to monitor their neurologic safety profile.

PMID:35372076 | PMC:PMC8964934 | DOI:10.3389/fonc.2022.824511

Front Pharmacol. 2022 Mar 18;13:837756. doi: 10.3389/fphar.2022.837756. eCollection 2022.

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative disorder with prominent dopamine (DA) neuron degeneration. PD affects millions of people worldwide, but currently available therapies are limited to temporary relief of symptoms. As an effort to discover disease-modifying therapeutics, we have conducted a screen of 1,403 bioactive small molecule compounds using an in vivo whole organism screening assay in transgenic larval zebrafish. The transgenic model expresses the bacterial enzyme nitroreductase (NTR) driven by the tyrosine hydroxylase (th) promotor. NTR converts the commonly used antibiotic pro-drug metronidazole (MTZ) to the toxic nitroso radical form to induce DA neuronal loss. 57 compounds were identified with a brain health score (BHS) that was significantly improved compared to the MTZ treatment alone after FDR adjustment (padj<0.05). Independently, we curated the high throughput screening (HTS) data by annotating each compound with pharmaceutical classification, known mechanism of action, indication, IC50, and target. Using the Reactome database, we performed pathway analysis, which uncovered previously unknown pathways in addition to validating previously known pathways associated with PD. Non-topology-based pathway analysis of the screening data further identified apoptosis, estrogen hormone, dipeptidyl-peptidase 4, and opioid receptor Mu1 to be potentially significant pathways and targets involved in neuroprotection. A total of 12 compounds were examined with a secondary assay that imaged DA neurons before and after compound treatment. The z'-factor of this secondary assay was determined to be 0.58, suggesting it is an excellent assay for screening. Etodolac, nepafenac, aloperine, protionamide, and olmesartan showed significant neuroprotection and was also validated by blinded manual DA neuronal counting. To determine whether these compounds are broadly relevant for neuroprotection, we tested them on a conduritol-b-epoxide (CBE)-induced Gaucher disease (GD) model, in which the activity of glucocerebrosidase (GBA), a commonly known genetic risk factor for PD, was inhibited. Aloperine, olmesartan, and nepafenac showed significant protection of DA neurons in this assay. Together, this work, which combines high content whole organism in vivo imaging-based screen and bioinformatic pathway analysis of the screening dataset, delineates a previously uncharted approach for identifying hit-to-lead candidates and for implicating previously unknown pathways and targets involved in DA neuron protection.

PMID:35370735 | PMC:PMC8971663 | DOI:10.3389/fphar.2022.837756

Int J Nephrol Renovasc Dis. 2022 Mar 26;15:115-126. doi: 10.2147/IJNRD.S354658. eCollection 2022.

ABSTRACT

INTRODUCTION: Indoxyl sulfate, a protein-bound uremic toxin, has been reported as an atherosclerosis and fibrosis accelerator. This study aimed to determine whether serum indoxyl sulfate is associated with cardiac abnormalities, cardiovascular events, and renal progression to dialysis in patients with chronic kidney disease (CKD).

METHODS: The prospective study enrolled 89 patients with CKD stage 3 to 5 patients. Serum biochemistry data and indoxyl sulfate were measured. All patients underwent echocardiographic examination. Global longitudinal strain (GLS) was calculated using two-dimensional speckle tracking. The clinical outcomes including cardiovascular event and dialysis initiation were recorded during a 2-year follow-up.

RESULTS: Patients were divided into 2 groups based on the median value of serum indoxyl sulfate (low and high indoxyl sulfate groups). Kaplan-Meier analysis revealed that patients with higher indoxyl sulfate (≥6.124 mg/L) were significantly associated with renal progression to dialysis (p < 0.001). There was no significant difference in cardiovascular events between 2 groups (p = 0.082). In addition, serum indoxyl sulfate level was independently associated with GLS (r = 0.62; p = 0.01). The risk of cardiovascular events was significantly higher in patients with impaired GLS (>-16%) (p = 0.015).

CONCLUSION: Serum indoxyl sulfate level was a significant predictor for CKD progression to dialysis and was correlated with GLS, a speckle tracking echocardiography parameter representing early LV systolic dysfunction. Furthermore, GLS was associated with cardiovascular events in CKD patients. Serum indoxyl sulfate measurement may help to identify the high dialysis and cardiovascular risk CKD patients beyond traditional risk factors.

PMID:35370416 | PMC:PMC8967989 | DOI:10.2147/IJNRD.S354658

Evid Based Complement Alternat Med. 2022 Mar 25;2022:4787643. doi: 10.1155/2022/4787643. eCollection 2022.

ABSTRACT

Diterpenes and their derivatives have many biological activities, including anti-inflammatory and immunomodulatory effects. To date, several diterpenes, diterpenoids, and their laboratory-derived products have been demonstrated for antiarthritic activities. This study summarizes the literature about diterpenes and their derivatives acting against rheumatoid arthritis (RA) depending on the database reports until 31 August 2021. For this, we have conducted an extensive search in databases such as PubMed, Science Direct, Google Scholar, and Clinicaltrials.gov using specific relevant keywords. The search yielded 2708 published records, among which 48 have been included in this study. The findings offer several potential diterpenes and their derivatives as anti-RA in various test models. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways. In addition, some important derivatives of triptolide and tanshinone IIA have also been shown to have anti-RA effects. Overall, findings suggest that these substances could reduce arthritis score, downregulate oxidative, proinflammatory, and inflammatory biomarkers, modulate various arthritis pathways, and improve joint destruction and clinical arthritic conditions, signs, symptoms, and physical functions in humans and numerous experimental animals, mainly through cytokine and chemokine as well as several physiological protein interaction pathways. Taken all together, diterpenes, diterpenoids, and their derivatives may be promising tools for RA management.

PMID:35368757 | PMC:PMC8975657 | DOI:10.1155/2022/4787643

Kidney360. 2021 Nov 3;3(1):37-50. doi: 10.34067/KID.0004802021. eCollection 2022 Jan 27.

ABSTRACT

BACKGROUND: Few studies have described associations between the AKI biomarkers urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) with AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin.

METHODS: Participants (n=159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured (1) pre-cisplatin infusion, (2) post-infusion (morning after), and (3) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin, on the basis of Kidney Disease Improving Global Outcomes guidelines criteria (stage 1 or higher).

RESULTS: Of 159 children, 156 (median [interquartile range (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty six of the 156 (29%) and 22 of the 127 (17%) children developed AKI within 10 days of cisplatin administration after early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with versus without AKI (near hospital discharge of late cisplatin infusion, median [IQR] NGAL levels were 76.1 [10.0-232.7] versus 14.9 [5.4-29.7] ng/mg creatinine; KIM-1 levels were 4415 [2083-9077] versus 1049 [358-3326] pg/mg creatinine; P<0.01). These markers modestly discriminated for AKI (area under receiver operating characteristic curve [AUC-ROC] range: NGAL, 0.56-0.72; KIM-1, 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROC range, 0.54-0.75) versus early infusions (AUC-ROC range, 0.48-0.65).

CONCLUSIONS: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and associations with late kidney outcomes.

PMID:35368557 | PMC:PMC8967607 | DOI:10.34067/KID.0004802021

EXCLI J. 2022 Feb 16;21:400-414. doi: 10.17179/excli2021-4534. eCollection 2022.

ABSTRACT

Polycystic ovary syndrome (PCOS) is the most common cause of women's infertility. Some inflammatory pathways play a pivotal role in the pathogenesis of PCOS. This study aimed to investigate the possible beneficial effects of minocycline on chemokine-like receptor 1 (CMKLR1) and Insulin Receptor (INSR) in a PCOS model. A molecular docking study was implemented using Molecular Operating Environment (MOE) software. The PCOS was induced in NMRI mice (mean body weight 14.47±0.23) by 28 days estradiol valerate injection (2 mg/kg/day). The mice were then divided into six groups (n=8 per group, mean body weight 17.77± 0.26): control (received normal saline), PCOS model, control for minocycline, minocycline treated PCOS (50 mg/kg), letrozole treated PCOS (0.5 mg/kg), and metformin-treated PCOS (300 mg/kg). Serum FSH, LH, estradiol (E2), and testosterone were detected by ELISA. The ovarian tissues were stained by hematoxylin and eosin. The CMKLR1 and INSR expression levels were determined by Real-time-PCR. The molecular docking studies showed scores of -10.92 and -9.30 kcal/mol, respectively, for minocycline with CMKLR1 and INSR. Estradiol valerate treatment led to a significant increase in E2, graffian follicle, and decrease in corpus luteum (CL) numbers (P<0.05), while minocycline treatment improved these PCOS features. The minocycline treatment significantly decreased the CMKLR1 expression and increased the INSR expression (P<0.05) while the CMKLR1 expression was increased in PCOS model. Minocycline may improve ovulation in PCOS model by returning E2 to a normal level and increasing CL number (ovulation signs). These beneficial outcomes may be related to the changes in CMKLR1 and INSR gene expression involved in glucose metabolism and inflammation.

PMID:35368462 | PMC:PMC8971357 | DOI:10.17179/excli2021-4534