Toxicol In Vitro. 2022 Apr 12:105357. doi: 10.1016/j.tiv.2022.105357. Online ahead of print.

ABSTRACT

Gastric cancer (GC) is among the deadliest cancers worldwide despite available therapies, highlighting the need for novel therapies and pharmacological agents. Metabolic deregulation is a potential study area for new anticancer targets, but the in vitro metabolic studies are controversial, as different ranges of glucose used in the culture medium can influence results. In this study, we evaluated cellular viability, glucose uptake, and LDH activity in gastric cell lines when exposed to different glucose concentrations: high (HG, 25 mM), low (LG, 5.5 mM), and free (FG, 0 mM) glucose mediums. Moreover, we evaluated how glucose variations may influence cellular phenotype and the expression of genes related to epithelial-mesenchymal transition (EMT), metabolism, and cancer development in metastatic GC cells (AGP-01). Results showed that in the FG metastatic cells evidenced higher viability when compared with other cell lines and that when exposed to either LG or HG mediums most of the phenotypic assays did not differ. However, cells exposed to LG increased colony formation and mRNA levels of metabolic-related genes when compared to HG medium. Our results recommend LG medium to metabolic studies once glucose concentration is closer to physiological levels. These findings are important to point out new relevant targets in metabolic reprogramming that can be alternatives to current chemotherapies in patients with metastatic GC.

PMID:35427737 | DOI:10.1016/j.tiv.2022.105357

J Biomol Struct Dyn. 2022 Apr 15:1-12. doi: 10.1080/07391102.2022.2062785. Online ahead of print.

ABSTRACT

CYP2A6 is a very important enzyme that plays a crucial role in nicotine compounds and is responsible for the metabolism of more than 3% drugs of total metabolized drugs by the CYP family and reported as one of very important pharmacogenes. CYP2A6 is highly polymorphic in nature and reported with more than 40 variants, most of these variants are SNPs originated and population specific. It has been well observed and reported that the presence of these population-specific non-synonymous SNPs in CYP2A6 alters the rate of drug metabolism and as a functional consequence, drugs produce an abnormal response. Though genomics and pharmacogenomics studies are there, very less is known about the structural effects of these SNPs on molecular-interaction and folding of CYP2A6. To fill the knowledge gap, SNPs based four variants, i.e., CYP2A6*2, CYP2A6*18, CYP2A6*21, and CYP2A6*35, which are frequently reported in the South Asian population, were considered for the study. Coumarin (DB04665), a well reported drug, is considered as a model substance, and the effect of all four variants on 'CYP2A6*-coumarin' complex was studied. MD simulation-based analysis (at 200 ns) was performed and comparative analysis with respect to wild type 'CYP2A6-coumarin' complex was done. Though observation didn't find any global effect on complete complex but found some crucial minor-local alteration in interaction and folding process. It is assumed that the change due to SNPs in the single amino acid did not bring global change in physiochemical properties of CYP2A6* but caused local-trivial changes which are very crucial for its metabolic activity.Communicated by Ramaswamy H. Sarma.

PMID:35427216 | DOI:10.1080/07391102.2022.2062785

Front Pharmacol. 2022 Mar 29;13:833174. doi: 10.3389/fphar.2022.833174. eCollection 2022.

ABSTRACT

Background: It is imperative to identify drugs that allow treating symptoms of severe COVID-19. Respiratory failure is the main cause of death in severe COVID-19 patients, and the host inflammatory response at the lungs remains poorly understood. Methods: Therefore, we retrieved data from post-mortem lungs from COVID-19 patients and performed in-depth in silico analyses of single-nucleus RNA sequencing data, inflammatory protein interactome network, and shortest pathways to physiological phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials. Results: Herein, we analyzed transcriptomics data of 719 inflammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 significantly expressed genes showed that the most relevant biological annotations were inflammatory response, innate immune response, cytokine production, interferon production, macrophage activation, blood coagulation, NLRP3 inflammasome complex, and the TLR, JAK-STAT, NF-κB, TNF, oncostatin M signaling pathways. Subsequently, we identified 34 essential inflammatory proteins with both high-confidence protein interactions and shortest pathways to inflammation, cell death, glycolysis, and angiogenesis. Conclusion: We propose three small molecules (baricitinib, eritoran, and montelukast) that can be considered for treating severe COVID-19 symptoms after being thoroughly evaluated in COVID-19 clinical trials.

PMID:35422702 | PMC:PMC9002106 | DOI:10.3389/fphar.2022.833174

Endocr Pract. 2022 Apr 11:S1530-891X(22)00480-3. doi: 10.1016/j.eprac.2022.04.002. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to assess treatment outcomes and disease control status in patients with acromegaly by patient- and clinician-reported outcome tools and to analyse correlations among different components of both tools.

METHODS: Cross-sectional study included 72 patients from the national referral centre with a median follow up of 8 (5-12) years. Baseline SAGIT at the diagnosis was determined retrospectively, while the follow up SAGIT and AcroQoL results were assessed at the most recent visit and by additional telephone interviews.

RESULTS: All SAGIT subscores significantly lowered from baseline to follow up (global score from 14 to 4 (P<0.001)). SAGIT at baseline did not discriminate the current disease control status. However, higher baseline SAGIT score and subscore T were associated with uncontrolled disease after the first-line treatment. Diagnostic delay correlated with baseline S, A, G, and global SAGIT scores. At follow up, global SAGIT score discriminated between cured/controlled and uncontrolled groups (4 vs. 6 (P=0.007)). AcroQoL score was 69.3, with »Personal relations subscale« being the least and »Physical scale« the most affected. There was no difference in AcroQoL between patients classified as uncontrolled or cured/controlled. At baseline and follow up, there were significant negative correlations between S and A subscores and AcroQoL. Higher BMI, presence of swelling, joint symptoms, headaches, sleep apnea, and hypertension significantly impaired QoL.

CONCLUSION: Our results emphasised the complementary nature of patient- and clinician-reported outcome tools in acromegaly management. We identified modifiable signs, symptoms, and comorbidities as treatment targets that might help clinicians improve QoL in this population.

PMID:35421593 | DOI:10.1016/j.eprac.2022.04.002

PLoS One. 2022 Apr 14;17(4):e0266590. doi: 10.1371/journal.pone.0266590. eCollection 2022.

ABSTRACT

BACKGROUND: Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that candidate genetic polymorphisms are associated with fall risk in older antidepressant users.

METHODS: The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated.

RESULTS: In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26-0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17-3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07-2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05-3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01-1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92-1.00).

CONCLUSION: This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.

PMID:35421149 | DOI:10.1371/journal.pone.0266590

Br J Clin Pharmacol. 2022 Apr 14. doi: 10.1111/bcp.15353. Online ahead of print.

ABSTRACT

AIM: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy in humans, can cause acute hemolysis resulting from exposure to certain medications, chemicals, infections and fava beans. Rasburicase, used to manage elevated uric acid levels in the oncologic emergency of tumor lysis syndrome, is one such drug. The Food & Drug Administration (FDA) recommends testing of G6PD status prior to rasburicase administration for patients at higher risk for G6PD deficiency.

METHODS: We performed a retrospective chart review of all oncology patients for whom a semi-quantitative biochemical test for detecting G6PD deficiency was performed prior to rasburicase administration over a 2.5 year period, in a large academic metropolitan hospital.

RESULTS: We identified 16 out of 260 tested individuals as G6PD-deficient (6.1%), including six females. On average, test results were electronically available to health-care providers within 4 hours of sample collection, with most results available within 2-3 hours. Four G6PD-deficient patients developed elevated uric acid levels. Two of the G6PD-deficient patients were treated with rasburicase, and subsequently developed hemolysis, which was appropriately managed.

CONCLUSION: In summary, by providing information about G6PD status with a rapid turnaround time, we have taken a significant step towards personalized medicine in our institution. In spite of the test implementation, two out of four G6PD deficient patients, who were no longer candidates for rasburicase use, still received the drug, highlighting the need for improved provider education.

PMID:35419830 | DOI:10.1111/bcp.15353

Transl Clin Pharmacol. 2022 Mar;30(1):24-36. doi: 10.12793/tcp.2022.30.e4. Epub 2022 Mar 9.

ABSTRACT

Pediatric patients with coronavirus disease 2019 (COVID-19) are increasing, and severe cases such as multisystem inflammatory syndrome are being reported. Nafamostat, a repurposing drug, is currently being explored for the treatment of COVID-19 in adults. However, the data supporting its exposure in pediatrics remains scarce. Physiologically-based pharmacokinetic (PBPK) modeling enables the prediction of drug exposure in pediatrics based on ontogeny of metabolic enzymes and age dependent anatomical and physiological changes. The study aimed to establish a PBPK model of nafamostat in adults, then scale the adult PBPK model to children for predicting pediatric exposures of nafamostat and an optimal weight-based nafamostat dose in pediatric population. The developed model adequately described adult exposure data in healthy volunteers following i.v. administration with three doses (10, 20, and 40 mg). Scaling adult PBPK models to five pediatric groups predicted that as age advances from neonate to adult, the exposure of nafamostat slightly increased from neonate to infant, steadily decreased from infant to child, and then increased from child to adult after the administration of 0.2 mg/kg/h for 14 days, a dosing regimen being conducted in a clinical trial for COVID-19. Based on the fold change of predicted area under the curve for the respective pediatric group over those of adults, weight-based dosages for each pediatric group may be suggested. The novel PBPK model described in this study may be useful to investigate nafamostat pharmacokinetics in a pediatric subgroup further.

PMID:35419314 | PMC:PMC8979760 | DOI:10.12793/tcp.2022.30.e4

Anal Chem. 2022 Apr 13. doi: 10.1021/acs.analchem.2c00446. Online ahead of print.

ABSTRACT

The clinical actionability of circulating tumor DNA requires sensitive detection methods with a short turnaround time. In the PADA-1 phase 3 trial (NCT03079011), metastatic breast cancer patients treated with an aromatase inhibitor and palbociclib were screened every 2 months for activating ESR1 mutations in blood (bESR1mut). We report the feasibility of the droplet digital polymerase chain reaction (ddPCR) and cross-validation with next-generation sequencing (NGS). bESR1mut testing was centralized in two platforms using the same ddPCR assay. Results were reported as copies/mL of plasma and mutant allele frequency (MAF). We analyzed 200 positive ddPCR samples with an NGS assay (0.5-1% sensitivity). Overall, 12,552 blood samples were collected from 1017 patients from 83 centers. Among the 12,525 available samples with ddPCR results, 11,533 (92%) were bESR1mut-negative. A total of 267 patients newly displayed bESR1mut (26% patients/2% samples) with a median copy number of 14/mL (range: 4-1225) and a median MAF of 0.83% (0.11-35), 648 samples (20% patients/5% samples) displayed persistent bESR1mut, and 77 (<1%) samples encountered a technical failure. The median turnaround time from blood drawing to result notification was 13 days (Q1:9; Q3:21 days). Among 200 ddPCR-positive samples tested, NGS detected bESR1mut in 168 (84%); 25 of the 32 cases missed by NGS had low MAF and/or low coverage. In these 200 samples, bESR1mut MAF by both techniques had an excellent intraclass correlation coefficient (ICC = 0.93; 95% CI [0.85; 0.97]). These results from a large-scale trial support the feasibility and accuracy of real-time bESR1mut tracking by ddPCR, opening new opportunities for therapeutic interventions.

PMID:35416669 | DOI:10.1021/acs.analchem.2c00446

Biochem Biophys Res Commun. 2022 Apr 6;609:62-68. doi: 10.1016/j.bbrc.2022.04.007. Online ahead of print.

ABSTRACT

RNF213, a susceptibility gene for moyamoya disease, is associated with stress responses to various stressors. We previously reported that Rnf213 knockout (KO) mitigated endoplasmic reticulum (ER) stress-induced diabetes in the Akita mouse model of diabetes. However, the role of RNF213 in ER stress regulation remains unknown. In the present study, RNF213 knockdown significantly inhibited the upregulation of ER stress markers (CHOP and spliced XBP1) by chemical ER stress-inducers in HeLa cells. Levels of SEL1L, a critical molecule in ER-associated degradation (ERAD), were increased by RNF213 knockdown, and SEL1L knockdown prevented the inhibitory effect of RNF213 suppression on ER stress in HeLa cells, indicating SEL1L involvement in this inhibition of ER stress. SEL1L upregulation was also confirmed in pancreatic islets of Rnf213 KO/Akita mice and in Rnf213 KO mouse embryonic fibroblasts. Additionally, RNF213 suppression increased levels of HRD1, which forms a complex with SEL1L to degrade misfolded protein in cells under ER stress. In conclusion, we demonstrate that RNF213 depletion inhibits ER stress possibly through elevation of the SEL1L-HRD1 complex, thereby promoting ERAD in vitro and in vivo.

PMID:35413541 | DOI:10.1016/j.bbrc.2022.04.007

Curr Neuropharmacol. 2022 Apr 11. doi: 10.2174/1570159X20666220411095508. Online ahead of print.

ABSTRACT

In this Editorial we discuss the neurobiological processes underlying early emergence of awareness that we term the "when" and "how" the mind comes to live inside the body. We describe an accumulative developmental process starting during embryonic life and continuing to fetal and postnatal development, of coupling of heart rate, body movements and sleep states on the behavioral level with underlying mechanisms on the structural, functional, cellular and molecular levels. A developmental perspective is proposed based on Perceptual Control Theory (PCT). This includes a developing sequence of modules starting from early sensing of neural intensities to early manifestation of human mindful capacities. We also address pharmacological treatments administered to preterm infants, which may interfere with this development and highlight the need to consider this potential "side effect" of current pharmaceuticals when developing novel pharmacogenomic treatments.

PMID:35410607 | DOI:10.2174/1570159X20666220411095508

Curr Med Res Opin. 2022 Apr 12:1-24. doi: 10.1080/03007995.2022.2061710. Online ahead of print.

ABSTRACT

BACKGROUND: The role of personalised treatment approaches, including those based on genetic testing are increasingly enabling informed decision making to improve health outcomes. Research involving Indigenous Australians has been lagging behind, although this population experiences higher prevalence of chronic disease and mental health disorders.

METHODS: Using community-based participatory research principles, this study purposefully interviewed participants with a diagnosed common mental disorder and a comorbid chronic disease condition. Inductive thematic analysis on semi-structured interviews with consenting participants (n = 48). Common themes and analytical domains were identified that provided a semantic understanding shared by participants.

RESULTS: Five emerging themes were identified, primarily focusing on: 1. the perceptions and understanding of genetics research; 2. culturally appropriate conduct of genetics research; 3. the role of indigenous-led genetics research; 4. future prospects of genetics research; and 5. the importance of genetics research for patients with mental and physical health comorbidities.

CONCLUSION: Indigenous Australians are under-represented in pharmacogenomics research despite well-documented epidemiological research demonstrating that Indigenous people globally experience greater risk of developing certain chronic diseases and more severe disease progression. Positive outcomes from this study highlight the importance of not only involving Indigenous participants, but providing leadership and governance opportunities for future genetics research.

PMID:35410562 | DOI:10.1080/03007995.2022.2061710

Mol Cancer. 2022 Apr 11;21(1):98. doi: 10.1186/s12943-022-01561-5.

ABSTRACT

The tumor microenvironment (TME) is essential for immune escape by tumor cells. It plays essential roles in tumor development and metastasis. The clinical outcomes of tumors are often closely related to individual differences in the patient TME. Therefore, reprogramming TME cells and their intercellular communication is an attractive and promising strategy for cancer therapy. TME cells consist of immune and nonimmune cells. These cells need to be manipulated precisely and safely to improve cancer therapy. Furthermore, it is encouraging that this field has rapidly developed in recent years with the advent and development of gene editing technologies. In this review, we briefly introduce gene editing technologies and systematically summarize their applications in the TME for precision cancer therapy, including the reprogramming of TME cells and their intercellular communication. TME cell reprogramming can regulate cell differentiation, proliferation, and function. Moreover, reprogramming the intercellular communication of TME cells can optimize immune infiltration and the specific recognition of tumor cells by immune cells. Thus, gene editing will pave the way for further breakthroughs in precision cancer therapy.

PMID:35410257 | DOI:10.1186/s12943-022-01561-5

Int J Mol Sci. 2022 Apr 4;23(7):4003. doi: 10.3390/ijms23074003.

ABSTRACT

The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.

PMID:35409362 | DOI:10.3390/ijms23074003

Int J Mol Sci. 2022 Mar 30;23(7):3830. doi: 10.3390/ijms23073830.

ABSTRACT

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients' prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones' survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host's immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.

PMID:35409190 | DOI:10.3390/ijms23073830

Int J Mol Sci. 2022 Mar 22;23(7):3451. doi: 10.3390/ijms23073451.

ABSTRACT

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

PMID:35408810 | DOI:10.3390/ijms23073451

Cancers (Basel). 2022 Mar 22;14(7):1604. doi: 10.3390/cancers14071604.

ABSTRACT

Ras homologous A (RHOA), a signal mediator and a GTPase, is known to be associated with the progression of gastric cancer (GC), which is the fourth most common cause of death in the world. Previously, we designed pharmacologically optimized inhibitors against RHOA, including JK-136 and JK-139. Based on this previous work, we performed lead optimization and designed novel RHOA inhibitors for greater anti-GC potency. Two of these compounds, JK-206 and JK-312, could successfully inhibit the viability and migration of GC cell lines. Furthermore, using transcriptomic analysis of GC cells treated with JK-206, we revealed that the inhibition of RHOA might be associated with the inhibition of the mitogenic pathway. Therefore, JK-206 treatment for RHOA inhibition may be a new therapeutic strategy for regulating GC proliferation and migration.

PMID:35406376 | DOI:10.3390/cancers14071604

Int J Antimicrob Agents. 2022 Apr 8:106587. doi: 10.1016/j.ijantimicag.2022.106587. Online ahead of print.

ABSTRACT

Azoles are among the most effective and widely used class of antifungals for prophylaxis, empirical and directed therapy against yeast and mould infections. Their use appears to be increasing worldwide. All triazoles cause hepatotoxicity, drug-drug interactions and QTc prolongation (except isavuconazole); however, there are growing concerns following increasing reports of off-target endocrinologic adverse events. Skeletal fluorosis, pseudohyperaldosteronism, adrenal insufficiency, hyponatraemia and hypogonadism have all been documented in relation to azole use, causing considerable morbidity. The following review provides new insights into the clinical incidence and underlying pathophysiology of azole-associated endocrinopathies. Routine clinical and biochemical monitoring (including therapeutic drug monitoring) of endocrinologic adverse events may play a role in their prevention and progression. Novel azoles in preclinical and clinical stages of development may offer therapeutic advantages due to their greater selectivity of binding to fungal CYP51. The integration of pharmacogenomics into routine clinical practice holds future promise in guiding antifungal drug and dose selection to reduce the risk of off-target phenomena, including endocrinologic adverse events.

PMID:35405267 | DOI:10.1016/j.ijantimicag.2022.106587

Steroids. 2022 Apr 8:109035. doi: 10.1016/j.steroids.2022.109035. Online ahead of print.

ABSTRACT

Neurosteroids have been associated with neurodegenerative diseases because they are involved in the modulation of neurotransmitter, neurotropic and neuroprotective actions. Emerging evidence suggests that the enzymes responsible for the synthesis of neurosteroids change during the progression of Alzheimer's disease (AD). The present study aimed to assess the changes in phase I and II enzymes involved in the metabolism of neurosteroids of the progestogen, androgenic and estrogenic steroidogenic pathways and the possibility that the neurosteroids are actively converted into the most abundant metabolites (i.e. glucuronides and sulphates). The gene expression for the phase I and II neurosteroid biosynthetic enzymes were studied in the hippocampus of streptozotocin AD rat model. Male Sprague-Dawley rats were randomly divided into control, sham (saline injected into the hippocampus) and 3 and 12 weeks post-STZ administration (STZ-G3w and STZ-G12w, respectively) groups. Behavioral assessments showed memory impairment in both STZ-injected groups, whereas the formation of amyloid-beta was more pronounced in the STZ-12w group. Gene expression of the hippocampus revealed that glucuronidation and sulphation enzymes transcript of the phase I metabolites were upregulated at the late stage of the disease progression (Hsd17b10, Hsd3b1, Akr1c3 and Cyp19a1) except for Sts. The phase II Sult and Ugt enzymes were mostly upregulated in the STZ-G12w rats (Sult1a1, Sult1e1, Ugt1a1, Ugt1a7c, Ugt1a6, Ugt2b35 and Ugt2b17) and normally expressed in the STZ-G3w group (Sult2a2, Sult2a6, Sult2b1, Ugt2b7, Sult4a1 and Ugt1a7c). In conclusion, changes occur in the phase I and II enzymes transcript of the progestogen, androgenic and estrogenic steroidogenic pathways during the progression of AD.

PMID:35405201 | DOI:10.1016/j.steroids.2022.109035

Arthritis Rheumatol. 2022 Apr 11. doi: 10.1002/art.42138. Online ahead of print.

ABSTRACT

OBJECTIVE: To identify hallmark genes and biomolecular processes in aortitis using high-throughput gene expression profiling. Additionally, to provide a range of potentially new drug targets (genes) and therapeutics from a pharmacogenomic network analysis.

METHODS: Bulk RNA-seq was performed on surgically resected ascending aortic tissues from inflammatory (giant cell arteritis [GCA] with or without polymyalgia rheumatica [PMR] = 8; clinically isolated aortitis [CIA] = 17) and non-inflammatory (n = 25) aneurysms undergoing surgical aortic repair. Differentially expressed genes (DEGs) between the two patient groups were identified while controlling for clinical covariates. A protein-protein interaction model, drug-gene target information, and the DEGs were used to construct a pharmacogenomic network for identifying promising drug targets and potentially new treatment strategies in aortitis.

RESULTS: Overall, tissue gene expression patterns were the most associated with disease state than with any other clinical characteristic. We identified 159 and 93 genes that were significantly upregulated and downregulated, respectively, in inflammatory aortic aneurysms compared to non-inflammatory aortic aneurysms. We found that the upregulated genes were enriched in immune-related functions, whereas the downregulated genes were enriched in neuronal processes. Notably, gene expression profiles of inflammatory aortic aneurysms from patients with GCA were no different than those from patients with CIA. Finally, our pharmacogenomic network analysis identified genes that could potentially be targeted by immunosuppressive drugs currently approved for other inflammatory diseases.

CONCLUSION: We performed the first global transcriptomics analysis in inflammatory aortic aneurysms from surgically resected aortic tissues. We identified signature genes and biomolecular processes, while finding that CIA may be a limited presentation of GCA. Moreover, our computational network analysis revealed potential novel strategies for pharmacologic interventions, and suggests future biomarker discovery directions for the precise diagnosis and treatment of aortitis.

PMID:35403833 | DOI:10.1002/art.42138

Adv Sci (Weinh). 2022 Apr 11:e2104986. doi: 10.1002/advs.202104986. Online ahead of print.

ABSTRACT

Chronic cerebral hypoperfusion-derived brain damage contributes to the progression of vascular cognitive impairment and dementia (VCID). Cumulative evidence has shown that microRNAs (miRs) are emerging as novel therapeutic targets for CNS disorders. In this study, it is sought to determine the regulatory role of miR-15a/16-1 in VCID. It is found that miR-15a/16-1 knockout (KO) mice exhibit less cognitive and sensorimotor deficits following VCID. Genetic deficiency of miR-15a/16-1 in VCID mice also mitigate myelin degeneration, axonal injury, and neuronal loss. Mechanistically, miR-15a/16-1 binds to the 3'-UTR of AKT3 and IL-10RA. Genetic deletion of miR-15a/16-1 increases AKT3 and IL-10RA expression in VCID brains, and intranasal delivery of AKT3 and IL-10RA siRNA-loaded nanoparticles partially reduce brain protection and cognitive recovery in miR-15a/16-1 KO mice after VCID. In conclusion, the miR-15a/16-1-IL/10RA/AKT3 axis plays a critical role in regulating vascular brain damage and cognitive decline after VCID. Targeting miR-15a/16-1 is a novel therapeutic approach for the treatment of VCID.

PMID:35403823 | DOI:10.1002/advs.202104986