Alpha-2b Research Articles

Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers.

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dysautonomia tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2 vaccination of healthy controls (N = 89; 71 females; mean/median age: 39/49 years) were compared with corresponding values of PACVS-affected persons (N = 191; 159 females; mean/median age: 40/39 years) exhibiting chronic fatigue/dysautonomia (≥three symptoms for ≥five months after the last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications. Normal vaccination response encompassed decreases in 11 receptor antibodies (by 25-50%, p < 0.0001), increases in two receptor antibodies (by 15-25%, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p < 0.0001) by increased Angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/mL, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/mL, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/mL, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers.

Electroacupuncture at GB20 improves cognitive ability and synaptic plasticity via the CaM-CaMKII-CREB signaling pathway following cerebral ischemia-reperfusion injury in rats.

This study aimed to investigate the effects of electroacupuncture (EA) on cognitive recovery and synaptic remodeling in a rat model of middle cerebral artery occlusion (MCAO) followed by reperfusion and explore the possible mechanism. Focal cerebral ischemia was modeled in healthy adult Sprague-Dawley rats by MCAO. The MCAO rats were classified into four groups: sham, MCAO, MCAO + GB20 (receiving EA at GB20) and MCAO + NA (receiving EA at a "non-acupoint" location not corresponding to any traditional acupuncture point location about 10 mm above the iliac crest). Neurological deficit scores and behavior were assessed before and during the treatment. After intervention for 7 days, the hippocampus was dissected to analyze growth-associated protein (GAP)-43, synaptophysin (SYN) and postsynaptic density protein (PSD)-95 expression levels by Western blotting. Bioinformatic analysis and primary hippocampal neurons with calcium-voltage gated channel subunit alpha 1B (CACNA1B) gene overexpression were used to screen the target genes for EA against MCAO. Significant amelioration of neurological deficits and learning/memory were found in MCAO + GB20 rats compared with MCAO or MCAO + NA rats. Protein levels of GAP-43, SYN and PSD-95 were significantly improved in MCAO + GB20-treated rats together with an increase in the number of synapses in the hippocampal CA1 region. CACNA1B appeared to be a target gene of EA in MCAO. There were increased mRNA levels of CACNA1B, calmodulin (CaM), Ca2+/calmodulin-dependent protein kinase type II (CaMKII) and cyclic adenosine monophosphate response element binding (CREB) and increased phosphorylation of CaM, CaMKII and CREB in the hippocampal region in MCAO + GB20 versus MCAO and MCAO + NA groups. CACNA1B overexpression modulated expression of the CaM-CaMKII-CREB axis. EA treatment at GB20 may ameliorate the negative effects of MCAO on cognitive function in rats by enhancing synaptic plasticity. EA treatment at GB20 may exert this neuroprotective effect by regulating the CACNA1B-CaM-CaMKII-CREB axis.

Broiler Heart Muscle Monoaminergic Receptors Alteration in Response to Chronic Heat Stress: Based on Transcription Analysis.

Chronic heat stress affects numerous physiological and behavioral mechanisms. Epigenetic changes following prolonged cyclic heat stress, creating new opportunities for molecular biology research. One of these changes involves monoamines, such as serotonin, epinephrine, norepinephrine, dopamine, and their transmission. Broiler chickens are highly susceptible to heat stress, and their hearts become insufficient during the growth phase, leading to hypertrophy of the left heart. RNA-seq data were obtained from NCBI with accession number SRP082125. The expression level of genes was determined with DESeq2 packages. Gene Ontology qualification, including biological processes, cellular components, and molecular role (MF), was performed from the Gene Ontology Resource. Cyclic heat stress in broilers significantly altered monoamine receptor expression. Twenty-nine genes of the monoamine pathway changed their expression in the left heart. Significant downregulation of expression was statistically associated with the ADRB1, HTR2A, and PNMT genes and upregulation of the MAOA gene (P<0.01). STRING database was used to construct the protein-protein interaction network; based on network analysis, the HTR2C, HTR2A, and HTR5A genes were identified as the major nodal genes in the network followed by MAOA, DRD2, DRD5, HTR1B, DRD1, DRD3, and HTR2B genes occupying the second important place in the network module. In conclusion, heat stress treatment prevented cardiac hypertrophy and altered the expression of monoamine genes. This would imply that monoamine transmission plays an important role in the development of cardiac hypertrophy, and that cyclic-chronic heat treatment modulates the cardiac monoaminergic system. These molecular biomarkers could be useful for screening, diagnosis, and treatment of cardiac hypertrophy.

Intergenic interactions of &lt;i&gt;ADRB2&lt;/i&gt;, &lt;i&gt;ADRB3&lt;/i&gt;, &lt;i&gt;FABP2&lt;/i&gt; and &lt;i&gt;PPARG&lt;/i&gt; genes in children with asthma associated with obesity

Introduction. The constant increase in the prevalence of bronchial asthma in children and adolescents raises concerns about a parallel increase in obesity-related asthma and suggests that obesity alters asthma towards a phenotype that is more difficult to control. The development of multifactorial diseases (asthma and obesity) is based on complex intergenic interactions that must be taken into account when predicting the risk of developing an unfavorable course of the pathological process.Aim. To study the contribution of polymorphic variants of the metabolism genes rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu) of the β2-adrenoceptor gene (ADRB2), rs4994 Trp64Arg of the β3-adrenoceptor gene (ADRB3), rs1801282 of the PPARG gene, rs1799883 Ala54Thr of the FABP2 gene using Multifactor Dimensionality Reduction (MDR) in patients with asthma and obesity to identify significant intergenic interactions.Materials and methods. 161 children withasthma were examined, including 59 patients with obesity of 1-3 degrees. The examination included general clinical, laboratory, and functional methods. The level of asthma control was determined according to the GINA criteria (2018). The study of gene polymorphisms was carried out by real-time polymerase chain reaction using sets of “Metabolism” (Research and Production Company “Litekh”, Moscow) on the CFX-96 Biorat device (USA).Results. When comparing groups of children with asthma associated with obesity, a significant model of the interaction of the ADRB3 and FABP2 genes was determined. This two-locus model of intergenic interaction. According to this model, children with bronchial asthma with the following genotypes have an increased risk of obesity: Trp64Arg ADRΒ3 and Ala54Thr FABP2; Trp64Arg ADRΒ3 and Thr 54Thr FABP2; Trp64 Trp ADRΒ3 and Ala54Thr FABP2; Trp64 Trp ADRΒ3 and Thr 54Thr FABP2. In patients with AD associated with obesity and lack of disease control, we identified another statistically significant two-locus model of the interaction of the rs1042713 genes of the ADRB2 gene and PPARG. According to this model, children with the following genotypes have an increased risk of lack of disease control in patients with obesity-associated asthma: Arg16Gly ADRB2 and Pro12Ala PPARG; Arg16Gly ADRB2 and Ala12Ala PPARG; Gly16Gly ADRB2 and Pro12Ala PPARG; Gly16Gly ADRB2 and Ala12Ala PPARG.Conclusion. The obtained results of the analysis of intergenic interactions indicate that a key role in the formation of predisposition to obesity in asthma patients belongs to the association of polymorphic variants of the ADRB3 (rs4994) and FABP2 (rs1799883) genes, and the risk of uncontrolled asthma in obese children are patients with a combination of polymorphisms rs1042713 of the ADRB2 gene and rs1801282 of the PPARG gene, as evidenced by revealed two-locus models of intergenic interactions that determine the predisposition to obesity in children with asthma and affect the course of the disease. Identification of genetic predictors of both asthma and obesity is important for identifying individuals with an increased risk of developing this disease, and requires further study in the search for probable cause-and-effect relationships and the creation of personalized programs depending on polymorphic gene variants.

Human Dental Pulp Stem Cells Are Subjected to Metabolic Reprogramming and Repressed Proliferation and Migration by the Sympathetic Nervous System via α1B-Adrenergic Receptor

IntroductionHuman dental pulp stem cells (hDPSCs) reside in specialized microenvironments in the dental pulp, termed “niches,” which are composed of diverse cellular components including nerves. Sensory nerves can positively regulate the expansion and differentiation of pulp cells, while the biological effects of the sympathetic nervous system (SNS) on hDPSCs remain elusive. This study is devoted to investigating the effects and underlying mechanisms of the SNS on the proliferation and migration of hDPSCs. MethodsThe distribution of sympathetic nerve fibers in human dental pulp was examined by immunofluorescence staining of tyrosine hydroxylase. The concentration of norepinephrine in healthy and carious human dental pulp tissues was detected using enzyme-linked immunosorbent assay. RNA-sequencing was applied to identify the dominant sympathetic neurotransmitter receptor in hDPSCs. Seahorse metabolic assay, adenosine triphosphate assay, lactate assay, and mitochondrial DNA copy number were performed to determine the level of glycometabolism. Transwell assay, wound healing assay, 5-ethynyl-2'-deoxyuridine staining assay, cell cycle assay, and Cell Counting Kit-8 assay were conducted to analyze the migratory and proliferative capacities of hDPSCs. ResultsSprouting of sympathetic nerve fibers and an increased concentration of norepinephrine were observed in inflammatory pulp tissues. Sympathetic nerve fibers were mainly distributed along blood vessels, and aldehyde dehydrogenase 1–positive hDPSCs resided in close proximity to neurovascular bundles. ADRA1B was identified as the major sympathetic neurotransmitter receptor expressed in hDPSCs, and its expression was enhanced in inflammatory pulp tissues. In addition, the SNS inhibited the proliferation and migration of hDPSCs through metabolic reprogramming via ADRA1B and its crosstalk with serine-threonine kinase and p38 mitogen-activated protein kinase signaling pathways. ConclusionsThis study demonstrates that the SNS can shift the metabolism of hDPSCs from oxidative phosphorylation to anaerobic glycolysis via ADRA1B and its crosstalk with serine-threonine kinase and p38 mitogen-activated protein kinase signaling pathways, thereby inhibiting the proliferative and migratory abilities of hDPSCs. This metabolic shift may facilitate the maintenance of the quiescent state of hDPSCs.

Polymorphic variants of the beta 2-adrenoreceptor gene (adrb2) in healthy Caucasians of the Gomel region

Objective. To study the frequency of polymorphic loci rs1042713 and rs1042714 of the β2-adrenoreceptor gene in healthy Caucasians of the Gomel region.Materials and methods. A one-step study of 143 healthy volunteers living in Gomel region was conducted. This group included 86 (60,14%) men and 57 (39,86%) women. The average age was 36.0±10.20 years. Two single nucleotide polymorphisms (SNPs) rs1042713 and rs1042714 were genotyped in blood samples of patients by polymerase chain reaction (PCR).Results. Among the genotypes of the rs1042713 polymorphic locus, the most common was the AG genotype (45.4%). The GG (44.1%) and AA (10.5%) genotypes were less common. The rs1042714 polymorphic locus was characterized by a more frequent presence of the CG genotype (48.9%). The CC (25.9%) and GG (25.2%) genotypes were detected less frequently. Among the alleles of polymorphic locus rs1042713, allele G was the most common (66.8%). Of the alleles of the polymorphic locus rs1042714, the C allele was more frequent (50.4%). The ADRB2 gene was more frequently represented by the AG/CG and GG/CG haplotypes (32.9% and 39.9%, respectively). AA/GG, AG/GG, and GG/ GG haplotypes were not detected among the volunteers examined.Conclusion. AG and CG genotypes, haplotypes AG/CG and GG/CG for the polymorphic locus rs1042713 and rs1042714, respectively, were more common among Caucasians living in the Gomel region. The G allele for the polymorphic locus rs1042713 and the C allele for rs1042714 turned out to be the most common among the alleles.

Adjuvant Topical Interferon Alpha 2b for the Treatment of Monkeypox Ocular Manifestations.

The aim of this study was to report a case of ocular Mpox that responded favorably to treatment with topical interferon and oral doxycycline. This is a case report of a previously healthy 24-year-old woman who developed a pustular rash, headache, fever, arthralgia, sore throat, and asthenia 3 weeks before attending to our clinic. Her main complaint at the moment of the visit was pain, photophobia, foreign body sensation, blurred vision, red eye, and discharge on the left eye. The slit-lamp examination of the left eye showed severe conjunctival hyperemia associated with tarsal follicles, 360 degrees ciliary injection, diffuse corneal epithelial edema with white linear epithelial infiltrates, pigmented and nonpigmented keratic precipitates, and two 1-mm peripheral corneal ulcers with white infiltrates, associated with positive fluorescein staining. Anterior chamber cellularity and flare were mildly present. Mpox with ocular manifestations diagnosis was confirmed by real-time quantitative reverse transcription polymerase chain reaction assay (qRT-PCR) testing; samples were taken from corneal, conjunctival, and nasopharynx swab as well as a skin scab. Topical interferon alpha 2b 1 MIU/mL every 6 hours for 1 month and oral doxycycline 100 mg BID were administered along with other medications with consequent decrease of inflammation and malaise symptoms 1 week later, associated with uncorrected visual acuity improvement. Alternative and efficacious treatment options for Mpox ocular manifestations are needed to prevent further disease progression and sequelae in countries with no access to the gold-standard therapy. Topical interferon alpha 2b and oral doxycycline have shown adequate response as shown with this patient.

Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents.

Gut microbiota are closely related to health, and the β2-adrenergic receptor (ADRB2) gene is associated with gastrointestinal diseases. However, little is known about the relationship between ADRB2 gene polymorphisms and intestinal microbiota. In the present study, we aimed to explore the relationship between ADRB2 gene polymorphisms and gut microbiota in Chinese Han adolescents. Data analysis showed that the relative abundance, PICRUSt function prediction, and Chao1 and ACE indices of gut microbiota were significantly different between males and females (P < 0.05). The rs1042711 was positively associated with the relative abundance of Actinobacteria, Coriobacteriia, Bifidobacteriales, Erysipelotrichi, and Erysipelotrichales. The rs12654778 was negatively associated with Bacilli, Lactobacillales, Bacteroidaceae, and Bacteroides. rs1042713 was positively associated with Lactobacillales and Bifidobacteriales. The rs1042717 was positively associated with Bifidobacteriales and negatively associated with Veillonellaceae. The rs1042719 was negatively associated with Erysipelotrichi and Erysipelotrichales and positively associated with Erysipelotrichi, Erysipelotrichales, Bifidobacteriales, and Ruminococcaceae in females. The rs1801704 was positively associated with Erysipelotrichi, Erysipelotrichales, Bifidobacteriales, Actinobacteria, Coriobacteriia, and Bifidobacteriales. The rs2053044 was positively associated with Ruminococcaceae, Dialister, Firmicutes, Clostridia, Clostridiales, Bifidobacteriales, and Faecalibacterium and negatively associated with Bacilli, Lactobacillales, Lachnospiraceae, and Porphyromonadaceae (P < 0.05). These results suggested that the relative abundance, diversity, and PICRUSt function predictions of male and female gut microbiomes differ significantly and that ADRB2 gene polymorphisms were associated with gut microbiome abundance in Chinese Han adolescents.

Effects of the Trp64Arg Polymorphism in the ADRB3 Gene on Body Composition, Cardiorespiratory Fitness, and Physical Activity in Healthy Adults.

The ADRB3 gene plays a role in energy expenditure by participating in lipolysis, which affects body composition and performance. The ADRB3 rs4994 polymorphism has been studied in groups of athletes, overweight individuals, and obese and diabetic patients, but it has not been studied in young and healthy adults so far. In the present study, we examined the association of ADRB3 rs4994 polymorphism with body composition, somatotype, cardiorespiratory fitness and physical activity in young, healthy adults (N = 304). All subjects had anthropometric measurements, and somatotypes were assessed using the Heath-Carter method. In addition, cardiorespiratory fitness and physical activity levels were assessed. Genotyping for the ADRB3 gene was performed using a PCR-RFLP method. In the male group, body components were associated with the Trp64Trp genotype (waist circumference (p = 0.035), hip circumference (p = 0.029), BF (%) (p = 0.008), and BF (kg) (p = 0.010), BMI (p = 0.005), WHtR (p = 0.021), and BAI (p = 0.006)). In addition, we observed that the Trp64Trp genotype was associated with somatotype components (p = 0.013). In contrast, the Arg allele was associated with the ectomorphic components (0.006). We also observed a positive impact of the Trp64Trp genotype with maximal oxygen uptake (p= 0.023) and oxygen pulse (p = 0.024). We observed a negative relationship of the Trp64Trp genotype in the female group with reported moderate-intensity exercise (p = 0.036). In conclusion, we found an association of the Trp64 allele with anthropometric traits, somatotype and parameters describing physical performance in the male group. In the female subpopulation, we only found an effect of the polymorphism Trp64Arg on the level of physical activity for moderate-intensity exercise.

Safety and efficacy of topical interferon alpha 2B and mitomycin C for localized conjunctival intraepithelial neoplasia: long-term report of their pharmacological safety and efficacy

PurposeOcular surface squamous neoplasia (OSSN) comprises a wide spectrum of squamous tumors, from which corneal/conjunctival intraepithelial neoplasia (CIN) is the most common one. The classic treatment is complete excision, but recurrence rates are high. Antineoplastic drugs such as mitomycin C (MMC) and interferon alpha 2b (IFNα2b) have been used as adjuvants or as primary treatment. To evaluate the efficacy and safety of topical IFNα2b and MMC in patients with CIN, a phase IIb double-blind clinical trial was performed.MethodsPatients diagnosed with localized CIN were evaluated by slit lamp and impression cytology and were randomly given MMC 0.04% or INF2b (1 million IU/mL) 4 times daily until neoplasia resolution. Time of resolution and frequency of adverse effects were analyzed to determine the pharmacological efficacy and safety of both medications.ResultsSeventeen patients were included. Nine patients were treated with MMC and 8 with IFNα2b. All patients responded to treatment. The resolution time in days was 59.11 ± 24.02 in patients treated with MMC and 143.50 ± 47.181 in those treated with IFNα2b (p < 0.001). In the MMC group, one recurrence was reported (11%). There were no recurrences at 2 years of follow-up in the IFNα2b group. Regarding adverse effects, one or more mild adverse reaction occurred in 77% of patients managed with MMC and in 50% of patients managed with IFNα2b (p > 0.05). No serious adverse effects were reported.ConclusionsTopical chemotherapy with MMC and IFNα2b demonstrate pharmacological safety and efficacy. Therefore, these drugs could be considered as primary therapies for localized CIN .

Role of beta-2 adrenergic receptor polymorphism (rs1042714) on body weight and glucose metabolism response to a meal-replacement hypocaloric diet

ObjectivesThe beta-2 adrenergic receptor (ADRB2) is involved in energy balance regulation. The objective of our study was to evaluate the role of the rs1042714 genetic variant of ADRB2 gene on weight loss, body composition, and metabolic changes secondary to partial meal replacement (pMR) hypocaloric diet in women with obesity. MethodsWe conducted an interventional study in 95 premenopausal women with body mass index ≥ 35 kg/m2. The subjects received two intakes per day of a normocaloric hyperproteic formula during 12 wk of a pMR diet. Body weight, body mass index, fat mass, waist circumference, lipid profile, fasting insulin levels, and homeostasis model assessment for insulin resistance were determined. All patients were genotyped rs1042714 and evaluated in a dominant model (CC versus CG + GG). ResultsGenotype frequencies were 31 (37.3%), 38 (45.8%), and 14 (16.9%) for the CC, CG, and GG genotypes, respectively. We found significant interaction effects between ADRB2 variant and pMR-induced changes (CC versus CG + GG) on body weight (–7.1 ± 0.3 versus –13.5 ± 0.5 kg; P = 0.03), body mass index (–0.9 ± 0.1 versus –1.2 ± 0.2 kg/m2; P = 0.03), fat mass (–4.9 ± 0.5 versus –10.2 ±1.2 kg; P = 0.01), waist circumference (–5.1 ± 0.2 versus –10.1 ± 1.9 cm; P = 0.03), glucose (–5.1 ± 1.3 versus –12.5 ± 2.5 mg/dL; P = 0.03), total cholesterol (–18.1 ± 9.3 versus –33.5 ± 4.5 mg/dL; P = 0.03), low-density lipoprotein cholesterol (–9.1 ± 5.3 versus –24.5 ± 4.1 mg/dL; P = 0.04), triacylglycerol levels (–6.1 ± 5.3 versus –31.5 ± 9.5 mg/dL; P = 0.04), fasting insulin levels (–1.8 ± 0.3 versus –6.3 ± 0.5 IU/L; P = 0.03), and homeostasis model assessment for insulin resistance (–0.6 ± 0.3 versus –1.9 ± 0.5 U; P = 0.03). The odds ratio to improve alteration in glucose metabolism adjusted by age and weight loss throughout the study was 0.26 (95% CI, 0.07–0.95; P = 0.02) in G allele carriers. ConclusionsThe G allele of rs1042714 predicts the magnitude of weight loss resulting from a pMR diet. These adiposity improvements produce a better improvement of insulin resistance and percentage of impaired glucose metabolism in G allele carriers.

Interaction of Fentanyl with Alpha 2B Adrenergic Receptor

Interaction of Fentanyl with Alpha 2B Adrenergic Receptor

Current Pharmacotherapy Trends for Hepatitis C in the Hospitals of Faisalabad, Pakistan

Hepatitis C infection is a global health issue. It is a growing challenge in Faisalabad, Pakistan, where at least 24% of the population is currently suffering from hepatitis C. If left untreated, HCV infection may lead to liver cirrhosis and hepatocellular carcinoma. The current study aimed to describe the various prescription trends of hepatitis C medication therapy in Faisalabad, Pakistan. It also aimed to evaluate the effectiveness of therapy and the satisfaction level of patients with their treatment. A comparative cross-sectional survey was carried out among patients receiving HCV medication therapy. For this purpose, a structured and close-ended questionnaire was completed by 270 patients. Comparative data analysis was performed based on selected variables, namely age, gender, marital status, current medication and its adverse effects. The prevalence of HCV in age group &gt;40 was 63.3% and in age group &lt;40, it was 36.7%. While, the prevalence of HCV in married individuals was 91% and its prevalence in unmarried individuals was 8.5%. Moreover, it was found that sofosbuvir was used by 24.8% of patients, daclatasvir was used by 24.4% of patients, entacavir was used by 0.4% of patients, acyclovir was used by 0.7% of patients, ribavirin was used by 7.8% of patients, and pegylated alpha 2b was used by 1.5% of patients. The trend of using combination therapy comprised interferon+ribavirin (1.5%) and velpatasvir+sofosbuvir (38.9%). The use of combination drug was found to be more common in patients of age group &gt;40 (34.1%) than patients in age group &lt;40 (8.8%). It was observed that lack of constant medical care and cost of therapy are major problems in the eradication of disease.

Soluble Polymer Microneedles Loaded with Interferon Alpha 1b for Treatment of Hyperplastic Scar.

To achieve the painless administration of interferon alpha 1b (rhIFNα-1b), a double-layered soluble polymer microneedle (MN) patch loaded with rhIFNα-1b was used to deliver rhIFNα-1b transdermally. The solution containing rhIFNα-1b was concentrated in the MN tips under negative pressure. The MNs punctured the skin and delivered rhIFNα-1b to the epidermis and dermis. The MN tips implanted in the skin dissolved within 30 min and gradually released rhIFNα-1b. The rhIFNα-1b had a significant inhibitory effect on the abnormal proliferation of fibroblasts and excessive deposition of collagen fibers in the scar tissue. The color and thickness of the scar tissue treated using the MN patches loaded with rhIFNα-1b were effectively reduced. The relative expressions of type I collagen (Collagen I), type III collagen (Collagen III), transforming growth factor beta 1 (TGF-β1), and α-smooth muscle actin (α-SMA) were significantly downregulated in scar tissues. In summary, the MN patch loaded with rhIFNα-1b provided an effective method for the transdermal delivery of rhIFNα-1b.

Investigating genes associated with cardiovascular disease among heart failure patients for translational research and precision medicine

AbstractBackgroundCardiovascular disease (CVD) is a leading cause of premature mortality in the United States and the world. CVD comprises several complex and mostly heritable conditions, which range from myocardial infarction to congenital heart disease. The risk factors contributing to the development of CVD and response to therapy in an individual patient are highly variable. Here, we report our findings from an integrative analysis of gene expression, disease‐causing gene variants and associated phenotypes among CVD populations, with a focus on high‐risk heart failure (HF) patients.MethodsWe built a cohort using electronic health records of consented patients with available samples and then performed high‐throughput whole genome and RNA sequencing of key genes responsible for HF and other CVD pathologies. Our in‐depth gene expression analysis revealed differentially expressed genes associated with HF and other CVDs. We performed a variant analysis of whole genome sequence data of CVD patients and identified genes with altered gene expression with functional and non‐functional mutations in these genes.ResultsOur results highlight the importance of investigating the mechanisms of CVD progression through multi‐omics datasets. Next, we performed splice mutation and variant distribution analysis of genes associated with HF and other CVD. We implemented Jensen–Shannon divergence (JSD)‐based method and identified HBA1, FADD, ADRB2, NPPB, ADRB1, ADB and NPPC genes with the greatest variance based on their JSD scores. Our study provided evidence that applying integrative data analysis approach involving genomics and transcriptomics data will not only help understand the pathophysiology of CVD diseases but also reduce heterogeneity in disease subtypes.

Norepinephrine as the Intrinsic Contributor to Contact Lens-Induced Pseudomonas aeruginosa Keratitis.

Contact lens wear (CLW) is one of the leading risk factors for Pseudomonas aeruginosa keratitis (PAK). However, the intrinsic factors that contribute to the high susceptibility to keratitis during CLW remain to be elucidated. CLW over an extended period can elevate corneal norepinephrine (NE) concentration. In this study, we investigated the role of NE in promoting PAK. We constructed an injury-induced PAK model and a CLW-induced PAK model to confirm the impact of NE during corneal infection. Pharmacological blockage of NE and gene knockdown mouse were used to investigate the downstream effector of NE. RNA sequencing was performed to explore the cellular alterations during NE treatment. Non-parametric Mann-Whitney U test or Kruskal-Wallis test were used to ascertain the significance (P < 0.05). Supplementation of NE led to PAK even without artificial corneal injury during CLW. The effect was mediated by the β2-adrenergic receptor (β2-AR) in the corneal epithelium. The β2-AR blockage by the NE antagonist ICI118,551 (ICI) or by deleting of its encoding gene Adrb2 significantly alleviated infection during CLW. Conversely, β2-AR activation compromised the integrity of the epithelium and significantly increased the cortical plaque marker ezrin. Transcriptome analysis identified that the protective effect of ICI on the keratitis was mediated by dual-specificity phosphatases. Suramin, a Dusp5 antagonist, abrogated the protective effect of ICI. These data reveal a new mechanism by which NE acts as an intrinsic factor that promotes CLW-induced PAK and provide novel therapeutic targets for treating keratitis by targeting NE-β2-AR.

Strong correlation between F2RL3 in the blood and osteoarthritis based on a retrospective cohort study.

Osteoarthritis (OA) is a common joint disease that mainly damages articular cartilage and involves the whole joint tissue. The purpose of this study was to explore the relationship between F2R Like Thrombin Or Trypsin Receptor 3 (F2RL3) and OA, so as to provide a new direction for the treatment of bone and joint. A total of 234 patients with OA were recruited. Clinical data was recorded and the expression levels of ELOVL Fatty Acid Elongase 7, F2RL3, glycoprotein IX platelet and Integrin Subunit Alpha 2b were measured. Pearson chi-square test and Spearman correlation coefficient were used to analyze the relationship between OA and related parameters. Univariate and multivariate Logistic regression were used for further analysis. Pearson chi-square test showed that F2RL3 (P < .001) was significantly associated with OA; Spearman correlation coefficient showed that OA and F2RL3 (ρ = -0.511, P < .001) significantly correlated; Univariate Logistic regression analysis showed that F2RL3 (odds ratio = 0.104, 95% confidence interval: 0.057-0.189, P < .001) was significantly associated with OA; multivariate logistic regression analysis showed that F2RL3 (odds ratio = 0.098, 95% confidence interval: 0.053-0.182, P < .001) were significantly associated with OA. The expression of F2RL3 is low in patients with OA. The lower the expression of F2RL3, the higher the probability of OA.

Anthra­cycline-Induced Cardiotoxicity: the Role of Genetic Predictors

Aim To evaluate the predictive significance of gene polymorphism in endothelin-1 type 2A receptor, NADPH oxidase, p53 protein, endothelial nitric oxide synthase, caspase 8, interleukin-1β, tumor necrosis factor-α, superoxide dismutase-2, glutathione peroxidase-1, β1-adrenoceptor, angiotensin-converting enzyme, and matrix metalloproteinase-3 (MMP-3) genes in evaluating the risk of anthracycline-induced cardiotoxicity (AIC) in women without concurrent cardiovascular diseases (CVD).Material and methods This study included 176 women aged 45.0 [42.0; 50.0] years with breast cancer without concurrent CVD who were scheduled for polychemotherapy (PCT) with anthracycline antibiotics. Echocardiography was performed for all patients at baseline and at 12 months after the end of PCT course. Genetic polymorphism was determined with the polymerase chain reaction.Results At 12 months, all patients were in remission of the underlying disease. They were retrospectively included into 2 groups: 1st group, 52 patients with AIC and 2nd group, 124 women without AIC symptoms. The development of AIC was associated with the presence of the p53 protein gene Arg / Arg genotype (odds ratio (OR), 2.972; p=0.001), NOS3 gene T / T genotype (OR, 3.059; p=0.018), NADPH oxidase gene T / T genotype (OR, 2.753; p=0.008), GPX1 gene C / C genotype (OR, 2.345; p=0.007), MMP-3 gene 5A / 5A genotype (OR, 2.753; p=0.008), and ADRB1 gene G / G genotype (OR, 3.271; p=0.043).Conclusion Evaluation of genetic polymorphism in p53 protein (rs1042522), NOS3 (rs1799983), NADPH-oxidase (rs4673), GPX1 (rs1050450), ADRB1 (Arg389Gly, rs1801253), and MMP-3 (rs3025058) genes can be recommended for use prior to starting chemotherapy in women with breast cancer without CVD for assessing the risk of AIC. A maximum risk of cardiotoxicity is associated with the presence of the p53 protein gene Arg / Arg genotype and NOS3 gene T / T genotype.

Long-term effects of Roluperidone on negative symptoms of schizophrenia.

Roluperidone has antagonist properties for 5-HT2A, sigma2, α1A- and α1B-adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32mg/day or 64mg/day for 24weeks (trial 1) or 40weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10%. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia.

Broiler Heart Muscle Monoaminergic Receptors Alteration in Response to Chronic Heat Stress: Based on Transcription Analysis

Chronic heat stress affects numerous physiological and behavioral mechanisms. Epigenetic changes following prolonged cyclic heat stress, creating new opportunities for molecular biology research. One of these changes involves monoamines, such as serotonin, epinephrine, norepinephrine, dopamine, and their transmission. Broiler chickens are highly susceptible to heat stress, and their hearts become insufficient during the growth phase, leading to hypertrophy of the left heart. RNA-seq data were obtained from NCBI with accession number SRP082125. The expression level of genes was determined with DESeq2 packages. Gene Ontology qualification, including biological processes, cellular components, and molecular role (MF), was performed from the Gene Ontology Resource. Cyclic heat stress in broilers significantly altered monoamine receptor expression. Twenty-nine genes of the monoamine pathway changed their expression in the left heart. Significant downregulation of expression was statistically associated with the ADRB1, HTR2A, and PNMT genes and upregulation of the MAOA gene (P&lt;0.01). STRING database was used to construct the protein-protein interaction network; based on network analysis, the HTR2C, HTR2A, and HTR5A genes were identified as the major nodal genes in the network followed by MAOA, DRD2, DRD5, HTR1B, DRD1, DRD3, and HTR2B genes occupying the second important place in the network module. In conclusion, heat stress treatment prevented cardiac hypertrophy and altered the expression of monoamine genes. This would imply that monoamine transmission plays an important role in the development of cardiac hypertrophy, and that cyclic-chronic heat treatment modulates the cardiac monoaminergic system. These molecular biomarkers could be useful for screening, diagnosis, and treatment of cardiac hypertrophy.