Pulmonary arterial hypertension: Navigating the pathways of progress in diagnosis, treatment, and patient care.

Pulmonary arterial hypertension (PAH) is a form of precapillary pulmonary hypertension caused by a complex process of endothelial dysfunction and vascular remodeling. If left untreated, this progressive disease presents with symptoms of incapacitating fatigue causing marked loss of quality of life, eventually culminating in right ventricular failure and death. Patient management is complex and based on accurate diagnosis, risk stratification, and treatment initiation, with close monitoring of response and disease progression. Understanding the underlying pathophysiology has enabled the development of multiple drugs directed at different targets in the pathological chain. Vasodilator therapy has been the mainstay approach for the last few years, significantly improving quality of life, functional status, and survival. Recent advances in therapies targeting dysfunctional pathways beyond endothelial dysfunction may address the fundamental processes underlying the disease, raising the prospect of increasingly effective options for this high-risk group of patients with a historically poor prognosis.

Total Alkaloids of Sophora alopecuroides Linn. Attenuates Rheumatoid Arthritis Through Regulating Follicular Helper T Cells.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease with abnormal differentiation of follicular helper T (Tfh) cells, Total alkaloids of Sophora alopecuroides Linn. (Leguminosae) (TASA) have potential effects on collagen-induced arthritis (CIA) mice, while the mechanism needs further elucidation. The purpose of this study is to explore the regulation of TASA on rheumatoid arthritis and related mechanism. Methods: The proportion of Tfh and B lymphocytes in peripheral blood lymphocytes of RA patients was examined by flow cytometry. We constructed the collagen induced arthritis DBA/1J mice model. Between days 15 and 45 following the first immunization, the mice were treated intraperitoneally with saline, TASA (100, 50, and 25 mg/kg), and dexamethasone (DXM) for 30 days. Molecular biological techniques such as FCM, PCR, ELISA, and Western-blotting were used to examine Tfh cells and associated signal pathways. Results: Our results indicated that the follicular helper T cells and B lymphocytes in rheumatoid arthritis patients were significantly increased compared with the healthy control. The percentage of Tfh cells are correlated with RA related inflammatory factors. Total alkaloids of Sophora alopecuroides Linn. could significantly attenuate joint swelling. Meanwhile, it reduced the frequencies of spleen Tfh, B lymphocytes and the expression of TLR2, TLR9, p-NF-κBp65, CXCR5, Bcl-6, ICOS of ankle joints in CIA mice. Conclusion: Total alkaloids of Sophora alopecuroides Linn. may down-regulate the frequency and function of Tfh cells and inhibit GCB cells via TLRs/NF-κB signal pathway to relieve the immune-pathological progression of CIA mice.

CXC chemokine receptor type 5 may induce trophoblast dysfunction and participate in the processes of unexplained missed abortion, wherein p-ERK and interleukin-6 may be involved.

Chemokines regulate the trophoblast dysfunction involved in the occurrence and development of pathological pregnancy, including missed abortions. In particular, CXC chemokine receptor type 5 mediates cell proliferation, migration, and inflammation; nonetheless, its role in missed abortions remains unclear. This study aimed to examine the expression of CXC chemokine receptor type 5 in missed abortions and to investigate the effects of CXC chemokine receptor type 5 on the biological behaviour of trophoblasts, as well as the underlying mechanisms. Our results indicated that CXC chemokine receptor type 5 was upregulated in the villi of women who experienced unexplained missed abortions, as compared with those who had normal pregnancies. CXC chemokine receptor type 5 inhibited the proliferation and migration of human first-trimester trophoblast/simian virus cells but promoted cell apoptosis. With respect to its mechanisms, CXC chemokine receptor type 5 activated the extracellular signal-regulated protein kinase 1/2 signalling pathway and upregulated the secretion of interleukin-6; however, it had no effect on the secretion of tumour necrosis factor-α. In conclusion, our findings suggest that CXC chemokine receptor type 5 induces trophoblast dysfunction and participates in the processes of unexplained missed abortions, wherein p-ERK and interleukin-6 may be involved.

Multimodal treatments based on Tadalafil during acute phase of Peyronie's disease: experience at two referral academic centers.

AIM: The purpose of this study is to identify the clinical outcomes of patients during acute phase of Peyronie's disease (PD) treated with daily Tadalafil 5 mg associated with non-surgical treatments such as intra-plaque verapamil injections (IVI), vacuum erection devices (VED) or extra corporeal shockwave therapy (ESWT). METHODS: 445 patients with PD in acute stage were treated as it follows: Group 1(G1) 117 men with only Tadalafil 5 mg once a day for 3 months; Group 2(G2) 106 men with IVI plus Tadalafil 5 mg for a period of 12 weeks; Group 3(G3) 124 men that received ESWT for 6 weeks plus Tadalafil with the same protocol of G1; Group 4(G4) 98 men with VED plus Tadalafil 5 mg for 3 months. There were assessed at baseline and follow-up: Erectile dysfunction (ED), presence and severity of painful erections, penile plaque size and penile curvature degree. The results were evaluated at baseline and 3,6,12 months. RESULTS: Not statistically significant differences emerged between the two groups at baseline, except for higher presence of patients with ED in in G3(7.4%) vs other groups(p < 0.001). Three months after the treatment in G3 men had a significant reduction of penile curvature degrees after 1 year by treatments, whereas pain in an erection or during intercourse was resolved completely in 75% of the patients. CONCLUSIONS: Our study highlights that multimodal therapy has beneficial long-term effects not only in the decrease of ED symptoms, but also in the relief of the penile curvature and the quality of life.

Phosphodiesterase type 5 inhibitors as treatment for erectile dysfunction: a webinar-based poll unveiling perceptions of healthcare professionals.

Aim: Erectile dysfunction (ED) is marked by a recurring incapacity to achieve or uphold a satisfactory erection during sexual activities. The study aims to increase awareness about male reproductive health, dispel misconceptions about ED and encourage physician-patient discussions. Materials & methods: A live online poll was conducted during a 3-day webinar titled "Turning the Tide of Men's Health" organized by Viatris™ in collaboration with the Saudi Society of Family and Community Medicine and attended by healthcare professionals (HCPs) from diverse specialties. The attendees voluntarily responded to nine poll questions on adherence to ED medication, use of phosphodiesterase type 5 inhibitors (PDE5is) as cure versus management of ED and patients' challenges. The responses to the poll questions were recorded and assessed to understand the perceptions of HCPs. Results: The poll garnered 10,423 responses from 5831 attendees on the second day of the webinar. The key findings included HCPs' perceptions that PDE5is contribute to ED management not complete cure. The respondents acknowledged that adherence to ED medications might decline on days without planned sexual activity, and long-term adherence on a daily PDE5i is exhibited by a relatively modest percentage of ED patients. The consensus among respondents was that PDE5is do not enhance or generate sexual desire, and the daily schedule of ED treatment may be burdensome for some patients. Conclusion: The findings from this poll offer insights into the perspectives of HCPs regarding the usage of PDE5is to treat ED. Responders of the poll generally agreed that PDE5is can help manage ED without affecting desire, though adherence may be lower on days without planned sexual activity. Furthermore, most respondents acknowledged that adhering to a daily pill regimen posed a greater burden than waiting for the medication to take effect.

Current treatment options for erectile dysfunction in kidney transplant recipients.

INTRODUCTION: Erectile dysfunction (ED) and kidney dysfunction share common risk factors linked to conditions involving endothelial impairment, such as coronary artery disease, dyslipidemia, diabetes mellitus, hypertension, smoking, and obesity. Men with chronic kidney disease experience a high incidence and prevalence of ED. While a functional renal graft can alleviate the issue for some patients, a significant portion of recipients still experience ED (20%-50%). OBJECTIVES: This narrative review describes the variety of current treatments modalities on ED in kidney transplant recipients (KTRs) and their clinical outcomes. METHODS: MEDLINE, Web of Science, PubMed, and Google Scholar were used to find eligible articles pertaining to the treatment options of ED in KTRs. A total of 64 articles were evaluated. RESULTS: In KTRs, ED stems from a multifaceted etiology: anxiety, drug side effects, interference with penile vascularity, or the response of cavernosal muscle to neurotransmitters, along with changes in the endocrine milieu. A diverse range of treatments to restore erectile function has proven to be safe and effective for KTRs. Options include drug therapy, surgical interventions, intracavernosal injection therapies, vacuum erection devices, and extracorporeal shockwave therapy. CONCLUSION: The initial treatment approach may involve the use of a phosphodiesterase type 5 inhibitors at a low dosage, especially if testosterone-circulating levels align with the diagnosis of hypogonadism. The consideration of a combination therapy involving testosterone and phosphodiesterase type 5 inhibitors should be contemplated due to the associated beneficial effects. Extracorporeal shockwave therapy has shown positive short-term clinical and physiological effects on erectile function in patients who did not respond to first-line treatments, resulting in spontaneous erections sufficient for sexual penetration in 50% of cases. Penile implants should be considered as third-line options based on specific patient needs and compliance with clinical conditions.

Phosphodiesterase-5 inhibitors use and the risk of alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: The management of Alzheimer's disease (AD) poses considerable challenges, necessitating the pursuit of innovative therapeutic approaches. Recent research has spotlighted the promising role of phosphodiesterase type 5 inhibitors (PDE5Is) in reducing the prevalence of AD, utilizing their vasodilatory properties to suggest a potential neuroprotective effect. This meta-analysis and systematic review aims to assess the relationship between the use of PDE5Is and the risk of AD. METHODS: A detailed examination was carried out across several electronic databases till March 2024, including PubMed, Web of Science, Scopus, CENTRAL, and Embase. The focus was on identifying studies that compare the occurrence of AD among PDE5I users vs non-users. Through a random-effects model, pooled hazard ratios (HRs) were calculated, in alignment with guidelines from the Cochrane Handbook for Systematic Reviews and Meta-Analysis and the PRISMA standards. RESULTS: This analysis included six studies, cumulating a participant count of 8,337,313, involving individuals treated with sildenafil, tadalafil, and vardenafil, against a control group undergoing other or no treatments. The cumulative HR for AD risk among PDE5I users versus the control group was 0.53 (95% CI: 0.32-0.86, p = 0.008), signaling a markedly reduced likelihood of AD development in the PDE5I group. Particularly, sildenafil usage showed a significant risk reduction (HR: 0.46, 95% CI: 0.31-0.70, p < 0.001), while findings for tadalafil and vardenafil were not significant. Test of subgroup differences found no difference between male and female participants in the risk of AD. CONCLUSIONS: Our findings suggest that the use of PDE5Is is associated with a reduced risk of AD, highlighting its potential as a protective agent against neurodegenerative diseases. Given the very low quality of evidence and the heterogeneity among the included studies, further high-quality research is warranted to confirm these findings and elucidate the underlying mechanisms. Register number PROSPERO 2024: CRD42024522197.

Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients. METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation. RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway. CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.

Effect of phosphodiesterase type 5 inhibitors on surgical outcome of ventricular septal defect and pulmonary hypertension patients.

BACKGROUND: Children with ventricular septal defect (VSD) and large systemic-to-pulmonary shunts eventually develop pulmonary hypertension (PH). The perioperative management of patients with VSD and PH is quite troublesome and still debatable, especially in developing countries where the different management options and standardization of treatment is not available. Oral phosphodiesterase type 5 (PDE-5) inhibitors are good treatment options being widely available, cheap, easy administration and do not require extensive monitoring. The aim of our study was to evaluate the effect of the PDE-5 inhibitors when given orally, early preoperative and continued for 3 months postoperative on controlling postoperative PH with its effect on right ventricle (RV) functions. Fifty-one patients were randomly assigned to either sildenafil or tadalafil, 1 week before and continued for 3 months after corrective surgery. The control group received a placebo. RESULTS: There was no significant difference in the improvement in the right ventricle systolic pressure (RVSP) between both groups, early in the postoperative period (P = 0.255) and in follow-up (P = 0.259). There was also no significant difference in the changes in mean pulmonary artery pressure (mPAP), postoperatively and on follow-up (P = 0.788 and 0.059, respectively). There was a drop in RV functions in both groups postoperatively which improved on follow-up; however, it was not significant between both groups. The length of intensive care unit (ICU) stay was similar between both groups (P = 0.143). CONCLUSION: Perioperative administration of PDE-5 inhibitors does not have an impact on the clinical course as regards improvement in pulmonary artery (PA) pressure, ventricular functions and ICU stay.

A universal recombinant adenovirus type 5 vector-based COVID-19 vaccine.

A universal recombinant adenovirus type-5 (Ad5) vaccine against COVID19 (Ad-US) was constructed, and immunogenicity and broad-spectrum of Ad5-US were evaluated with both intranasal and intramuscular immunization routes. The humoral immune response of Ad5-US in serum and bronchoalveolar lavage fluid were evaluated by the enzyme-linked immunosorbent assay (ELISA), recombinant vesicular stomatitis virus based pseudovirus neutralization assay, and angiotensin-converting enzyme-2 (ACE2) -binding inhibition assay. The cellular immune response and Th1/Th2 biased immune response of Ad5-US were evaluated by the IFN-γ ELISpot assay, intracellular cytokine staining, and Meso Scale Discovery (MSD) profiling of Th1/Th2 cytokines. Intramuscular priming followed by an intranasal booster with Ad5-US elicited the broad-spectrum and high levels of IgG, IgA, pseudovirus neutralizing antibody (PNAb), and Th1-skewing of the T-cell response. Overall, the adenovirus type-5 vectored universal SARS-CoV-2 vaccine Ad5-US was successfully constructed, and Ad5-US was highly immunogenic and broad spectrum. Intramuscular priming followed by an intranasal booster with Ad5-US induced the high and broad spectrum systemic immune responses and local mucosal immune responses.

PDE5is-naïve versus non-naïve patients at first investigation for erectile dysfunction-findings from a long-term, real-life cross-sectional study.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5is) represent a first-line pharmacological therapy for erectile dysfunction (ED). Men could obtain PDE5is for recreational purposes without any proper medical prescription. OBJECTIVE: We aimed to analyze clinical characteristics of patients who already used any PDE5i for ED without previous formal medical prescription. MATERIALS AND METHODS: Data from 2012 heterosexual, sexually active men seeking first medical help for ED at our outpatient clinic between 2005 and 2022 were analyzed. All patients were assessed with a comprehensive sexual and medical history and completed the International Index of Erectile Function (IIEF) at baseline. Comorbidities were scored with the Charlson comorbidity index (CCI). Thereof, according to exposure to any PDE5i before their first visit, patients were subdivided into: PDE5i-naïve and non-PDE5i-naïve patients. Descriptive statistics tested the sociodemographic and clinical characteristics of both groups. A logistic regression model predicted the likelihood of being PDE5i-naïve at the baseline. Linear regression analysis (LRA) estimated the likelihood of being PDE5i-naïve versus non-PDE5i-naïve over the analyzed timeframe. Lastly, local polynomial regression models graphically explored the likelihood of being PDE5i-naïve at the first clinical assessment over the analyzed timeframe, and the sensitivity analyses tested the probability of being PDE5i-naïve at baseline. RESULTS: Overall, 1,491 (70.9%) patients were PDE5i-naïve and 611 (29.1%) were non-PDE5i-naïve at the first assessment. PDE5is-naïve patients were younger, with a lower prevalence of CCI ≥ 1 and of normal erectile function (EF) than non-PDE5i-naïve men (all p < 0.05). Multivariable logistic regression found that patients with lower BMI (OR: 0.99), higher IIEF-EF scores (OR: 1.02), lower rates of severe ED (OR: 0.94), and who had been assessed earlier throughout the study timeframe (OR: 1.27) were less likely to be PDE5i-naïve at baseline. Univariate LRA revealed that younger patients (Coeff: -0.02), with lower CCI (Coeff: -0.29) and higher alcohol intake per week (Coeff: 0.52) were more likely to be PDE5i-naïve over the analyzed timeframe. Moreover, for the same IIEF-EF score, patients with higher CCI had lower probability of being PDE5i-naïve. CONCLUSIONS: Self-prescription of PDE5is is an attitude presents in the general population, despite this phenomenon has decreased overtime. Current data outline the importance to keep promoting educational campaigns to promote PDE5is as effective and safe medicinal products, while avoiding their improper use.

HBO1/KAT7/MYST2 HAT complex regulates human adenovirus replicative cycle.

Human adenoviruses (HAdV) belong to a small DNA tumor virus family that continues as valuable models in understanding the viral strategies of usurping cell growth regulation. A number of HAdV type 2/5 early viral gene products interact with a variety of cellular proteins to build a conducive environment that promotes viral replication. Here we show that HBO1 (Histone Acetyltransferase Binding to ORC1), a member of the MYST histone acetyltransferase (HAT) complex (also known as KAT7 and MYST2) that acetylates most of the histone H3 lysine 14, is essential for HAdV5 growth. HBO1/MYST2/KAT7 HAT complexes are critical for a variety of cellular processes including control of cell proliferation. In HBO1 downregulated human cells, HAdV5 infection results in reduced expression of E1A and other viral early genes, virus growth is also reduced significantly. Importantly, HBO1 downregulation reduced H3 lysine 14 acetylation at viral promoters during productive infection, likely driving reduced viral gene expression. HBO1 was also associated with viral promoters during infection and co-localized with viral replication centers in the nuclei of infected cells. In transiently transfected cells, overexpression of E1A along with HBO1 stimulated histone acetyltransferase activity of HBO1. E1A also co-immunoprecipitated with HBO1 in transiently transfected cells. In summary, our results demonstrate that HAdV recruits the HBO1 HAT complex to aid in viral replication.

[McArdle's disease revealed by acute low back pain]. / Une maladie de McArdle révélée par une lombalgie aiguë.

INTRODUCTION: McArdle disease, or glycogen storage disease type V (GSD 5), is a rare metabolic myopathy linked to an autosomal recessive myophosphorylase deficiency. CASE REPORT: We report the case of a 17-year-old male patient who was referred to the emergency department for the management of acute inflammatory low back pain, without traumatic context, associated with an increase of CK at 66,336 UI/L (N<192UI/L) and a CRP at 202mg/L. The immunological assessment was negative and the spinal MRI showed images in favor of necrotizing fasciitis affecting the erector spinae muscles, among others. Faced with the description of difficulties in practicing physical activities since childhood and a non-ischaemic forearm exercise test showing no elevation in lactacidemia, genetic tests were carried out, finding two heterozygous variants in the PYGM gene: c.1963G>A (p.Glu655Lys) class 5 and c.2178-1G>A class 4, confirming the diagnosis of McArdle disease. DISCUSSION: GSD 5 is a disease characterized essentially by muscular fatigability during exercise. The case reported here is original in the clinical circumstances leading to the diagnosis, i.e., inaugural acute low back pain with rhabdomyolysis. This symptomatology had already been described before, but in a patient whose diagnosis was already known. Spinal MRI showed non-specific muscle inflammation and necrosis. Muscle biopsy only found necrosis but no pathological elements typical of the diagnosis. If the symptoms are suggestive, it may be preferable to directly perform a non-ischaemic forearm exercise test, in order to go directly to molecular genetic analysis. There is no specific curative treatment of GSD 5. However, some measures can be implemented to limit the symptoms, such as learning physical exercises, limiting intense efforts and adopting dietary recommendations.

Phosphodiesterase type 5 inhibitors related hearing impairment: a real world study based on the FDA adverse event reporting system.

Recent studies focused on exploring phosphodiesterase type 5 inhibitors (PDE5Is)-related hearing impairment. This study aimed to comprehensively explore real-world hearing impairment associated with PDE5Is based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). The characteristics and correlation of PDE5Is-related hearing impairment reported in the FAERS database from the fourth quarter of 2003 to the second quarter of 2023 were analyzed using disproportionality analysis. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) were used to analyze the adverse events (AEs) of hearing impairment. A total of 1,438 reported cases of hearing impairment were associated with four PDE5Is, revealing statistically significant reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) with the SMQ. The average age of all patients was more than 55 years, over 70% of AEs were reported in men. Most of the reported cases were from the United States. Reports for all the drugs indicated an increase since 2008, except for avanafil. This study showed that the disability rates of PDE5Is were 8.14-40%, the rates of initial or prolonged hospitalization were 6.21-10.24%, and the rates of required intervention were 3.31-9.45%. The pharmacovigilance study identified a potential risk of hearing impairment associated with PDE5Is, indicating the need for continuous monitoring and appropriate management.

Metabotropic Glutamate Receptors Type 3 and 5 Feature the "NeuroTransmitter-type" of Glioblastoma: A Bioinformatic Approach.

BACKGROUND: Glioblastoma (GBM) represents an aggressive and common tumor of the central nervous system. The prognosis of GBM is poor, and despite a refined genetic and molecular characterization, pharmacological treatment is largely suboptimal. OBJECTIVE: Contribute to defining a therapeutic line in GBM targeting the mGlu3 receptor in line with the principles of precision medicine. METHODS: Here, we performed a computational analysis focused on the expression of type 3 and 5 metabotropic glutamate receptor subtypes (mGlu3 and mGlu5, respectively) in high- and low-grade gliomas. RESULTS: The analysis allowed the identification of a particular high-grade glioma type, characterized by a high expression level of both receptor subtypes and by other markers of excitatory and inhibitory neurotransmission. This so-called neurotransmitter-GBM (NT-GBM) also shows a distinct immunological, metabolic, and vascularization gene signature. CONCLUSION: Our findings might lay the groundwork for a targeted therapy to be specifically applied to this putative novel type of GBM.

Sildenafil, alone and in combination with imipramine or escitalopram, display antidepressant-like effects in an adrenocorticotropic hormone-induced (ACTH) rodent model of treatment-resistant depression.

BACKGROUND: Major depressive disorder (MDD) represents a challenge with high prevalence and limited effectiveness of existing treatments, particularly in cases of treatment-resistant depression (TRD). Innovative strategies and alternative drug targets are therefore necessary. Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is known to exert neuroplastic, anti-inflammatory, and antioxidant properties, and is a promising antidepressant drug candidate. AIM: To investigate whether sildenafil monotherapy or in combination with a known antidepressant, can elicit antidepressant-like effects in an adrenocorticotropic hormone (ACTH)-induced rodent model of TRD. METHODS: ACTH-naïve and ACTH-treated male Sprague-Dawley (SD) rats received various sub-acute drug treatments, followed by behavioural tests and biochemical analyses conversant with antidepressant actions. RESULTS: Sub-chronic ACTH treatment induced significant depressive-like behaviour in rats, evidenced by increased immobility during the forced swim test (FST). Sub-acute sildenafil (10 mg/kg) (SIL-10) (but not SIL-3), and combinations of imipramine (15 mg/kg) (IMI-15) and sildenafil (3 mg/kg) (SIL-3) or escitalopram (15 mg/kg) (ESC-15) and SIL-3, exhibited significant antidepressant-like effects. ACTH treatment significantly elevated hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin, norepinephrine, kynurenic acid (KYNUA), quinolinic acid (QUINA), and glutathione. The various mono- and combined treatments significantly reversed some of these changes, whereas IMI-15 + SIL-10 significantly increased glutathione disulfide levels. ESC-15 + SIL-3 significantly reduced plasma corticosterone levels. CONCLUSION: This study suggests that sildenafil shows promise as a treatment for TRD, either as a stand-alone therapy or in combination with a traditional antidepressant. The neurobiological mechanism underlying the antidepressant-like effects of the different sildenafil mono- and combination therapies reflects a multimodal action and cannot be explained in full by changes in the individually measured biomarker levels.

Antagonism of metabotropic glutamate receptor type 5 prevents levodopa-induced dyskinesia development in a male rat model of Parkinson's disease: Electrophysiological evidence.

Levodopa-induced dyskinesia (LID) is a common complication in patients with advanced Parkinson's disease (PD) undergoing treatment with levodopa. Glutamate receptor antagonists can suppress LID; however, the underlying mechanisms remain unclear. Here, we aimed to evaluate the effect of 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP), a metabotropic glutamate receptor 5 (mGluR5) antagonist, on dyskinesia. We recorded the neuronal activity of the entopeduncular nucleus and examined responses to cortical electric stimulation in the control group (n = 6) and three groups of rats (male PD model). Saline was intraperitoneally administered to dopamine lesioned (DL) rats (n = 6), levodopa/benserazide (L/B) was administered to LID rats (n = 8), and L/B combined with MTEP was administered to MTEP rats (n = 6) twice daily for 14 days. We administered L/B to LID and MTEP rats 48 h after the final administration of MTEP to examine the chronic effect of MTEP. The control and DL groups did not have LID. The MTEP group had less LID than the LID group (p < .01) on day 1 and day 18. The control group had a typical triphasic pattern consisting of early excitation (early-Ex), inhibition, and late excitation (late-Ex). However, the inhibition phase disappeared, was partially observed, and was fully suppressed in the DL, LID, and MTEP groups, respectively. The cortico-striato-entopeduncular pathway is important in the pathophysiology of LID. mGluR5 antagonism suppresses LID progression by preventing physiological changes in the cortico-striato-entopeduncular pathway. Future studies are required to validate these results.

SPINK5 inhibits esophageal squamous cell carcinoma metastasis via immune activity.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a predominant subtype of esophageal cancer with relatively high mortality worldwide. Serine peptidase inhibitor Kazal-type 5 (SPINK5) is reported to be downregulated in ESCC. However, its explicit role in ESCC remains further investigation. METHODS: The tumor tissues and adjacent non-cancerous tissues were obtained from 196 patients with ESCC for the determination of SPINK5 mRNA levels. Additionally, the relationship between SPINK5 mRNA levels and clinicopathological features of ESCC patients was explored. The effects of SPINK5 on the invasion and migration of ESCC cells were assessed using Transwell assays. Furthermore, SPINK5 mRNA and LEKTI protein were measured in ESCC cell lines after treatment with poly (I:C), lipopolysaccharide (LPS) or unmethylated CpG DNA. Moreover, the correlation between expression of SPINK5 and nuclear factor-kappa B (NF-κB) signaling pathway-related genes was analyzed in the TCGA-ESCC cohort, and the effects of SPINK5 on NF-κB transcription was analyzed using a luciferase reporter gene assay. Finally, the correlations between SPINK5 and infiltration of immune cells, immune scores, stromal scores and ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) scores were explored. RESULTS: SPINK5 mRNA levels were downregulated in tumor tissues, which was significantly correlated with higher lymph node metastases. Overexpressed SPINK5 inhibited cell invasion and migration in ESCC cell lines. Mechanistically, LPS-induced activation of Toll-like receptor 4 (TLR4) decreased SPINK5 mRNA and LEKTI in KYSE150 and KYSE70 cells. Spearman correlation analysis revealed that SPINK5 mRNA was significantly negatively correlated with a total of seven NF-κB signaling pathway-related genes in TCGA-ESCC patients. Moreover, downregulation of SPINK5 increased and upregulation of SPINK5 decreased the activity of the NF-κB promoter in HEK293T cells. Finally, immune cells infiltration analysis revealed that SPINK5 was significantly correlated with the infiltration of various immune cells, stromal scores, immune scores and ESTIMATE scores. CONCLUSIONS: SPINK5 plays critical roles in the TLR4/NF-κB pathway and immune cells infiltration, which might contribute to the ESCC metastasis. The findings of the present study may provide a promising biomarker for the diagnosis and treatment of esophageal squamous cell carcinoma.