Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic liver disease closely associated with the epidemics of obesity and type 2 diabetes mellitus (T2DM), but without licensed pharmacological treatment to date. As glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved anti-diabetic and anti-obesity medications, they were also considered a potential therapeutic option for NAFLD. Preclinical studies suggest that GLP-1RAs have a beneficial effect on major NAFLD histological outcomes, i.e., hepatic steatosis and inflammation, through multiple intrahepatic mechanisms, including increased fatty acid ß-oxidation, activation of autophagy, suppression of inflammation, and oxidative stress. Data on hepatic fibrosis are limited or inconclusive, although some studies reported improvement in indices of fibrosis or prevention of fibrosis initiation or reduction of collagen deposition. Whether the positive impact of GLP-1RAs on hepatic histology is indirect, i.e., through their action on extrahepatic tissues, or whether their action is direct, i.e., through activating GLP-1R on the hepatocytes, is still a controversial issue. Alongside GLP-1RAs, newly emerging peptide polyagonists (i.e., synthetic molecules that combine the amino acid sequences of more than one peptide, thus having the ability to bind more than one receptor) are now being investigated in NAFLD with high expectations. This review summarizes the existing knowledge derived from animal studies on the effects of GLP-1RAs and GLP-1RA related peptide polyagonists on NAFLD in an attempt to illuminate areas of uncertainty and provide the groundwork for future animal and clinical research in the field.

The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease, associated with obesity, type 2 diabetes mellitus and dyslipidemia, which can lead to liver cirrhosis and hepatocellular carcinoma in some patients. Apart from lifestyle modifications, which are the cornerstone for its management, several drugs are under evaluation, including glucagon-like peptide-1 receptor agonists (GLP-R1RAs). In this review, we summarized major clinical data concerning the effects of GLP-1RAs on NAFLD, trying to highlight existing knowledge and to elucidate areas of uncertainty, thus providing clues to potential clinical implications and research. AREAS COVERED: Selected clinical studies on GLP-R1As in NAFLD are presented in this narrative review. EXPERT OPINION: There is evidence that treatment with GLP-R1As in NAFLD has beneficial effects on NAFLD, i.e. improvement in liver function tests and histological improvement in hepatic steatosis and inflammation, but not fibrosis. Further research is required toward the early use of GLP-R1Αs, i.e. in NAFLD patients without fibrosis to evaluate whether they may prevent the progression to fibrosis, or in patients with advanced disease in combination with other medications, which may have additive or even synergistic effects on NAFLD.

COVID-19 and Male Infertility: Is There a Role for Antioxidants?

Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), jeopardizes male fertility because of the vulnerability of the male reproductive system, especially the testes. This study evaluates the effects of the virus on testicular function and examines the potential role of antioxidants in mitigating the damage caused by oxidative stress (OS). A comprehensive PubMed search examined exocrine and endocrine testicular function alteration, the interplay between OS and COVID-19-induced defects, and the potential benefit of antioxidants. Although the virus is rarely directly detectable in sperm and testicular tissue, semen quality and hormonal balance are affected in patients, with some changes persisting throughout a spermatogenesis cycle. Testicular pathology in deceased patients shows defects in spermatogenesis, vascular changes, and inflammation. Acute primary hypogonadism is observed mainly in severely infected cases. Elevated OS and sperm DNA fragmentation markers suggest redox imbalance as a possible mechanism behind the fertility changes. COVID-19 vaccines appear to be safe for male fertility, but the efficacy of antioxidants to improve sperm quality after infection remains unproven due to limited research. Given the limited and inconclusive evidence, careful evaluation of men recovering from COVID-19 seeking fertility improvement is strongly recommended.

The Silent Threat to Women's Fertility: Uncovering the Devastating Effects of Oxidative Stress.

Oxidative stress (OS), which arises through an imbalance between the formation of reactive oxygen species (ROS) and antioxidant defenses, plays a key role in the pathophysiology of female infertility, with the latter constituting just one of a number of diseases linked to OS as a potential cause. The aim of the present article is to review the literature regarding the association between OS and female infertility. Among the reproductive diseases considered are endometriosis and polycystic ovary syndrome (PCOS), while environmental pollutants, lifestyle variables, and underlying medical conditions possibly resulting in OS are additionally examined. Current evidence points to OS likely contributing to the pathophysiology of the above reproductive disorders, with the amount of damage done by OS being influenced by such variables as duration and severity of exposure and the individual's age and genetic predisposition. Also discussed are the processes via which OS may affect female fertility, these including DNA damage and mitochondrial dysfunction. Finally, the last section of the manuscript contains an evaluation of treatment options, including antioxidants and lifestyle modification, capable of minimizing OS in infertile women. The prime message underlined by this review is the importance of considering OS in the diagnosis and treatment of female infertility. Further studies are, nevertheless required to identify the best treatment regimen and its ideal duration.

PDE5 inhibitors and male reproduction: Is there a place for PDE5 inhibitors in infertility clinics or andrology laboratories?

The objective of this review study is to evaluate the therapeutic role of PDE5 inhibitors (PDE5is) in the amelioration of oligoasthenospermia in infertile males. PDE5is have a beneficial influence on the secretory function of the Leydig and Sertoli cells, the biochemical environment within the seminiferous tubule, the contractility of the testicular tunica albuginea, and the prostatic secretory function. In several studies, the overall effect of sildenafil and vardenafil increased quantitative and qualitative sperm motility. Furthermore, some studies indicate that PDE5is influence positively the sperm capacity to undergo capacitation under biochemical conditions that are known to induce the sperm capacitation process. Additional research efforts are necessary in order to recommend unequivocally the usage of sildenafil, vardenafil, or avanafil for the alleviation of male infertility.

Redox Balance in Male Infertility: Excellence through Moderation-"Μέτρον ἄριστον".

Male infertility, a relatively common and multifactorial medical condition, affects approximately 15% of couples globally. Based on WHO estimates, a staggering 190 million people struggle with this health condition, and male factor is the sole or contributing factor in roughly 20-50% of these cases. Nowadays, urologists are confronted with a wide spectrum of conditions ranging from the typical infertile male to more complex cases of either unexplained or idiopathic male infertility, requiring a specific patient-tailored diagnostic approach and management. Strikingly enough, no identifiable cause in routine workup can be found in 30% to 50% of infertile males. The medical term male oxidative stress infertility (MOSI) was recently coined to describe infertile men with abnormal sperm parameters and oxidative stress (OS), including those previously classified as having idiopathic infertility. OS is a critical component of male infertility, entailing an imbalance between reactive oxygen species (ROS) and antioxidants. ROS abundance has been implicated in sperm abnormalities, while the exact impact on fertilization and pregnancy has long been a subject of considerable debate. In an attempt to counteract the deleterious effects of OS, urologists resorted to antioxidant supplementation. Mounting evidence indicates that indiscriminate consumption of antioxidants has led in some cases to sperm cell damage through a reductive-stress-induced state. The "antioxidant paradox", one of the biggest andrological challenges, remains a lurking danger that needs to be carefully avoided and thoroughly investigated. For that reason, oxidation-reduction potential (ORP) emerged as a viable ancillary tool to basic semen analysis, measuring the overall balance between oxidants and antioxidants (reductants). A novel biomarker, the Male infertility Oxidative System (MiOXSYS®), is a paradigm shift towards that goal, offering a quantification of OS via a quick, reliable, and reproducible measurement of the ORP. Moderation or "Μέτρον" according to the ancient Greeks is the key to successfully safeguarding redox balance, with MiOXSYS® earnestly claiming its position as a guarantor of homeostasis in the intracellular redox milieu. In the present paper, we aim to offer a narrative summary of evidence relevant to redox regulation in male reproduction, analyze the impact of OS and reductive stress on sperm function, and shed light on the "antioxidant paradox" phenomenon. Finally, we examine the most up-to-date scientific literature regarding ORP and its measurement by the recently developed MiOXSYS® assay.

Reliability of Refraction, Keratometry, and Intraocular Pressure Measurements with an Automated All-in-one Device.

SIGNIFICANCE: This study explores the reliability of TonoRef II (Nidek, Tokyo, Japan), which represents a simple tool to obtain rapid refractometry and tonometry measurements. The present device demonstrates very high repeatability of refraction and intraocular pressure (IOP) readings as compared with subjective measurements and a higher concordance of IOP readings to Goldmann application tonometry (GAT). PURPOSE: This study aimed to evaluate the repeatability of measurements acquired with the Autorefractometer/Keratometer/Tonometer TonoRef II and assess their agreement to subjective measurements and readings of other established devices. METHODS: In a cross-sectional study, 54 eyes of 54 healthy subjects were enrolled. Each subject underwent five measurements with the TonoRef II, three measurements with the Canon RK-F1 Autorefractor Keratometer (Canon Europe NV, Amstelveen, the Netherlands), three IOP measurements with the Canon TX-F Noncontact Tonometer (Canon Inc., Tokyo, Japan), three measurements with GAT, and a thorough subjective refraction. Repeatability coefficient (r), intraclass correlation coefficient (ICC), and Bland-Altman plots were used to evaluate repeatability of readings and agreement to the subjective values. RESULTS: TonoRef II showed high repeatability (ICC >0.9) in all parameters tested (sphere, r = 0.157; cylinder, r = 0.196; IOP, r = 2.653). A strong correlation was found between TonoRef and Canon instruments (P < .001 in all parameters). Mean differences and limits of agreement (mean ± 1.96 standard deviation) were -0.01 ± 0.69 D, -0.11 ± 0.7 D, and 2.1 ± 3.4 mmHg for sphere, cylinder, and IOP, respectively. Both autorefractors achieved a very good to excellent agreement to the values obtained with the subjective refraction for most of the parameters tested, without any significant difference to each other (P > .05). Intraocular pressure measurements of TonoRef II showed higher agreement to the GAT values compared with those obtained with the Canon tonometer (ICC, 0.9114 and 0.7002, respectively; P < .001). CONCLUSIONS: Intraocular pressure and refraction readings acquired with TonoRef II demonstrate very high repeatability and agreement to the subjective measurements. Regarding IOP evaluation, TonoRef II shows higher concordance to GAT compared with another established noncontact tonometer.

The Effect of Antioxidant Supplementation on Operated or Non-Operated Varicocele-Associated Infertility: A Systematic Review and Meta-Analysis.

In patients with varicocele-associated infertility, the effect of antioxidant supplementation on fertility is unknown. We performed a systematic review and meta-analysis to explore their role in patients with operated or non-operated varicocele. We searched major databases and sources of grey literature until May 2021 (PROSPERO: CRD42021248195). We included 14 studies (980 individuals) in the systematic review. Of the 14 studies, 2 explored the effect of antioxidant supplementation in patients with non-operated varicocele, 1 compared antioxidants versus surgical repair of varicocele, while 11 explored antioxidants after surgical repair of varicocele and were also included in the meta-analysis. Regarding pregnancy rates, no significant differences were demonstrated after treatment with antioxidants versus no treatment at three (OR: 2.28, 95% CI: 0.7-7.48) and six months (OR: 1.88, 95% CI: 0.62-5.72). Accordingly, contradictory findings were reported in sperm concentration, morphology, and motility, as well as DNA fragmentation. Our findings indicate that antioxidant supplementation does not improve pregnancy rates and semen parameters in patients with varicocele-associated infertility, in the absence of previous screening for oxidative stress. Based on the previous notion, most included studies also raised methodological concerns. Therefore, definitive conclusions about the efficacy of antioxidant supplementation in this setting cannot be drawn and further research on the field is mandatory.

Endothelial Biopsy for the Diagnosis and Management of Culture-Negative Retrocorneal Fungal Keratitis With the Assistance of Optical Coherence Tomography Imaging.

PURPOSE: To report a case of a culture-negative deep fungal corneal infection that was diagnosed after histopathology of an anterior segment optical coherence tomography-guided endothelial biopsy. METHODS: A 22-year-old woman with history of contact lens wear and concomitant topical steroid use presented with a mid-stromal corneal infiltrate that failed to respond to oral acyclovir and topical fortified antibiotics. Although cornea stains, cultures, and confocal microscopy showed negative results, there was high clinical suspicion for fungal keratitis. After 2 months on topical natamycin, oral voriconazole, and serial intrastromal and intracameral voriconazole injections, the infiltrate enlarged and deepened. Imaging with anterior segment optical coherence tomography revealed that the infection had progressed to an endothelial plaque. RESULTS: Diagnostic endothelial biopsy was performed in the operating room. Cultures showed again negative results, whereas histopathology of the removed specimen revealed fungal elements. The postoperative edema at the site of the biopsy resolved over the course of 4 weeks, and a posterior stromal scar formed. Serial intrastromal and intracameral voriconazole injections were continued for the first postoperative month. At the 1-year and the 3-year follow-up examinations, the patient's vision was 20/20 without recurrence. CONCLUSIONS: Intraoperative scraping of the endothelial plaque and histopathologic evaluation of the specimen proved to be of utmost importance for definitive diagnosis and resolution of the culture-negative deep fungal infection in this case. This young patient's cornea was retained and vision remains excellent.

Optical coherence tomography angiography in children with spontaneously regressed retinopathy of prematurity.

PURPOSE: To assess optical coherence tomography angiography (OCTA) parameters in children born preterm who developed spontaneously regressed retinopathy of prematurity (sr-ROP, group 1), or had no ROP (PreT, group 2), compared with term-born age-matched controls (group 3). METHODS: Cross-sectional comparative case series. Children aged 6-8 years had a complete ocular examination and OCT and OCTA imaging (Optovue RTVue AVANTI instrument). Foveal avascular zone (FAZ) area, FAZ perimetry, and vascular density in three slabs were measured automatically, and foveal depth was measured manually by two graders. RESULTS: Groups 1, 2, and 3 (26, 32, and 34 eyes respectively) did not differ in age or gender, but differed in gestational age and birth weight. Both inner retinal thickness and foveal depth differed significantly between group 1 and 2, as did vascular density in the superficial and deep vascular plexus. VA, FAZ area, and perimetry were distinct in all three groups. VA correlated positively with FAZ area and foveal depth, negatively with vascular density. CONCLUSION: OCTA parameters reveal microvascular changes that distinguish eyes with sr-ROP from premature eyes without ROP, as does visual acuity. It is not possible to infer if the cause is the presence of retinopathy or the different severity of retinal immaturity.

The Sertoli cell as the orchestra conductor of spermatogenesis: spermatogenic cells dance to the tune of testosterone.

Spermatogenesis is contingent upon hormones and growth factors acting through endocrine and paracrine pathways either in vivo or in vitro. Sertoli cells (SCs) furnish essential factors for the successful advancement of spermatogenesis and spermiogenesis. Moreover, receptors for follicle stimulating hormone (FSH) and testosterone, which are the main hormonal regulators of spermatogenesis, are identified on SCs. Testosterone, FSH and luteinizing hormone are known to determine the destiny of germ cells and in their absence germ cells undergo apoptosis. Bcl-2 family proteins determine one signaling pathway which seems to be crucial for the homeostasis of male gametes. In addition to paracrine signals, germ cell development also relies on signals generated by SCs via direct membrane contact. The regulatory peptide somatostatin has an important role in the regulation of the proliferation of the male germ cells. Activin A, follistatin and FSH control germ cell development. In vitro culture systems have provided initial evidence supporting the achievement of the completion of the first and second male meiotic division in vitro. This review article provides an overview of the literature regarding the hormonal pathways governing spermatogenesis and spermiogenesis.