A Second-Generation Fungerp Analog, SCY-247, Shows Potent In Vitro Activity against Candida auris and Other Clinically Relevant Fungal Isolates.

Due to the increase of antifungal drug resistance and difficulties associated with drug administration, new antifungal agents for invasive fungal infections are needed. SCY-247 is a second-generation fungerp antifungal compound that interferes with the synthesis of the fungal cell wall polymer ß-(1,3)-d-glucan. We conducted an extensive antifungal screen of SCY-247 against yeast and mold strains compared with the parent compound ibrexafungerp (IBX; formerly SCY-078) to evaluate the in vitro antifungal properties of SCY-247. SCY-247 demonstrated similar activity to IBX against all of the organisms tested. Moreover, SCY-247 showed a higher percentage of fungicidal activity against the panel of yeast and mold isolates than IBX. Notably, SCY-247 showed considerable antifungal properties against numerous strains of Candida auris Additionally, SCY-247 retained its antifungal activity when evaluated in the presence of synthetic urine, indicating that SCY-247 maintains activity and structural stability under environments with decreased pH levels. Finally, a time-kill study showed SCY-247 has potent anti-Candida, -Aspergillus, and -Scedosporium activity. In summary, SCY-247 has potent antifungal activity against various fungal species, indicating that further studies on this fungerp analog are warranted.

Intermittent Fasting Attenuates High-Fat Diet-Induced Cerebellar Changes in Rats: Involvement of TNF-α, Autophagy, and Oxidative Stress.

Obesity has become a prevalent global health issue, and recently it has been reported to be intimately associated with neuronal health. Obesity triggers peripheral inflammatory responses concomitant with neuroinflammation, elevated oxidative stress, and compromised autophagy. Intermittent fasting (IF) positively influences lowering body weight and improving the metabolic changes accompanying obesity. IF also has a beneficial impact on neuronal function; however, no studies have discussed this effect on high-fat diet (HFD)-induced cerebellar damage. This study examines the effect of IF on the cerebellum of HFD-fed rats. Male Wister Albino rats (n = 16) were fed HFD for 16 weeks (HFD group); half of them were subjected to IF alternating with HFD for 6 weeks starting at the 11th week till the end of the experiment (fasting + HFD group). The control group of rats (n = 8) was kept on a basal diet. The animals were euthanized after 16 weeks. Their tissue was harvested and processed for morphology using H&E, cresyl violet, and luxol fast stains, and immunohistochemical staining was carried out for inflammatory marker (TNF-α), gliosis marker (GFAP), and autophagy markers (LC3 II and P62). Oxidative stress markers (SOD, MDA) were measured, and protein expression of phosphorylated-AMP-activated protein kinase (p-AMPK) and phosphorylated-rapamycin complex (p-mTOR) in cerebellar tissue was detected via western blotting. IF mitigated HFD-induced cerebellar morphological changes, reduced cerebellar TNF-α expression, decreased oxidative stress markers, and balanced p-AMPK and p-mTOR with autophagy improvement. Moreover, a decrease in body weight and ameliorated obesity-induced metabolic changes in the serum levels of glucose, insulin, cholesterol, and triglyceride were seen. These observations suggest that IF can improve both peripheral and central changes prompted by HFD through attenuating inflammation, oxidative stress, and reestablishing the autophagy balance.

Do Antifungals and Local Anesthetic Affect the Efficacy of Antibiotic Dipping Solution?

BACKGROUND: The rates of infection after inflatable penile prosthesis (IPP) range from 1% to 3%; however, with changes in antibiotic practice intraoperatively and the incorporation of local anesthetic dips, it is unclear whether this incidence of infection is affected. AIM: To evaluate whether the utilization of local anesthetic dips and antifungal solutions affect the efficacy of previously established dips across multiple species and strains. METHODS: Strains of four different species of bacteria and one fungus were prepared in a standardized confluency. A standardized, and sterile protocol was used to punch out 6mm circular discs from the reservoir of a Coloplast Titan device. The discs were submerged in a standardized concentration of antimicrobials (combinations of Bactrim, Rifampin + Gentamicin, Vancomycin, Zosyn, and Amphotericin B) and plated. The zone of inhibition (ZOI) was measured at 24, 48, and 72 hours. Five repetitions of each organism was performed (>1700 discs), and the mean ZOI was calculated. Saline and DMSO were used as control on each plate. OUTCOMES: Main outcome was the ZOI identified with each antibiotic solution, and the secondary outcome was the efficacy of the antibiotic over the course of 72 hours. RESULTS: Difference in antibiotic efficacy was seen when each bacterial species was evaluated separately, with rifampin and gentamicin having less efficacy towards all organisms other than S. epidermidis. When looking specifically at the Candida species, amphotericin B was significantly better than other antibiotic solutions. In regards to efficacy of antibiotics over 72 hours, all treatment groups showed a decrease in ZOI over time. However, treatment groups that included rifampin demonstrated the ability to inhibit S. aureus and S. epidermidis over the 72-hour period. CLINICAL IMPLICATIONS: To improve clinical practice and alleviate concerns that incorporation of local anesthetic and antifungals may decrease the efficacy of antibiotic solutions. STRENGTHS AND LIMITATIONS: A major strength of the study is that it is the most robust and scientifically sound study performed on this topic with approximately 1700 repetitions. It is also the first study of its kind to include a wide spectrum of bacterial and fungal strains and antibiotic solutions along with temporal data on drug elution over a 72-hour period. A limitation of the study is the in vitro model, and this needs to be validated in a clinical setting. CONCLUSIONS: Dipping prosthetics in antifungal and local anesthetic does not decrease the efficacy of the antimicrobials. The drug elution capabilities of the hydrophilic coating lasts primarily for 24-48hours. Mishra K, Bukavina L, Long L, et al. Do Antifungals and Local Anesthetic Affect the Efficacy of Antibiotic Dipping Solution?. J Sex Med 2021;18:966-973.

Alteration of Aquaporins 1 and 4 immunohistochemical and gene expression in the cerebellum of diabetic albino rat.

Aquaporins (AQPs) are a family of transmembrane channel proteins. AQP1 and AQP4 are expressed in cerebellum amongst others. This study was designed to assess the effect of diabetes on AQP1 and AQP4 expression in cerebellum of rats. Diabetes was induced by a single intraperitoneal injection of Streptozotocin 45 mg/kg in 24 adult male Sprague Dawley rats. Six rats from control and diabetic groups were sacrificed at one, four, and eight weeks post diabetic confirmation. After eight weeks, measurement of malondialdehyde (MDA), reduced glutathione (GSH) concentrations, and cerebellar mRNA expression for AQP1 and AQP4 genes were performed. Immunohistochemical evaluation of AQP1, AQP4, and glial fibrillary acidic protein (GFAP) for cerebellar sections was performed for all groups. Diabetes caused degenerative changes in Purkinje cells with a significant increase in the cerebellar level of MDA and AQP1 immunoreactivity and a significant decrease in GSH level and AQP4 expression levels. However, the alteration in the AQP1 mRNA level was not statistically significant. GFAP immunoreactivity was increased in 8 W diabetic rats following its decrease in 1 W diabetic rats. Diabetes caused some alteration in the AQPs 1 and 4 expression in the cerebellum of diabetic rats which may contribute to diabetes-induced cerebellar complications.

Effect of low-level laser physiotherapy on left ventricular function among patients with chronic systolic heart failure.

BACKGROUND: Low-level laser therapy (LLLT) is a promising noninvasive physiotherapeutic approach that has been demonstrated to improve cardiac performance. This study aimed to assess the impact of low-level laser therapy on cardiac functions and clinical status in patients with chronic left ventricular systolic heart failure who were not candidates for cardiac revascularization or resynchronization. A case series of 27 patients received a course of low-level laser physiotherapy, the clinical outcomes, echocardiographic parameters, and serum nitric oxide levels were evaluated before and after LLLT. RESULTS: Of the total patients enrolled in the study, 21 (or 77.8%) were male, with a mean age of 57.7 ± 6.89 years. NYHA classification significantly improved after low-level laser therapy, 15 patients were in class III,12 were in class IV, and no one was in class II before laser therapy while after laser therapy; 25 patients shifted to class II, two patients were in class III with P < 0.001, Six-minute walk distance test was performed, and the results showed that the mean of 6MWT was less than 200 m (148.556 ± 39.092) before the study but increased to more than 300 after laser therapy (385.074 ± 61.740), left ventricular ejection fraction before laser therapy was 26 ± 7.5 while after laser therapy it became 30 ± 8.6 but diastolic function did not change after low-level laser therapy, the mean peak TR pressure was 40.0 ± 9.0 mmHg and 33.0 ± 7.0 before and after laser therapy respectively P < 0.001. A significant change was observed in NO level from 4.1 ± 1.4 IU/ml before laser therapy to 5.2 ± 1.7 IU/ml after laser therapy P < 0.001. CONCLUSIONS: Low-level laser therapy may add benefits to improve symptoms, clinical condition, and quality of life in patients with left ventricular systolic dysfunction, further studies are necessary to evaluate the changes in cardiac functions at a longer follow-up duration.

Independent of Calorie Intake, Short-term Alternate-day Fasting Alleviates NASH, With Modulation of Markers of Lipogenesis, Autophagy, Apoptosis, and Inflammation in Rats.

Non-alcoholic steatohepatitis (NASH) is a worldwide health problem. Alternate-day fasting (ADF), although thought to be aggressive, has proven safety and efficacy. We aimed to evaluate the effect of short-term ADF against already established high-fat-fructose (HFF)-induced NASH, independent of the amount of calorie intake, and to study the effect of ADF on lipogenesis, apoptosis, and hepatic inflammation. Male Sprague Dawley rats were divided into two groups: (1) negative control and (2) NASH group fed on HFF for 9 weeks, and then randomized into two subgroups of either HFF alone or with ADF protocol for 3 weeks. The ADF could improve HFF-related elevation in serum lactate dehydrogenase and could decrease the mRNA expression of lipogenesis genes; acetyl CoA carboxylase, peroxisome proliferator-activated receptor γ, and peroxisome proliferator-activated receptor α; apoptotic genes caspase-3, p53, and inflammatory cyclo-oxygenase 2; and immunohistochemical staining for their proteins in liver with upregulation of LC3 and downregulation of P62 immunoexpression. Moreover, ADF ameliorated HFF-induced steatosis, inflammation, ballooning, and fibrosis through hematoxylin and eosin, Oil Red O, and Sirius Red staining, confirmed by morphometric analysis, without significant weight loss. Significant correlation of morphometric parameters with levels of gene expression was found. These findings suggest ADF to be a safe effective therapeutic agent in the management of NASH.

Effect of human umbilical cord blood derived CD34+ hematopoietic stem cell on the expression of Wnt4 and P53 genes in a rat model of hepatocellular carcinoma.

BACKGROUND AND AIM OF THE WORK: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy. Chronic liver injuries as chronic hepatitis C and hepatitis B viruses, aflatoxins consumption and nonalcoholic fatty liver disease are well-established causes of HCC. HCC is associated with a series of molecular changes, as alternation in glypican-3, P53 expression and Wnt/ß-catenin pathway. Hepatic cancer progenitor cells could contribute to HCC development. This research aimed to study the effectiveness of human CD34+ hematopoietic stem cell on Wnt4 and P53 genes expression, histopathological grading and hepatic progenitor cells percentage in HCC rat model. MATERIALS AND METHODS: HCC was induced in the experimental group of outbred Sprague Dawley rats by administration of 50 mg/L N-nitroso-Di-Ethylamine (DEN) in drinking water for 15 weeks. Forty-six animals were used in total, they were initially subdivided into two groups; control (n = 6) and experimental (n = 40), the latter consisting of 4 DEN-unaffected, 6 DEN-lethalities and 30 surviving DEN-animals with elevated AFP. These 30 animals with elevated AFP were then subdivided into a new HCC control group (n = 15) and the stem cell treated group (n = 15). The latter group was injected with CD34+ human hematopoietic stem cell (1 × 106 cells/rat) in the rat's tail vein. Cyclosporine A (10 mg/kg) was injected intraperitoneal, starting 24 h before human stem cell transplantation. After 20 weeks passing since the beginning of the experiment, all rats were sacrificed and liver specimens were subjected to histopathological examination, RT-PCR in order to examine Wnt4 and P53 gene expression and flow cytometry to measure hepatic progenitor OV6 positive cells percentage. RESULTS: The saline-treated HCC group (with prior 15 week DEN exposure) showed higher levels of wnt4 and p53 gene expression (1.59 and 1.36 fold, respectively) and increased percentage in OV6+ progenitor cells (+4.9% in absolute terms) compared to saline-treated controls (p < 0.01, ANOVA). Compared with the saline HCC-group, transplantation with CD34+ human hematopoietic stem cells produced a further increase in the levels of wnt4 (+19.4%) and p53 gene expression (+53%), a 2-fold increase in the percentage of cancer progenitor cells and increased HCC pathology grading (all p < 0.01). The positive correlation between p53 and HCC grade (Spearman rho +0.73, p < 0.05) and negative correlation between wnt and OV6+% levels (rho -0.65, p < 0.05) in the saline-HCC group were not observed in the CD34+ HCC group. CONCLUSIONS: Human CD34+ cells transplantation has a deteriorating effect on HCC.

Effect of cerebrolysin on the cerebellum of diabetic rats: An imunohistochemical study.

BACKGROUND: Diabetes mellitus represents one of the disorders in the metabolism that affects all body systems including CNS. Cerebrolysin contains many neurotrophic factors, and many studies reported that it can be used treatment of many neurological disorders. AIM OF THE WORK: The aim of the current study was to study the potential neuroprotective effect of cerebrolysin on the cerebellum of diabetic rat. MATERIALS AND METHODS: Sprague Dawley male rats were divided randomly into four groups: control, cerebrolysin (Cbl), diabetes and diabetes treated with Cbl groups. Induction of diabetes was performed by intraperitoneal injection of 60mg/kg streptozotocin once. Eight weeks later, the rats were anaesthetized, sacrificed and the cerebellum was removed. Cerebellum oxidative stress markers were analysis. Cerebellar tissue was subjected to histolopathological examination and immune-histological assessment of GFAP and Synaptophysin. RESULTS: As compared to the control group, diabetes caused degenerative changes in the cerebellum with significant elevation of MDA and decrease of SOD levels and gliosis confirmed by increase the GFAP expression area fraction. Diabetes increased significantly the optical density of synaptophysin expression with increase in its area fraction in the granular layer. Although Cbl treatment succeeded in minimizing the changes in the oxidative stress markers, it had no effect on pathological changes of the diabetic cerebellum. Cerebrolysin treatment of diabetic rats decreased the area fraction of GFAP positive immunoreactivity and had no effect on synaptophysin expression. CONCLUSION: Cerebrolysin can potentially protect against diabetes induced changes in the cerebellum through minimizing the oxidative stress and improving the gliosis.