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To compare umbilical cord blood pro-BNP levels in newborns of SARS-COV-2 positive pregnancies to those of SARS-COV-2 negative pregnancies.Prospectively cord blood samples from newborns of 42 SARS-COV-2 positive women, and 42 negative pregnant were collected at birth and analyzed for pro-BNP levels.The mean cord blood pro-BNP level was significantly higher in newborns of SARS-COV-2 positive women than in controls. Furthermore, the pro-BNP level was an independent predictor of NİCU admission in both SARS-COV-2 positive and control patients.Cord blood pro-BNP level may be a parameter that can predict the under-stress fetus and adverse perinatal outcomes especially, in cases where placental involvement is present as in SARS-COV-2 infection.

To investigate the effects of laboratory-confirmed SARS-CoV-2 infection on thyroid function tests (TFTs) in pregnant women and to evaluate whether TFT changes are related to the severity and prognosis.Consecutive pregnant women tested for SARS-CoV-2 by RT-PCR at Ankara City Hospital were recruited between January 2021 and September 2021. Thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3), thyroid peroxidase antibody (anti-TPO), and thyroglobulin antibody (anti-TG) were measured on admission.Among 747 eligible pregnant women with the same baseline characteristics, 369 RT-PCR-positive women in the patient group and 378 RT-PCR-negative women in the control group were included in the analyses. Pregnant women in the patient group had significantly lower TSH, FT4, FT3, Anti TPO, and Anti TG concentrations compared with those in the control group (p 0.001). The proportion of patient groups with mild, moderate, severe, and critical diseases were 297 (80.4%), 40 (10.8%), 17 (4.6%), and 15 (4.2%), respectively, among which with the moderate, severe, and critical disease had significantly lower FT3 values (2.5 vs 2.19 pg/mL, p 0.001) and higher nonthyroidal illness syndrome (NTIS) (29.2 vs. 8.4%, p 0.001) than those with mild disease. Lower FT3 values increased the risk of ICU admission, NICU admission, and severe disease (p 0.001). FT3 and TSH correlated positively with lymphocytes (p 0.001) and negatively correlated with C-reactive protein (CRP) (p 0.001, p = 0.005).The SARS-CoV-2 infection seems to have an impact on the TFTs of pregnant women, and particularly FT3 level seems to be correlated with disease severity.

Composite films were prepared by combining different concentrations of curcumin with chitin and glucan complexes (CGCs) extracted from Agaricus bisporus via a solution casting method. The developed curcumin doped CGC (CGC/Cu) films were characterized in terms of surface, optical, structural, barrier, mechanical, antioxidant, and antimicrobial properties. The biodegradability of CGC/Cu films was determined in soil for 14 days. The incorporation of curcumin significantly affected the surface morphology and improved light barrier properties, radical scavenging activity, and total phenolic content of the films. The CGC/Cu films containing different concentrations of curcumin showed antibacterial activity against Escherichia coli, while antibacterial activity against Staphylococcus aureus was not observed with the developed films. Afterward, the microbial properties of the fresh chicken breast were examined during refrigerated storage for 10 days. The shelf-life of chicken samples wrapped in the developed film was extended at least 40 % compared to the control sample. In conclusion, curcumin incorporated CGC based films can serve as a promising biodegradable active packaging material to improve the shelf-life of meat products.

OBJECTIVES: Colorectal cancer (CRC) remains a crucial health problem due to the toxicity of 5-Fluorouracil (5-FU) as first-line chemotherapy agent for treating CRC. The anticancer effects of boron and its compounds have been shown in various cell lines. This study aimed to examine the cytotoxic and apoptotic effects of borax (sodium tetraborate) alone or along with 5-FU on human CRC cells, DLD-1. MATERIALS AND METHODS: Cytotoxicity and apoptosis were determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, 4’,6-diamidino-2-phenylindole and annexin V/propidium iodide staining. RESULTS: The results showed that combined treatment revealed a significant time- and concentration-dependent cytotoxic effect on DLD-1 cells compared with borax or 5-FU treatment alone. The combination of borax and 5-FU induced a clear increase in the early apoptotic cell percentage, compared to the cells treated with monotherapies. Additionally, a significant increase in condensed and fragmented nuclei was detected in DLD-1 cells treated with the combination treatment compared with borax or 5-FU alone. CONCLUSION: Our current findings suggest that the combination of borax with 5-FU has a strong cytotoxic and apoptotic effect on the human CRC DLD-1 cells.

Background In different animal models, a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu) reduced inflammation, oxidative stress and fibrosis which were involved in the pathogenesis of erectile dysfunction (ED), but whether NaBu could improve ED in an experimental animal model of benign prostate hyperplasia (BPH) was not known. Objective To investigate the preventive effect of NaBu on ED in a partial bladder outlet obstruction (PBOO) rat model. Materials and methods PBOO was induced by partial urethral obstruction. NaBu (20 mg/kg/day) was administered orally to rats for 6 weeks after creation of PBOO. In vivo erectile responses, in vitro relaxation and contraction responses in cavernosal tissue were measured. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to determine the gene and protein expression. Inflammation, fibrosis, and localization of proteins were evaluated using histological techniques. HDAC activity and tumor necrosis factor (TNF)-alpha levels were measured in penile tissues. Results NaBu improved decreased intracavernosal pressure/mean arterial pressure, nitrergic and endothelium-dependent relaxation responses, and contractile responses to phenylephrine and electrical field stimulation in the PBOO group without affecting increased bladder weight. Increased endothelial nitric oxide synthase (eNOS), transforming growth factor (TGF)-beta 1, and nuclear factor kappa B (NF-kappa B) gene levels in PBOO group were ameliorated by NaBu treatment. The administration of NaBu to PBOO rats significantly increased neuronal NOS (nNOS) and decreased TGF-beta 1 protein expression. The nuclear/cytosolic ratio of NF-kappa B demonstrated a decrease in PBOO and all treatment groups compared to control. A significant increase in the nuclear-to-cytoplasmic ratio of nuclear factor erythroid 2-related factor 2 (Nrf2) after PBOO was reduced by the treatment. Both eNOS and inducible NOS (iNOS) protein expression, together with TNF-alpha levels did not differ in the penile tissue of all groups. In histological analysis, increased TGF-beta 1 protein expression and fibrosis, as well as decreased nNOS protein in PBOO, were reversed by the treatment. NaBu did not normalize moderate inflammation in obstructed rats. An increase in the HDAC activity in PBOO was significantly suppressed by NaBu. Discussion Inhibition of the HDAC activity by NaBu in penile tissue could ameliorate fibrosis-associated changes induced by PBOO. Conclusion NaBu promotes recovery of erectile function, and also significantly prevents penile fibrosis and normalizes TGF-beta 1 and nNOS protein expression in a rat model of PBOO. The HDAC pathway may present a promising target to prevent ED in patients with BPH.

Objectives This study aimed to present perinatal outcomes, clinical challenges, and basic ICU management in pregnant women with severe-critical COVID-19 at our tertiary referral center. Methods In this prospective cohort study, patients were divided into two groups, whether they survived or not. Clinical characteristics, obstetric and neonatal outcomes, initial laboratory test results and radiologic imaging findings, arterial blood gas parameters at ICU admission, and ICU complications and interventions were compared between groups. Results 157 of the patients survived, and 34 of the patients died. Asthma was the leading health problem among the non-survivors. Fifty-eight patients were intubated, and 24 of them were weaned off and discharged healthfully. Of the 10 patients who underwent ECMO, only 1 survived (p Conclusions Overweight pregnant women and pregnant women with comorbidities, especially asthma, may have a higher risk of mortality related to COVID-19. A worsening maternal health condition can lead to increased rates of cesarean delivery and iatrogenic prematurity.

OBJECTIVES: This study aimed to investigate the role of new adipocytokines (omentin, vaspin, irisin and visfatin) in the development of endometriosis and the relationship of these adipocytokines with the inflammatory marker, C-reactive protein (CRP) levels in serum. MATERIALS AND METHODS: In this study, endometriosis (n=16) and control groups (n=14) were determined via ultrasound. Serum omentin, vaspin and irisin levels were measured by ELISA method. CRP levels in serum and the gene expression of visfatin and vaspin in whole blood samples were determined by clinical analyzer and the real-time polymerase chain reaction, respectively. RESULTS: Serum irisin and CRP levels in the endometriosis group were significantly higher than in the control group. Irisin protein levels demonstrated a positive correlation with body mass index and CRP in women diagnosed with endometriosis. No statistically significant difference was found in serum omentin and vaspin levels between groups. The visfatin and vaspin gene expression in whole blood samples from the endometriosis group was found to be significantly lower than the control group. CONCLUSION: Increased levels of serum irisin and decreased visfatin and vaspin gene expressions in blood may be considered as a potential biomarker in endometriosis. The identification of new adipocytokines, which demonstrate an alteration in the presence of endometriosis and the relationship between these adipocytokines and inflammation will facilitate the detection of mechanisms involved in endometriosis and will lead to the development of targeted therapy.

Emergency service physicians have forensic physician duties in addition to providing treatment and protective services. Errors in forensic report writing could affect the judicial process negatively.A 16-year old male presented at the Emergency Department (ED) following an assault. With a diagnosis of epidural hematoma on the computed tomography taken because of head trauma, the patient was transferred to the brain surgery ward. In the forensic report written in ED, there was stated to be a danger to life. In the repeated evaluation, there was seen to be a mass in the calvarium and surgery was performed. In the histopatholgical evaluation, the diagnosis was made of Langerhans Cell Histiocytosis. It must not be forgotten that errors or ommissions in a forensic report constitute malpractice. The necessary care and attention must be paid to forensic reports prepared in the Emergency Department.

Benign prostatic hyperplasia (BPH) is one of the most prevalent conditions among aged men. The use of 5α-reductase inhibitors (5-ARIs) to treat BPH was linked to erectile dysfunction (ED). Many medicinal plants and secondary metabolites are used in the management of ED. Onion (Allium cepa L.) is an economically affordable vegetable with vital phytochemicals and biological functions. The study aimed to identify the beneficial effects of onion juice on dutasteride (a 5-ARI)-induced ED. Rats were divided into two groups (n = 5 per group): control and dutasteride-treated rats (0.5 mg/kg/day). Dutasteride was administered in drinking water for 12 weeks. Experiments were performed at the end of the 12th week. In vivo erectile responses were measured before and after intracavernosal injection of onion. Relaxant responses to onion juice were examined in the corpus cavernosum (CC). Acetylcholine (ACh)-, electrical field stimulation (EFS)-, sodium nitroprusside (SNP)-induced relaxation responses in CC tissues were evaluated in the absence and presence of onion juice. Total intracavernosal pressure (ICP) and ICP/ mean arterial pressure were significantly reduced in dutasteride-treated rats (1881.14 ± 249.72 mmHg, P

Active packaging aims to reduce food waste by extending food shelf life. Packaging materials developed from biodegradable, sustainable and renewable resources are required to reduce environmental pollution and conserve natural resources. Therefore, curcumin, a natural extract with antioxidant and antimicrobial properties, was encapsulated into zeolitic imidazole framework-8 nanocrystals (K-ZIF-8) in this study. Chitin nanocomposites, support materials of the designed active package, were extracted from the cultivated mushroom. Bioactive properties of the films improved as the amount of K-ZIF-8 increased. Addition of K-ZIF-8 did not have a significant effect on mechanical, barrier, optical, thermal and morphological properties of chitin films. Antimicrobial test revealed that chitin-based nanocomposite films were effective against E.coli, but not against S.aureus. The highest antimicrobial effect, total phenolic content and antioxidant activity was obtained in the film containing 10XMIC equivalent of K-ZIF-8 concentration. However, film durability tests indicated that these films are not suitable for long-term storage., Aktif paketleme uygulamaları gıda raf ömrünü uzatarak gıda israfını azaltmayı hedeflemektedir. Geliştirilen paketleme malzemelerinin biyobozunur, sürdürülebilir ve yenilenebilir kaynaklardan olması çevre kirliğinin azaltılması ve doğal kaynakların korunabilmesi için gereklidir. Bu nedenle, bu çalışmada antioksidan ve antimikrobiyal özelliklere sahip doğal bir özüt olan kurkumin, zeolitik imidazol çerçeve-8 (K-ZİF-8) nanokristalleri içerisine kapsüllenmiştir. Tasarlanan aktif paketin destek malzemesi olan kitin nanokompozitler ise kültür mantarından elde edilmiştir. Kitin nanokompozit film içerisine farklı konsantrasyonlarda K-ZİF-8 eklenmiş ve konsantrasyon arttıkça filmlerin biyoaktif özelliklerinin arttığı gözlemlenmiştir. Diğer taraftan K-ZİF-8 eklemenin kitin filmlerin mekanik, bariyer, optik, termal ve morfolojik özelliklerine istatistiksel olarak önemli bir etkisi olmamıştır. Antimikrobiyal test sonuçları filmlerin E.coli bakteri kolonilerine karşı etkili olduğunu ortaya koyarken S.aureus kolonilerine karşı aynı etki gözlemlenememiştir. En yüksek antimikrobiyal etki, toplam fenolik madde miktarı ve antioksidan aktive 10XMÖK değerinde K-ZİF-8 içeren filmde elde edilmiştir. Ancak film dayanıklılık testleri bu filmlerin uzun süre depolamaya uygun olmadığını ortaya koymuştur.

Background: Erectile dysfunction (ED) is an evolving health problem in the aging male population. Chronic low-grade inflammation is a critical component of ED pathogenesis and a probable intermediate stage of endothelial dysfunction, especially in metabolic diseases, with the inclusion of obesity, metabolic syndrome, and diabetes. Objective: This review will present an overview of preclinical and clinical data regarding common inflammatory mechanisms involved in the pathogenesis of ED associated with metabolic diseases and the effect of antiinflammatory drugs on ED. Methods: A literature search of existing pre-clinical and clinical studies was performed on databases [Pubmed (MEDLINE), Scopus, and Embase] from January 2000 to October 2019. Results: Low-grade inflammation is a possible pathological role in endothelial dysfunction as a consequence of ED and other related metabolic diseases. Increased inflammation and endothelial/prothrombotic markers can be associated with the presence and degree of ED. Pharmacological therapy and modification of lifestyle and risk factors may have a significant role in the recovery of erectile response through reduction of inflammatory marker levels. Conclusion: Inflammation is the least common denominator in the pathology of ED and metabolic disorders. The inflammatory process of ED includes a shift in the complex interactions of cytokines, chemokines, and adhesion molecules. These data have established that anti-inflammatory agents could be used as a therapeutic opportunity in the prevention and treatment of ED. Further research on inflammation-related mechanisms underlying ED and the effect of therapeutic strategies aimed at reducing inflammation is required for a better understanding of the pathogenesis and successful management of ED.

Background Testosterone (T) deficiency is associated with erectile dysfunction (ED). The relaxant response of T on the corporal smooth muscle through a non-genomic pathway has been reported; however, the in vitro modulating effects of T on human corpus cavernosum (HCC) have not been studied. Objectives To compare the effects of various concentrations of T on nitric oxide (NO)-dependent and nitric oxide-independent relaxation in organ bath studies and elucidate its mode of action, specifically targeting the cavernous NO/cyclic guanosine monophosphate (cGMP) pathway. Materials and methods Human corpus cavernosum (HCC) samples were obtained from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) precontraction, the effects of various relaxant drugs of HCC strips were performed using organ bath at low (150 ng/dL), eugonadal (400 ng/dL), and hypergonadal (600 ng/dL) T concentrations. The penile tissue measurements of endothelial nitric oxide synthase (eNOS), neuronal (n)NOS, and phosphodiesterase type 5 (PDE5) were evaluated via immunostaining, Western blot, cGMP and nitrite/nitrate (NOx) assays. Results Relaxation responses to ACh and EFS in isolated HCC strips were significantly increased at all T levels compared with untreated tissues. The sildenafil-induced relaxant response was significantly increased at both eugonadal and hypergonadal T levels. Normal and high levels of T are accompanied by increased eNOS, nNOS, cGMP, and NOx levels, along with reduced PDE5 protein expression. Conclusion This study reveals an important role of short-term and modulatory effects of different concentrations of T in HCC. T positively regulates functional activities, inhibition of PDE5 expression, and formation of cGMP and NOx in HCC. These results demonstrate that T indirectly contributes to HCC relaxation via downstream effects on nNOS, eNOS, and cGMP and by inhibiting PDE5. This action provides a rationale for normalizing T levels in hypogonadal men with ED, especially when PDE5 inhibitors are ineffective. T replacement therapy may improve erectile function by modulating endothelial function in hypogonadal men.

Introduction Cardiometabolic syndrome (CMS), as a bunch of metabolic disorders mainly characterized by type 2 diabetes mellitus (T2DM), hypertension, atherosclerosis, central adiposity, and abdominal obesity triggering androgen deficiency, is one of the most critical threats to men. Although many significant preclinical and clinical findings explain CMS, new approaches toward common pathophysiological mechanisms and reasonable therapeutic targets are lacking. Aim To gain a further understanding of the role of androgen levels in various facets of CMS such as the constellation of cardiometabolic risk factors including central adiposity, dyslipidemia, insulin resistance, diabetes, and arterial hypertension and to define future directions for development of effective therapeutic modalities. Methods Clinical and experimental data were searched through scientific literature databases (PubMed) from 2009 to October 2019. Main Outcome Measure Evidence from basic and clinical research was gathered with regard to the causal impact and therapeutic roles of androgens on CMS. Results There are important mechanisms implicated in androgen levels and the risk of CMS. Low testosterone levels have many signs and symptoms on cardiometabolic and glycometabolic risks as well as abdominal obesity in men. Clinical Implications The implications of the findings can shed light on future improvements in androgen levels and add potentially predictive risk for CMS, as well as T2DM, abdominal obesity to guide clinical management in the early stage. Strengths & Limitations This comprehensive review refers to the association between androgens and cardiovascular health. A limitation of this study is the lack of large, prospective population-based studies that analyze the effects of testosterone treatment on CMS or mortality. Conclusion Low testosterone levels have several common features with metabolic syndrome. Thus, testosterone may have preventive role in the progress of metabolic syndrome and subsequent T2DM, abdominal obesity, and cardiovascular disease and likely affect aging men’s health mainly through endocrine and vascular mechanisms. Further studies are necessary to evaluate the therapeutic interventions directed at preventing CMS in men.

Aims To evaluate the impacts of hydrogen sulfide (H2 S) donor, sodium hydrogen sulfide (NaHS), and phosphodiesterase type-5 inhibitor (PDE5i), tadalafil per se and their combination treatment on partial bladder outlet obstruction (PBOO)-induced erectile dysfunction (ED). Methods Sprague-Dawley rats were equally divided into five groups: (a) sham-operated control; (b) PBOO; (c) PBOO-treated with NaHS (5.6 mg/kg/day, ip); (d) PBOO-treated with tadalafil (2 mg/kg/day, oral); and (e) PBOO-treated with combination of NaHS and tadalafil. The obstruction was created by urethral ligation for 6 weeks. In vivo erectile responses, in vitro relaxant and contractile responses in penile tissue as well as protein expression of nitric oxide synthases (NOS), H2 S synthesis enzymes, oxidative stress, hypoxia, fibrosis markers, and the smooth muscle/collagen ratio and apoptosis were analyzed. Results Combined treatment entirely returned increased bladder mass, reduced erectile responses, relaxation responses to acetylcholine, and electrical field stimulation in obstructed rats, while partial amelioration was observed after mono-treatment. Decreased neuronal NOS and 3-mercaptopiruvate transferase enzyme expressions in penile tissue from obstructed rats were also entirely restored by the combined treatment. Mono-treatment partially improved increased hypoxia, oxidative stress, fibrosis markers, decreased smooth muscle mass, and H2 S levels, while combined therapy completely recovered. Conclusions The combination therapy with H2 S donor and PDE5i had positive effects on erectile responses through the improvement of ischemia-induced morphological and functional penile alterations in obstruction. H2 S and NO may likely play a synergistic role in the regulation of erectile function and have constructive effects on clinical outcomes in male patients with ED and benign prostatic hyperplasia/lower urinary tract symptoms.

Niemann‐Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier disease is caused by a defect in ABCA1. Tangier disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the disease. When a Tangier disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic diseases. In this study, we found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.

[This corrects the article DOI: 10.1371/journal.pone.0238697.].

Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1−/− mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1−/− mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1−/− mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders., This study investigates the disease-modifying effect of acetyl-DL-leucine in two neurodegenerative lysosomal storage diseases with different aetiologies: Niemann-Pick type C and GM2 gangliosidosis in both murine models and clinical studies. Acetyl-DL-leucine and its L enantiomer provide neuroprotection likely by altering metabolism – a new therapeutic approach for these diseases., Graphical Abstract Graphical Abstract

Niemann-Pick type C disease is a lysosomal storage disease affecting primarily the nervous system that results in premature death. Here we present the first report and investigation of Niemann-Pick type C disease in Australian Angus/Angus-cross calves. After a preliminary diagnosis of Niemann-Pick type C, samples from two affected calves and two obligate carriers were analysed using single nucleotide polymorphism genotyping and homozygosity mapping, and NPC1 was considered as a positional candidate gene. A likely causal missense variant on chromosome 24 in the NPC1 gene (NM_174758.2:c.2969C>G) was identified by Sanger sequencing of cDNA. SIFT analysis, protein alignment and protein modelling predicted the variant to be deleterious to protein function. Segregation of the variant with disease was confirmed in two additional affected calves and two obligate carrier dams. Genotyping of 403 animals from the original herd identified an estimated allele frequency of 3.5%. The Niemann-Pick type C phenotype was additionally confirmed via biochemical analysis of Lysotracker Green, cholesterol, sphingosine and glycosphingolipids in fibroblast cell cultures originating from two affected calves. The identification of a novel missense variant for Niemann-Pick type C disease in Angus/Angus-cross cattle will enable improved breeding and management of this disease in at-risk populations. The results from this study offer a unique opportunity to further the knowledge of human Niemann-Pick type C disease through the potential availability of a bovine model of disease.

Background: Colchicine, a tricyclic alkaloid, is commonly used in treatment due to its antiinflammatory and anti-fibrotic effects. Besides its toxicity at high doses, colchicine is reported for its potential anticancer effects at lower concentrations. The present study aimed to evaluate the anticancer effects of colchicine in SW480 cells. Methods: The effect of colchicine on cell proliferation was determined by MTT assay. The cellular colchicine uptake was measured by HPLC analysis. The apoptotic effects was evaluated by annexin v binding assay and MMP-9 mRNA expression was determined by RT-PCR experiments. Results: Colchicine showed significant cytotoxicity at 10 ng/ml and higher concentrations and caused a cell cycle arrest of SW480 cells at G2/M phase. The results of HPLC analysis showed that colchicine uptake was increased in correlation with treated concentrations. Colchicine concentrations have increased the amount of apoptotic cell population. The elisa and western blot measurements showed that colchicine led to nuclear translocation of NF-κB proteins and increased caspase levels. The real time PCR experiments showed that colchicine has inhibitory effect on MMP-9 mRNA expression in a concentration dependent manner. Conclusion: These results illustrated that low dose colchicine efficiently induced cell death and apoptosis of SW480 cells and the inhibition of MMP-9 mRNA levels was significantly correlated with the amount of cellular colchicine uptake, suggesting that colchicine has a potential value in the treatment of human colorectal cancer.

Diabetic men are at a higher risk of erectile dysfunction (ED). A tropical plant, clove (Syn. Eugenia caryophyllata, Caryophyllus aromaticus L., Syzygium aromaticum (L.) Merr. & L.M. Perry) from the Myrtaceae family has displayed aphrodisiac activity. The present research aimed to investigate the impacts of clove essential oil (CEO) and the ingredient of CEO, eugenol (E) on ED in diabetic rats. We divided Sprague-Dawley rats into control and diabetic groups. Erectile function was evaluated before and after CEO and E intracavernosal injection. CEO- and E-induced relaxation responses were investigated in isolated corpus cavernosum (CC) using various inhibitors. The intracavernous administration of CEO and E restored erectile responses in diabetic rats. CEO and E induced remarkable relaxation in all groups. CEO- and E-induced relaxation responses were partially inhibited after pre-contraction with KCl. Tetraethylammonium and glibenclamide inhibited the relaxation response to CEO. Glibenclamide inhibited maximum relaxation to E. The inhibitors of nitric oxide synthase (NOS), soluble guanylyl cyclase and nifedipine did not change CEO- and E-induced relaxation responses. The current results suggest that CEO and the major compound of the essential oil, E improved diabetes-induced ED in rats, and CEO caused CC relaxation via K+ channels independently NO signalling pathway.

Background: Erectile dysfunction (ED) affects 30 million men in the US with a decrease in quality of life. Thirty percent of hypertensive men suffer from ED. Objective: This review will debate the interplay between hypertension and ED, discovering novel insights concerning hypertension-linked ED, as well as the influence of antihypertensive medications on patients with ED. Method: Total number of records screened from PubMed yielded by the search which performed from January 2000 - June 2018. Results: Hypertension can cause ED as a consequence of high blood pressure or antihypertensive treatment. Both hypertension and ED have endothelial dysfunction as a common base mechanism, which can lead to an increase in vascular smooth muscle contraction. Also, some phosphodiesterase (PDE)-5 inhibitors used to treat ED can recover blood pressure. Conclusion: Understanding of common mechanisms involved in ED accompanied with hypertension and the research on antihypertensive drugs that impact ED will bring important approaches for identifying novel therapeutic strategies that will improve quality of life in patients with these conditions.

The sympathetic nervous system is one component of the nervous regulatory system of the physiological function of the lower genitourinary tract. Our knowledge on the role of this sympathetic system has advanced during the last decade due to the characterization of β3-adrenoceptors (β3-ARs) in the urogenital system. This review focuses on the pharmacological and molecular evidence supporting the functional roles of β3-AR in male genitourinary tissues of various species. An electronic search in two different databases was performed including MEDLINE (PubMed) and EMBASE from 2010 to 2016. β3-agonists may be a promising alternative to antimuscarinics in the treatment of overactive bladder (OAB) based on available evidence. Although more recent studies have evaluated the involvement of β3-ARs in the physiological control and regulation of various tissues of the lower genitourinary tract mainly urinary bladder, penis, urethra, ureter, there are few innovations in the pipe-line. Among the β3-agonists, mirabegron is a unique drug licensed for the treatment of patients with OAB. Many drugs classified as β3-agonists are still under investigations for the treatment of OAB, lower urinary tract symptoms, ureteral stones, benign prostate hyperplasia, prostate cancer and erectile dysfunction. This review discusses the potential roles of β3-AR as new therapeutic targets by evaluating the results of preclinical and clinical studies related to male lower genitourinary tract function. Looking into the future, the potential benefits of β3- AR agonists from experimental and clinical investigations may provide an attractive therapeutic option.

Niemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks include hypomyelination and cerebellar atrophy. We previously demonstrated the efficacy of recombinant human heat shock protein 70 (rhHSP70) in preclinical models of the disease. It reduced glycosphingolipid levels in the central nervous system (CNS), improving cerebellar myelination and improved behavioural phenotypes in Npc1We administered bimoclomol daily or rhHSP70 6 times per week to Npc1Treatment with either bimoclomol or rhHSP70 improved myelination and increased the numbers of mature oligodendrocytes (OLs) as well as the ratio of active-to-inactive forms of phosphorylated Fyn kinase in the cerebellum of Npc1These data increase our understanding of the mechanisms by which HSP70 regulates myelination and provide further support for the clinical development of HSP-amplifying therapies in the treatment of NPC.Funding for this study was provided by Orphazyme A/S (Copenhagen, Denmark) and a Pathfinder Award from The Wellcome Trust.

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

Aim To investigate the possible beneficial effect of mirabegron [a selective β3-adrenoceptor (AR) agonist] treatment on erectile dysfunction (ED) in streptozotocin-induced diabetic rats. Methods Sprague-Dawley rats (n=20) were divided into two groups: control group and streptozotocin-induced diabetic group. In vivo erectile responses were evaluated after intracavernosal injection of mirabegron (0.4 mg/kg) in rats. The relaxation responses to electrical field stimulation (EFS, 10 Hz), sodium nitroprusside (SNP, 10 nM) and sildenafil (1 μM) of corpus cavernosum (CC) strips were examined after the incubation with mirabegron (10 μM). β3-ARs expression and localization were determined by Western blot and immunohistochemical analyses in CC tissue. Results In vivo erectile responses of diabetic rats [intracavernasal pressure (ICP) / mean arterial pressure, 0.17±0.01] were decreased, which were restored after administration of mirabegron (0.75±0.01, P Conclusions This is the first study to show that intracavernosal administration of mirabegron improved erectile function and neurogenic relaxation of CC in diabetic rats. These results may be supported by further studies using combinations of mirabegron and phosphodiesterase type 5 (PDE5) inhibitors for the treatment of diabetic ED, especially in patients who do not respond to PDE5 inhibitor therapy.

INTRODUCTION AND OBJECTIVES:Lower urinary tract symptoms (LUTS) in men are strictly linked to benign prostatic hyperplasia (BPH), which may lead to bladder outlet obstruction (BOO). The phosphodies...

Erectile dysfunction (ED) is associated with diabetes mellitus (DM). Pomegranate juice (PJ) is a potent antioxidant in diabetes induced oxidative stress. The aim of this study was to evaluate whether the administration of PJ ameliorates ED in streptozotocin (STZ)-diabetic rat model. Adult male Sprague-Dawley rats were divided into three groups (n=10-12, each): (1) Control, (2) STZ (25-35 mg kg

Aim We investigated the effects of silodosin (selective α1A-adrenoceptor antagonist) on erectile dysfunction (ED) in a rat model of bladder outlet obstruction. Methods Adult male Sprague–Dawley rats (n = 32) were divided into four groups: (i) sham-operated control; (ii) silodosin-treated (sham) control (0.1 mg/kg/day); (iii) partial bladder outlet obstruction (PBOO); and (iv) silodosin-treated with PBOO. PBOO was induced by ligation of the urethra for 6 weeks. In vivo, erectile responses were monitored by evaluating ratios of intracavernosal pressure (ICP)/mean arterial pressure (MAP). Organ-bath studies were performed on corpus cavernosum (CC) strips. Penises were assessed at baseline for protein expression of neuronal nitric oxide synthase (nNOS) and Rho-associated protein kinase (ROCK2) by Western blot. Immunohistochemistry and Masson trichrome staining were performed for analysis of nNOS protein levels and tissue alterations. Results The ratio of ICP/MAP was significantly decreased in obstructed rats (0.26 ± 0.043, P

PubMedID: 31741421 Objective: To evaluate the effect of the If channel inhibitor, ivabradine on human corpus cavernosum (HCC) smooth muscle tone. Methods: HCC samples were obtained from erectile dysfunction(ED) patients (n = 12) undergoing penile prosthesis surgery. Concentration–response curves for ivabradine were exposed to various inhibitory and stimulatory agents. The relaxant and contractile responses to electrical field stimulation (EFS, 10 Hz and 80 Hz) were examined in the presence or absence of ivabradine (10 µM). HCN3 and HCN4 channel expression and localization were determined by Western blot and immunohistochemical analyses of HCC tissues. Results: Increasing ivabradine concentrations dependently reduced the maximal contractile responses of isolated HCC strips induced by KCl (59.5 ± 2.5%) and phenylephrine (84.0 ± 9.8%), which was not affected by nitric oxide synthase and soluble guanylyl cyclase inhibitors after phenylephrine-induced contraction. Nifedipine and tetraethylammonium inhibited the maximum relaxation to ivabradine by 75% and 39.3%, respectively. Fasudil and sildenafil increased the relaxation response to ivabradine without altering the maximum response. Pre-incubation with ivabradine significantly increased relaxant responses to EFS (p < 0.01) and reduced the contractile tension evoked by EFS (72.3%) (p < 0.001). Ivabradine incubation did not affect the expression and localization of HCN3 and HCN4 channels in the HCC smooth muscle cells. Conclusions: Ivabradine exhibits a relaxant effect on HCC tissues, which is likely to be attributed to the blocking of L-type Ca2+ channels and the opening of K+ channels, independent of changes in the activation of the nitric oxide/cyclic guanosine monophosphate system. Inhibition of HCN channels localized in cavernosal smooth muscle cells may offer pharmacological benefits for patients with cardiovascular risk factors. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

PubMedID: 31207098 Objective: This study evaluated the effect of human umbilical cord blood mononuclear cells (HUCB-MNCs) on bladder dysfunction in streptozotocin (STZ; 35 mg/kg, i.v.)-induced diabetic rats. Methods: Adult male Sprague–Dawley rats (n = 30) were equally divided into three groups: control group, STZ-diabetic group, and HUCB-MNC-treated group (1 × 106 cells). HUCB-MNCs were isolated by density gradient centrifugation from eight healthy donors and injected into the corpus cavenosum in STZ-diabetic rats 4 weeks after the induction of diabetes. Studies were performed 4 weeks after HUCB-MNC or vehicle injection. In vitro organ bath studies were performed on bladder strips, whereas protein expression of hypoxia-inducible factor (HIF)-1?, vascular endothelial growth factor (VEGF), and ?-smooth muscle actin (SMA) in the bladder and the ratio of smooth muscle cells (SMCs) to collagen were determined using western blotting and Masson trichrome staining. Results: Neurogenic contractions of detrusor smooth muscle strips were 55% smaller in the diabetic group than control group (P < 0.05); these contractions were normalized by HUCB-MNC treatment. In addition, HUCB-MNC treatment restored the impaired maximal carbachol-induced contractile response in detrusor strips in the diabetic group (29%; P < 0.05). HUCB-MNC treatment improved the KCl-induced contractile response in the diabetic bladder (68%; P < 0.05), but had no effect on ATP-induced contractile responses. Increased expression of HIF-1? and VEGF protein and decreased expression of ?-SMA protein and the SMC/collagen ratio in diabetic rats were reversed by HUCB-MNC. Conclusion: Administration of HUCB-MNCs facilitates bladder function recovery, which is likely related to downregulation of HIF-1? expression and attenuation of fibrosis in STZ-diabetic rats. © 2019 John Wiley & Sons Australia, Ltd

The dermcidin-derived peptide DCD-1L has a broad spectrum of antimicrobial activity over a wide pH range and in high salt concentrations. Thus, it offers a promising alternative to conventional antibiotics. Furthermore, it plays a role in wound healing, atopic dermatitis and acne vulgaris, indicating applications in cosmetic industries. Recently, dermcidin has been identified as a tumor marker improving cancer prognosis. Hence, large quantities of purified DCD-1L peptide are required to meet the needs of basic research and clinical trials. In the current study, we demonstrate SUMO-based heterologous DCD-1L production inEscherichia coli, followed by affinity chromatography purification. The SUMO tag is cleaved with SUMO-specific protease following purification, leaving free DCD-1L peptide without any additional amino acids. The mass of the peptide was further confirmed by MALDI-TOF-TOF analysis. Furthermore, the cleaved DCD-1L showed antimicrobial activity against theE. coliDH5 alpha test strain. The production and purification of DCD-1L using SUMO tag compare advantageously to other protocols previously described. Thus, the SUMO tag system enables large scale recombinant production of the antimicrobial peptide DCD-1L, which constitutes pharmaceutical and therapeutic potential as an alternative antibiotic.

Transient receptor potential (TRP) channels comprise a family of cation channels implicated in a variety of cellular processes including light, mechanical or chemical stimuli, temperature, pH, or osmolarity. TRP channel proteins are a diverse family of proteins that are expressed in many tissues. We debated our recent knowledge about the expression, function, and regulation of TRP channels in the different parts of the male urogenital system in health and disease. Emerging evidence suggests that dysfunction of TRP channels significantly contributes to the pathophysiology of urogenital diseases. So far, there are many efforts underway to determine if these channels can be used as drug targets to reverse declines in male urogenital function. Furthermore, developing safe and efficacious TRP channel modulators is warranted for male urogenital disorders in a clinical setting.