GYY4137 attenuates functional impairment of corpus cavernosum and reduces fibrosis in rats with STZ-induced diabetes by inhibiting the TGF-ß1/Smad/CTGF pathway.

Erectile dysfunction (ED) is a common diabetic complication. Recent evidence has illuminated the role of hydrogen sulfide (H2S) as a dynamic mediator of the erection process. H2S is a potent endogenous relaxant gas. It has been shown to relax human and animal penile tissue in vitro and induce erection in animals in vivo. The reported penile expression of H2S-synthesizing enzymes also supports the potential role of the endogenous L-cysteine/H2S pathway in penile homeostasis. Several pathological changes take place in the diabetic penile tissue, including inflammation, oxidative stress, neuropathy and fibrosis of the corpus cavernosum (CC), the major erectile structure of the penis. The present study is experimental and has been performed in the diabetic rat model. The study will investigate the role of H2S as a potential protective mediator against diabetes-induced structural and functional alterations in the CC by examining if it: (1) reduces corporal contraction and/or enhances corporal relaxation following pharmacological stimulation, (2) attenuates fibromuscular changes in diabetic CC, and (3) whether there is a link with H2S plasma/urine level and CC tissue generation, as well as studying the expression of some proteins in the transforming growth factor (TGF)-ß1-associated pathway. The major findings of the study reveal that- compared to the nondiabetic controls - the diabetic animals CC showed: (1) augmented contraction and attenuated relaxation in response to phenylephrine and carbachol, respectively, (2) marked fibromuscular degeneration with a significantly lower smooth muscle/collagen ratio and upregulation of TGF-ß-1/Smad/CTGF fibrosis signaling pathway, (3) reduced H2S plasma and urinary levels and cavernosal tissue generation. Chronic GYY4137 treatment prevented most of these pathological changes in diabetic CC, thus may be considered a potential new strategy for the prevention and/or treatment of diabetes-induced ED.

H2S donor GYY4137 ameliorates paclitaxel-induced neuropathic pain in mice.

Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect that largely affects the patient's quality of life and may limit the use of the drug as a chemotherapeutic agent for treating metastatic breast cancer and other solid tumors. Recently, a putative role for the gaseous mediator hydrogen sulfide (H2S) in nociception modulation has been suggested. The aim of the present study was to investigate the potential efficacy of the slow release H2S donor GYY4137 to alleviate and prevent PINP. Female BALB/c mice that were intraperitoneally (i.p.) injected with paclitaxel (2 mg/kg) for 5 consecutive days developed thermal hyperalgesia, cold and mechanical allodynia and had reduced of H2S, generation in the spinal cord and paw skin. Treatment of mice with established thermal hyperalgesia with GYY4137 or the analgesic positive control drug gabapentin produced antihyperalgesic activities. The antihyperalgesic activity of GYY4137 was antagonized by the ATP sensitive potassium channels (KATP channels) blocker glibenclamide. Co-treatment with GYY4137 and paclitaxel prevented the paclitaxel-induced decrease in H2S, generation as well as the paclitaxel-induced thermal hyperalgesia, cold allodynia and mechanical allodynia. GYY4137 enhanced paclitaxel's anti-proliferative effects against the breast cancer cell line MCF-7. The present results suggest that GYY4137 alleviates paclitaxel-induced thermal hyperalgesia, via KATP channels. GYY4137 prevents PINP possibly by blocking the paclitaxel-induced reduction in the generation of H2S, in the tissues, while enhancing the anti-cancer activity of paclitaxel, and therefore warrants further research as a candidate for prevention of PINP in clinical settings.

Structure-Antibacterial Activity Relationships of N-Substituted-(d-/l-Alaninyl) 1H-1,2,3-Triazolylmethyl Oxazolidinones.

Bacterial resistance towards the existing class of antibacterial drugs continues to increase, posing a significant threat to the clinical usefulness of these drugs. These increasing and alarming rates of antibacterial resistance development and the decline in the number of new antibacterial drugs' approval continue to serve as a major impetus for research into the discovery and development of new antibacterial agents. We synthesized a series of d-/l-alaninyl substituted triazolyl oxazolidinone derivatives and evaluated their antibacterial activity against selected standard Gram-positive and Gram-negative bacterial strains. Overall, the compounds showed moderate to strong antibacterial activity. Compounds 9d and 10d (d- and l-alaninyl derivatives bearing the 3,5-dinitrobenzoyl substituent), 10e (l-alaninyl derivative bearing the 5-nitrofurancarbonyl group) and 9f and 10f (d- and l-alaninyl derivatives bearing the 5-nitrothiophene carbonyl moiety) demonstrated antibacterial activity (MIC: 2 µg/mL) against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Moraxella catarrhalis standard bacterial strains. No significant differences were noticeable between the antibacterial activity of the d- and l-alaninyl derivatives as a result of the stereochemistry of the compounds.

Antimycobacterial Activities of Novel 5-(1H-1,2,3-Triazolyl)Methyl Oxazolidinones.

The antibacterial activities of a series of triazolyl oxazolidinones against Mycobacterium tuberculosis strain in vitro and in vivo in a mice model are presented. Most active compounds were noncytotoxic against VERO cells with acceptable selectivity indexes (SI) as measures of compound tolerability. Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC(90): < 0.2 to 0.422 µg/mL) and arylcarbonyl (IC(90): < 0.2 to 2.103 µg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC(90): < 0.2 µg/mL) analog, linezolid (IC(90): < 0.2 µg/mL), and isoniazid (IC(90): < 0.034 µg/mL). The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive. Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most active in vivo, but relatively less efficacious than isoniazid.

The effect of systematic structural modifications on the antibacterial activity of novel oxazolidinones.

A novel series of tetraethylene glycol (TEG) triazolyl and squaramide containing oxazolidinones were synthesized and tested for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. The 4-TEG-triazolyl derivatives were prepared by 'click reaction'. The introduction of the TEG and squaramide groups did not favor antibacterial activity. The three nucleoside-containing oxazolidinones were also prepared by 'click' methodology resulted in weak antibacterial activity.