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Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil’s therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil’s broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application.

Background and objectives: Worldwide, approximately 500 million people suffer from diabetes and at least 50% of these people develop neuropathy. Currently, therapeutic strategies for reducing diabetic neuropathy (DN)-associated pain are limited and have several side effects. The purpose of the study was to evaluate the antihyperalgesic action of different sildenafil (phosphodiesterase-5 inhibitor) and metformin (antihyperglycemic agent) combinations in alloxan-induced DN. Methods: The study included 100 diabetic mice and 20 non-diabetic mice that were subjected to hot and cold stimulus tests. Furthermore, we determined the influence of this combination on TNF-α, IL-6 and nitrites levels in brain and liver tissues. Results: In both the hot-plate and tail withdrawal test, all sildenafil–metformin combinations administered in our study showed a significant increase in pain reaction latencies when compared to the diabetic control group. Furthermore, all combinations decreased blood glucose levels due to the hypoglycemic effect of metformin. Additionally, changes in nitrite levels and pro-inflammatory cytokines (TNF-α and IL-6) were observed after 14 days of treatment with different sildenafil–metformin combinations. Conclusions: The combination of these two substances increased the pain reaction latency of diabetic animals in a dose-dependent manner. Moreover, all sildenafil–metformin combinations significantly reduced the concentration of nitrites in the brain and liver, which are final products formed under the action of iNOS.

Patients with type-2 diabetes mellitus (T2DM) have normal or increased bone mineral density (BMD) but despite that, they are characterized by an increased hip and vertebral fracture risk that involves the alteration of bone quality and not the reduction in bone mass. BMD is utilized for the diagnosis and evaluation of osteoporosis, but BMD itself cannot provide an accurate diagnosis of the individuals at increased risk of fracture and, therefore, studies have focused on identifying other risk factors that are partially or fully independent of BMD. The fracture risk score tool-FRAX® models provide information about a 10-year probability of osteoporotic fractures, but do not include risk factors specific to illness such as diabetes duration, diabetes drug therapy, glycemic control, or the presence of micro-vascular complications. Multiple markers have been investigated to provide information on the risk of fractures in patients with T2DM such as: advanced glycation end products (AGEs), insulin-like growth factor-I (IGF-I), osteocalcin (OC), adiponectin, and sclerostin, but epidemiological studies did not provide homogeneous information regarding the link between these markers and bone fragility in T2DM subjects. Markers that increase the accuracy of fracture risk estimation in patients with T2DM need to be identified and employed in current medical practice.

Ziziphus jujuba Mill. (jujube) is a well-known medicinal plant with pronounced wound healing properties. The present study aimed to establish the chemical composition of the lyophilized ethanolic extract from Romanian Ziziphus jujuba leaves and to evaluate the healing and anti-inflammatory properties of a newly developed lipophilic ointment containing 10% dried jujube leaves extract. The ultra-High-Performance Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry method was used, and 47 compounds were detected, among them the novel epicatechin and caffeic acid. The extract contains significant amounts of rutin (29.836 mg/g), quercetin (15.180 mg/g) and chlorogenic acid (350.96 µg/g). The lipophilic ointment has a slightly tolerable pH, between 5.41–5.42, and proved to be non-toxic in acute dermal irritation tests on New Zealand albino rabbits and after repeated administration on Wistar rats. The ointment also has a healing activity comparable to Cicatrizin (a pharmaceutical marketed product) on Wistar rats and a moderate anti-inflammatory action compared to the control group, but statistically insignificant compared to indomethacin in the rat-induced inflammation test by intraplantar administration of kaolin. The healing and anti-inflammatory properties of the tested ointment are due to phenolic acids and flavonoids content, less because of minor components as apocynin, scopoletin, and isofraxidin.

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.

The aim of this work was to assess the analgesic effect of three Vitis vinifera L. leaf extracts and the anti-inflammatory effect of three gels obtained from Aesculus hippocastanum L. seed extracts using animal models, as a preliminary study for the future development of topical preparations based on the combination of extracts with synergistic therapeutic effects on hemorrhoid disease. The analgesic effect was determined by means of the writhing test in mice. The anti-inflammatory effect was determined after administration of carrageenan or kaolin in the rat paw. Extraction using glycerol yielded the highest amounts of flavonoids for both V. vinifera leaves (37.27 ± 1.174 mg/L) and A. hippocastanum seeds (53.48 ± 0.212 mg/L). The highest total phenolic contents were registered for the V. vinifera 20% ethanolic extract (615.3 ± 34.44 mg/L) and for the A. hippocastanum glycerolic extract (247.8 ± 6.991 mg/L). The writhing test revealed that the V. vinifera ethanolic extract induced the most efficient analgesia (57.20%, p < 0.01), better than that induced by the positive control. In the carrageenan inflammation model, only the gel obtained from the A. hippocastanum glycerolic extract significantly reduced paw edema (17.27%, p < 0.05). An anti-inflammatory effect was also observed in the kaolin inflammation model but was not statistically significant (10.12%, p > 0.05). Our findings indicate that V. vinifera and A. hippocastanum extracts may have potential uses for the treatment of pain and inflammation associated with hemorrhoid disease.