Elif Nur Barut

Verbascum species are traditionally used for respiratory disorders and are rich sources of iridoid glycosides, phenylethanoid glycosides, and triterpenoid saponins. However, V. kurdicum and V. longipedicellatum have not previously been investigated phytochemically or biologically. This study aimed to identify their bioactive constituents and characterize their protective effects against cigarette smoke extract (CSE)-induced bronchial epithelial injury. Bioactivity-guided fractionation of 50% methanol extracts yielded twelve compounds identified by NMR. Cytoprotective potential was evaluated in BEAS-2B cells, and selected compounds were investigated for effects on IL-6, IL-8, HO-1, TLR4 expression and downstream effectors (MyD88 and NF-κB), GSH, 8-OHdG levels, and SOD activity. Ajugol exhibited the strongest cytoprotective activity and significantly restored viability following CSE exposure. Ajugol, aucubin, and 1-O-caffeoyl-β-D-glucopyranose were selected for mechanistic evaluation. Aucubin and 1-O-caffeoyl-β-D-glucopyranose significantly reduced CSE-induced IL-6 release, while all three suppressed IL-8, with ajugol producing the greatest effect. Ajugol also attenuated TLR4 upregulation and reduced 8-OHdG levels and the CSE-induced increase in SOD activity, whereas MyD88, total NF-κB, p-NF-κB^Ser536, and GSH were not significantly improved. These findings provide the first phytochemical and biological characterization of both species and identify ajugol as a promising lead against CSE-induced bronchial epithelial damage.

Inflammatory pain mediated by pro‐inflammatory factors remains a major clinical challenge, highlighting the need for safer alternatives to conventional anti‐inflammatory drugs. Here, the antinociceptive effects of methanolic extracts from the aerial parts of Alchemilla daghestanica (AD) and Alchemilla minusculiflora (AM) were evaluated in mice using the formalin test, and anti‐inflammatory activity was assessed by measuring formalin‐induced paw edema. Phytochemical characterization was performed by LC–MS/MS, and potential activities of major constituents were predicted using PASS Online. LC–MS/MS identified miquelianin as the predominant compound in both extracts. AD (100–200 mg/kg) and AM (200 mg/kg) significantly inhibited the inflammatory phase of the formalin test ( p < 0.001 and p < 0.01, respectively) without affecting the neurogenic phase, and AM extract reduced paw edema ( p < 0.05). PASS predicted high probabilities (Pa > 0.7) for anti‐inflammatory activity of miquelianin, isoquercitrin, and tannic acid. These findings suggest that these extracts may represent valuable candidates for further investigation in inflammatory pain management.

Overactive bladder (OAB) is a prevalent syndrome whose first‐line pharmacotherapy with antimuscarinics and β ₃ ‐adrenoceptor agonists is limited by suboptimal efficacy and poor tolerability, underscoring the unmet need for novel molecular targets. As key regulators of detrusor smooth muscle excitability and bladder afferent signaling, ion channels have emerged as a compelling target class capable of modulating bladder function with high spatial precision. This review summarizes current evidence on the role of cation and anion channels in OAB pathophysiology and critically appraises their therapeutic potential, covering the principal channel families implicated in detrusor and afferent dysfunction, including voltage‐gated Ca ²⁺ and Na ⁺ channels, K ⁺ channel subfamilies, HCN, TRP, and PIEZO channels, ligand‐gated cation channels, ENaC/ASIC, and Cl ⁻ channels, with preclinical and clinical evidence integrated throughout. Despite this strong mechanistic rationale, clinical translation has been hampered by ubiquitous channel expression, patient heterogeneity, and the absence of stratifying biomarkers. Although the supporting evidence remains uneven, spanning genetic, ex vivo, and early‐phase clinical studies, future progress will likely depend on tissue‐selective compounds, biomarker‐defined subphenotypes, and emerging targets such as TMEM16A, TRPM4, and PIEZO channels, which represent particularly promising avenues for next‐generation OAB pharmacotherapy.

Diabetic erectile dysfunction (DMED) is a prevelant urological complication in diabetic men. Increased oxidative stress accompanied with diminished Nrf2 antioxidant pathway has been shown to impair NO/cGMP signaling and distrupt the penile vascular endothelial function in DMED. The present study aimed to investigate the therapeutic effect of dimethyl fumarate (DMF), a clinically approved Nrf2 activator used for psoriasis and multiple sclerosis, in a rat model of streptozotocin (STZ)-induced DMED. Male Sprague Dawley rats were injected with a single intraperitoneal dose of STZ (60 mg/kg) to induce DMED. At week 8, both diabetic and nondiabetic rats were treated orally with DMF (25 or 100 mg/kg) or vehicle for 4 weeks. At week 12, erectile function was evaluated by measuring the intracavernosal pressure (ICP) responses to the electrical stimulation of cavernous nerves. Penile tissues were collected for biochemical and molecular analysis. DMED occurred in diabetic rats, evidenced by reduced the maximum ICP/ mean arterial pressure (MAP) and total ICP/MAP ratios. The penile tissues of diabetic rats exhibited increased MDA level along with decreased Nrf2 and HO-1 protein levels, SOD and CAT activities, and reduced phosphorylated eNOS at serine 1177 and phosphorylated VASP at serine 239. Treatment with DMF at 100 mg/kg was effectively reversed these functional reponses and tissue biochemical alterations in DMED rats. This study provides the first evidence that DMF improved DMED by alleviating oxidative stress and endothelial dysfunction via the activation of Nrf2 antioxidant pathway, suggesting a potential clinical repurposing of DMF for DMED. Graphical Abstract

Cylophosphamide (CP)‐induced acute cystitis is a debilitating bladder dysfunction commonly observed in cancer patients, primarily resulting from oxidative damage and inflammation in the bladder tissue. Dimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of multiple sclerosis due to its antioxidant and anti‐inflammatory properties. Thus, we aimed to investigate the multiple effects of DMF, involving both its potential synergistic effect with CP on the SH‐SY5Y cells and its uroprotective effect on CP‐induced acute cystitis. Female Balb/c mice were orally administrated DMF (100 or 300 mg/kg/day) for five consecutive days before a single intraperitoneal (i.p) dose of CP. Mesna was administered 20 min before and at 4 h, 8 h after CP application. Following 24 h of CP injection, bladders were removed for functional, biochemical analysis and evaluation of vesical vascular permeability. SH‐SY5Y cell viability was assayed by MTT test. CP markedly decreased carbachol‐induced contraction of detrusor strips (p < 0.01), which was prevented by the high‐dose DMF treatment (p < 0.05). Evans blue dye extravasation was greatly increased in the bladders of cystitis group (p < 0.001), which was significantly decreased in DMF‐treated mice with cystitis (p < 0.01). Total GSH content was decreased (p < 0.01) whereas TNF‐α level was increased (p < 0.05) in the bladders of cystitis group. High‐dose DMF‐treated mice showed an increment in total GSH content (p < 0.05) without any alterations on TNF‐α levels of the bladders with cystitis. Additionally, combination of different concentrations of CP and DMF exhibited a potent synergistic cytotoxic effect in SH‐SY5Y cells. DMF improved CP‐induced acute cystitis by partially suppressing oxidative stress and inflammation, while also enhancing the cytotoxic effects of CP.

Objective: Overactive bladder (OAB) is a common urological disorder associated with detrusor overactivity linked to local tissue inflammation resulting in bladder hypersensitivity. The present study was aimed to investigate the therapeutic potential of vildagliptin (VIL), an anti-diabetic drug with anti-inflammatory effects, in a mouse model of cyclophosphamide (CP)-induced OAB. Material and Method: To induce an animal model of OAB, female Balb/c mice were intraperitoneally (i.p) injected with CP (80 mg/kg) every two days for 7 days. Then, mice were orally treated with saline (OAB model), VIL (10 or 50 mg/kg/day) or solifenacin (10 mg/kg/day) for 7 consecutive days. On the 17th day of experiment, organ-bath experiments were performed using isolated mouse detrusor muscle to evaluate tissue contractility. In another set of mice, bladder inflammation was assessed by Evans blue extravasation. Result and Discussion: Carbachol-induced contraction of detrusor strips significantly increased in OAB mice, which was reversed by treatment with VIL at 50 mg/kg or solifenacin. In addition, VIL treatment (50 mg/kg) reduced relative bladder weight and Evans blue dye extravasation into the bladders in CP-injected mice, demonstrating the inhibitory effect of VIL on CP-induced bladder inflammation. Our results showed that VIL ameliorated detrusor overactivity in a mouse model of CP-induced OAB by partially suppressing bladder inflammation.

Aim: The present study aimed to investigate potential effect of dimethyl fumarate (DMF) on bladder dysfunction in streptozotocin (STZ)-induced diabetic rats. Material and Methods: Adult male Sprague Dawley rats were given a single intraperitoneal dose of streptozotocin (60 mg/kg) to induce diabetes. After eight weeks, diabetic and nondiabetic rats were orally treated with DMF (25 or 100 mg/kg/day) or vehicle for four weeks orally. At 12 week after diabetes induction, in vitro organ bath studies were performed on detrusor strips of each rat and the contractile responses to KCl and carbachol (CCh) of the strips were evaluated. Results: The maximal KCl (80 mM)- and CCh-induced contractile responses of detrusor strips significantly (p