Murat Oz

Background/Objectives: Statins are currently one of the most commonly used cholesterol-lowering drugs. In recent years, in addition to their well-known effects on the cardiovascular system, statins have been shown to exert beneficial effects in the progression of various neuropsychiatric and neurodegenerative diseases. Methods: In this study, the effects of lovastatin on the function of α7-nicotinic acetylcholine (nACh) receptors expressed in rat hippocampus and Xenopus oocytes were investigated. Results: In whole-cell patch clamp studies in hippocampal neurons, 21-day chronic (20 mg/kg), but not acute (20 min), lovastatin treatment caused significant potentiation of choline (a selective agonist for α7 nACh receptors)-induced currents and choline-induced increases in GABA_A receptor-mediated currents. Further studies in Xenopus oocytes expressing human α7-nACh receptors indicated that 72 h pretreatment with lovastatin caused a significant increase in α7-nACh receptor function with an EC₅₀ value of 296 nM. Other statins, such as simvastatin and pravastatin, also potentiated α7-nACh receptors. Potentiation by lovastatin treatment was associated with a significant decrease in oocyte cholesterol content and was diminished by Go6983, an inhibitor of protein kinase C (PKC), suggesting that both decreased cholesterol levels and activation of PKC are involved in statin potentiation of α7-nACh receptors. Conclusions: In conclusion, our findings indicate that chronic lovastatin treatment potentiates the function of α7-nACh receptors in hippocampal neurons and in Xenopus oocytes expressing human α7-nACh receptors and provides important insights that could guide future efforts to design novel drugs targeting α7-nACh receptors.

Objective: The COVID-19 pandemic has strained healthcare systems and has been associated with substantial morbidity and mortality. Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) enters host cells by binding to angiotensin-converting enzyme 2 (ACE2), implicating dysregulation of the renin–angiotensin system (RAS) in COVID-19 pathophysiology. Measurement of circulating RAS components, including ACE and ACE2, may therefore provide an insight into disease severity and underlying mechanisms. Subjects and Methods: In this retrospective cohort study, 224 adults with PCR-confirmed COVID-19 were stratified by World Health Organization disease-severity criteria into asymptomatic, mild, mild-pneumonia, severe, and critical groups. Plasma ACE and ACE2 concentrations were quantified by ELISA. Demographic, clinical, and laboratory data were extracted from electronic medical records. Results and Conclusions: Increasing disease severity was associated with higher mortality, elevated body mass index, and higher viral load estimates. Severe and critical illness was characterized by leukocytosis with neutrophilia, marked lymphopenia, anemia, elevated inflammatory and coagulation markers, renal dysfunction, and hypoalbuminemia. Plasma ACE2 levels declined progressively with increasing severity and were significantly lower in patients with mild-pneumonia, severe, or critical illness compared with asymptomatic or mild cases, showing a strong inverse correlation with severity. In contrast, plasma ACE levels increased significantly with disease severity. The resulting increase in the ACE/ACE2 ratio indicates a progressive shift toward the pro-inflammatory arm of the RAS, providing mechanistic insight into the COVID-19 pathophysiology.

Capsaicin, a naturally occurring polyphenol, is known to affect energy expenditure and muscle fatigue and modulate contractions in skeletal muscle. The L-type Ca²⁺ channels are known to be an important ion channel involved in the various muscle functions and the effect of capsaicin on the skeletal L-type Ca²⁺ channels is currently unknown. In this study, the effects of capsaicin and capsaicin analogs on depolarization-induced Ca²⁺ effluxes through L-type Ca²⁺ channels in transverse tubule membranes from rabbit skeletal muscle and L-type Ca²⁺ currents recorded using the whole-cell patch clamp technique in rat myotubes were examined. Capsaicin, in the concentration range of 3–100 µM, inhibited depolarization-induced Ca²⁺ effluxes. The effect of capsaicin was not reversed by TRPV1 antagonist SB-366791 (10 µM). While vanilloids (30 µM) including vanillin, vanillyl alcohol, and vanillylamine were ineffective, other capsaicinoids (30 µM) including dihydrocapsaicin, nonivamide, and nordihydrocapsaicin significantly inhibited Ca²⁺ effluxes, suggesting that hydrocarbon chains are required for inhibition. In rat myotubes, capsaicin inhibited L-type Ca²⁺ currents with an IC₅₀ value of 27.2 μM in the presence of SB-366791. Furthermore, in docking studies and molecular dynamic simulations, capsaicinoids with an aliphatic tail showed stronger binding and stable bent conformations in CaV1.1, forming hydrogen bonds with Ser1011 and Thr935 and hydrophobic/π–alkyl contacts with Phe1008, Ile1052, Met1366, and Ala1369, resembling the binding mode of amlodipine. In conclusion, the results indicate that the function of L-type Ca²⁺ channels in mammalian skeletal muscle was inhibited by capsaicin and capsaicin analogs in a TRPV1-independent manner.

The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural and functional attributes, highlighting its therapeutic potential in neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic plasticity, modulate inflammatory responses, and influence dopamine release, positioning them as a promising pharmacological target. Positive allosteric modulators (PAMs) enhance α7-nAChR activity mainly by reducing desensitization, offering a superior therapeutic approach compared with direct agonists. Emerging preclinical studies suggest that α7-nAChR activation mitigates dopaminergic neurodegeneration, improves L-dopa-induced dyskinesia, and reduces neuroinflammation. Despite promising findings, clinical trials have yielded mixed results, necessitating further research into optimizing α7-targeted therapies. This review underscores the significance of α7-nAChRs in PD pathophysiology and highlights future directions for their translational potential in neuroprotection and symptomatic relief.

Objective: Naringenin, a major flavonoid found in citrus juice, has been shown to inhibit human ether-a-go-go-related gene (HERG) channels and cause QT prolongation. Statins, the most commonly used class of cholesterol reducing drugs, have also been reported to inhibit HERG channels and prolong QT interval in patients using these drugs. However, the interaction between naringenin and statins on the function of HERG channels has not been studied. Materials and Methods: In the present study, we expressed HERG channels in Xenopus oocytes, tested the effects of naringenin and statins separately, and combined on HERG channels. Results: When 30 µm naringenin was added to statins (1 µm rosuvastatin or 3 µm atorvastatin), significantly greater inhibition of HERG was demonstrated, compared to the inhibition caused by statins alone. Conclusions: The results indicate that an additive interaction occurs between naringenin and statins; this could pose an increased risk of arrhythmias by decreasing repolarization reserve.

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10–30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 mg/kg, i.p.). BTBR mice pretreated with APG (20 mg/kg) or ARP (1 mg/g, i.p.) displayed significant improvements in the marble-burying test (MBT), cotton-shredding test (CST), and self-grooming test (SGT) (all p < 0.05). However, a lower dose of APG (10 mg/kg, i.p.) failed to modulate behaviors in the MBT or SGT, but significantly attenuated the increased shredding behaviors in the CST of tested mice. Moreover, APG (10–30 mg/kg, i.p.) and ARP (1 mg/kg) moderated the disturbed levels of oxidative stress by mitigating the levels of catalase (CAT) and superoxide dismutase (SOD) in the hippocampus and cerebellum of treated BTBR mice. In patch clamp studies in hippocampal slices, the potency of choline (a selective agonist of α7-nAChRs) in activating fast inward currents was significantly potentiated following incubation with APG. Moreover, APG markedly potentiated the choline-induced enhancement of spontaneous inhibitory postsynaptic currents. The observed results propose the potential therapeutic use of APG in the management of ASD. However, further preclinical investigations in additional models and different rodent species are still needed to confirm the potential relevance of the therapeutic use of APG in ASD.

Capsaicin is a naturally occurring alkaloid derived from chili pepper that is responsible for its hot pungent taste. Capsaicin is known to exert multiple pharmacological actions, including analgesia, anticancer, anti‐inflammatory, antiobesity, and antioxidant effects. The transient receptor potential vanilloid subfamily member 1 (TRPV1) is the main receptor mediating the majority of the capsaicin effects. However, numerous studies suggest that the TRPV1 receptor is not the only target for capsaicin. An increasing number of studies indicates that capsaicin, at low to mid µM ranges, not only indirectly through TRPV1‐mediated Ca²⁺ increases, but also directly modulates the functions of voltage‐gated Na⁺, K⁺, and Ca²⁺ channels, as well as ligand‐gated ion channels and other ion transporters and enzymes involved in cellular excitability. These TRPV1‐independent effects are mediated by alterations of the biophysical properties of the lipid membrane and subsequent modulation of the functional properties of ion channels and by direct binding of capsaicin to the channels. The present study, for the first time, systematically categorizes this diverse range of non‐TRPV1 targets and discusses cellular and molecular mechanisms mediating TRPV1‐independent effects of capsaicin in excitable, as well as nonexcitable cells.

The effects of methylene blue (MB) on cromakalim-induced K⁺ currents were investigated in follicle-enclosed Xenopus oocytes. In concentrations ranging from 3–300 μM, MB inhibited K⁺ currents (IC₅₀: 22.4 μM) activated by cromakalim, which activates K_ATP channels. MB inhibited cromakalim-activated K⁺ currents in a noncompetitive and voltage-independent manner. The respective EC₅₀ and slope values for cromakalim-activation of K⁺ currents were 194 ± 21 µM and 0.91 for controls, and 206 ± 24 µM and 0.87 in the presence of 30 μM MB. The inhibition of cromakalim-induced K⁺ currents by MB was not altered by pretreatment with the Ca²⁺ chelator BAPTA, which suggests that MB does not influence Ca²⁺-activated second messenger pathways. K⁺ currents mediated through a C-terminally deleted form of Kir6.2 (KirΔC26), which does not contain the sulfonylurea receptor, were still inhibited by MB, indicating direct interaction of MB with the channel-forming Kir6.2 subunit. The binding characteristics of the K_ATP ligand [³H]glibenclamide are not altered by MB in a concentration range between 1 μM-1 mM, as suggested by radioligand binding assay. The presence of a membrane permeable cGMP analogue (8-Br-cGMP, 100 µM) and a guanylate cyclase activator (BAY 58-2667, 3 µM) did not affect the inhibitory effects of MB, suggesting that MB does not inhibit cromakalim-activated K⁺ currents through guanylate cyclase. Collectively, these results suggest that MB directly inhibits cromakalim-activated K⁺ currents in follicular cells of Xenopus oocytes.