Efficacy and safety of visnadine in the treatment of symptoms of sexual dysfunction in heterosexual women: a systematic review of randomized clinical trials.

OBJECTIVE: To synthesize the primary evidence on the efficacy and safety of visnadine on symptoms of sexual dysfunction (SD) in heterosexual women. METHODS: We conducted a systematic review of randomized clinical trials (RCTs) with a primary search without language restriction in PubMed/Medline, Scopus, Embase, Web of Science, Cochrane Library, and international clinical trial registries. Trials reporting the use of visnadine by any route in women with SD were eligible. We performed screening, data extraction, and risk of bias assessment in a double-blind approach. The primary outcomes were the Female Sexual Function Index (FSFI) and its domains. Secondary outcomes were safety, arousal, lubrication, pleasure, orgasm, negative sensations, duration, and overall satisfaction. RESULTS: Initially, 242 records were retrieved. We selected nine papers for full-text reading and finally included two RCTs: one with a parallel design and one with a crossover design with a total of 96 patients. One study compared visnadine aerosol with a placebo, while the other compared different frequencies of visnadine aerosol use. Visnadine use showed a statistically significant improvement (p < 0.05) in overall FSFI scores, regardless of the frequency of use. A meta-analysis was not possible due to the high clinical and methodological heterogeneity between available studies. CONCLUSION: RCTs regarding the use of visnadine for the Female SD are scarce and methodologically limited. This preliminary evidence shows visnadine as a potentially effective and safe option to alleviate some of the clinical symptoms of SD in heterosexual women. However, future better-designed randomized studies with larger sample numbers are required.

Trolox and recombinant Irisin as a potential strategy to prevent neuronal damage induced by random positioning machine exposure in differentiated HT22 cells.

Neuronal death could be responsible for the cognitive impairments found in astronauts exposed to spaceflight, highlighting the need to identify potential countermeasures to ensure neuronal health in microgravity conditions. Therefore, differentiated HT22 cells were exposed to simulated microgravity by random positioning machine (RPM) for 48 h, treating them with a single administration of Trolox, recombinant irisin (r-Irisin) or both. Particularly, we investigated cell viability by MTS assay, Trypan Blue staining and western blotting analysis for Akt and B-cell lymphoma 2 (Bcl-2), the intracellular increase of reactive oxygen species (ROS) by fluorescent probe and NADPH oxidase 4 (NOX4) expression, as well as the expression of brain-derived neurotrophic factor (BDNF), a major neurotrophin responsible for neurogenesis and synaptic plasticity. Although both Trolox and r-Irisin manifested a protective effect on neuronal health, the combined treatment produced the best results, with significant improvement in all parameters examined. In conclusion, further studies are needed to evaluate the potential of such combination treatment in counteracting weightlessness-induced neuronal death, as well as to identify other potential strategies to safeguard the health of astronauts exposed to spaceflight.

Histopathological studies of nonhuman primates exposed to supralethal doses of total- or partial-body radiation: influence of a medical countermeasure, gamma-tocotrienol.

Despite remarkable scientific progress over the past six decades within the medical arts and in radiobiology in general, limited radiation medical countermeasures (MCMs) have been approved by the United States Food and Drug Administration for the acute radiation syndrome (ARS). Additional effort is needed to develop large animal models for improving the prediction of clinical safety and effectiveness of MCMs for acute and delayed effects of radiation in humans. Nonhuman primates (NHPs) are considered the animal models that reproduce the most appropriate representation of human disease and are considered the gold standard for drug development and regulatory approval. The clinical and histopathological effects of supralethal, total- or partial-body irradiations (12 Gy) of NHPs were assessed, along with possible protective actions of a promising radiation MCM, gamma-tocotrienol (GT3). Results show that these supralethal radiation exposures induce severe injuries that manifest both clinically as well as pathologically, as evidenced by the noted functionally crippling lesions within various major organ systems of experimental NHPs. The MCM, GT3, has limited radioprotective efficacy against such supralethal radiation doses.

Six New Compounds from the Herbaceous Stems of Ephedra intermedia Schrenket C. A. Meyer and Their Lung-Protective Activity.

Six new compounds, (7R,8S,8'R)-balanophorone (1), (7'S,8'R,8R)-yunnanensin A (2), (3S)-thunberginol C (3), (8R,8'R)-maninsigin B (4), (7S,8R)-4,7,8-dihydroxy-9,9-dimethyl-chroman (5), and 4-hydroxy-1-(4-hydroxy-3-methoxyphenyl)butan-1-one (6), along with eight known compounds (7-14), were isolated from the herbaceous stems of Ephedra intermedia Schrenket C. A. Meyer. Their structures were elucidated based on their spectroscopic (MS, NMR, IR, and UV) data, and their absolute configurations were determined by comparing their calculated and experimental electronic circular dichroic (ECD) spectra. Moreover, compounds 1 and 3-6 were evaluated for their ability to protect human pulmonary epithelial cells (BEAS-2B) from injury induced by lipopolysaccharide (LPS) in vitro. The results showed that compound 6 exhibited a significant protective effect against LPS-induced injury in BEAS-2B, and compound 5 exhibited a slightly protective effect at the concentration of 10 µM.

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation.

Currently, no radioprotectors have been approved to mitigate hematopoietic injury after exposure to ionizing radiation. Acute ionizing radiation results in damage to both hematopoietic and immune system cells. Pre-exposure prophylactic agents are needed for first responders and military personnel. In this study, the ability of gamma-tocotrienol (GT3), a promising radioprotector and antioxidant, to ameliorate partial-body radiation-induced damage to the hematopoietic compartment was evaluated in a nonhuman primate (NHP) model. A total of 15 rhesus NHPs were divided into two groups, and were administered either GT3 or vehicle 24 h prior to 4 or 5.8 Gy partial-body irradiation (PBI), with 5% bone marrow (BM) sparing. Each group consisted of four NHPs, apart from the vehicle-treated group exposed to 5.8 Gy, which had only three NHPs. BM samples were collected 8 days prior to irradiation in addition to 2, 7, 14, and 30 days postirradiation. To assess the clonogenic ability of hematopoietic stem and progenitor cells (HSPCs), colony forming unit (CFU) assays were performed, and lymphoid cells were immunophenotyped using flow cytometry. As a result of GT3 treatment, an increase in HSPC function was evident by an increased recovery of CFU-granulocyte macrophages (CFU-GM). Additionally, GT3 treatment was shown to increase the percentage of CD34+ cells, including T and NK-cell subsets. Our data further affirm GT3's role in hematopoietic recovery and suggest the need for its further development as a prophylactic radiation medical countermeasure.

Manipulation of metabolic responses enhances SHetA2 efficacy without toxicity in cervical cancer cell lines and xenografts.

OBJECTIVE: The high frequency of cervical cancer recurrence after primary therapy necessitates alternative treatments. High-risk human papillomavirus (HR-HPV) causes cervical cancer and it's continued presence supports elevated metabolism, proliferation and survival of cancer cells. The low-to-no toxicity new investigational drug, SHetA2, counteracts high-risk human papillomavirus (HR-HPV) effects on cell proliferation and survival in cervical cancer cells and xenograft tumors by disrupting heat shock protein 70 chaperone protection of oncogenic proteins. Our objective was to study the involvement of metabolism in SHetA2 effects on cervical cancer cells and tumors. METHODS: SHetA2-mediated proteomic and metabolic effects were measured in HR-HPV-positive CaSKi and SiHa and HR-HPV-negative C-33 A cervical cancer cell lines. Combined treatment with 2-deoxyglucose (2-DG) was evaluated in cell culture and SiHa xenografts. RESULTS: SHetA2 inhibited oxidative phosphorylation (OxPhos) and altered levels of proteins involved in metabolism, protein synthesis, and DNA replication and repair. Cervical cancer cells responded by elevating glycolysis. Inhibition of the glycolytic responses using galactose media or 2-DG increased SHetA2 sensitivity of two HR-HPV-positive, but not an HR-HPV-negative cervical cancer cell line. Interaction of 2-DG and SHetA2 was synergistic in HR-HPV positive cell lines in association with augmentation of SHetA2 ATP reduction, but not SHetA2 DNA damage induction. These results were verified in a SiHa xenograft tumor model without evidence of toxicity. CONCLUSIONS: Compensatory glycolysis counteracts OxPhos inhibition in SHetA2-treated HR-HPV-positive cervical cancer cell lines. Prevention of compensatory glycolysis with 2-DG or another glycolysis inhibitor has the potential to improve SHetA2 therapy without toxicity.

L116 Deletion in CSPα Promotes α-Synuclein Aggregation and Neurodegeneration.

Parkinsonism is a clinical syndrome that is caused by Parkinson's disease (PD) and other neurodegenerative diseases. Here, we report a patient who exhibited progressive parkinsonism, epilepsy, and cognitive impairment and was diagnosed with adult-onset neuronal ceroid lipofuscinoses (ANCLs). The patient carries a mutation (p.Leu116 del) in the DNAJC5 gene that encodes cysteine string protein (CSPα). Since the patient shows typical parkinsonism and loss of dopamine transporter in the striatum, we investigated the effect of wild-type and L116del mutant CSPα on the aggregation of α-synuclein (α-syn) and neurotoxicity in vitro. Overexpression of wild-type CSPα attenuated the phosphorylation, ubiquitination, and aggregation of α-syn induced by α-syn fibrils. Moreover, wild-type CSPα inhibits oxidative stress and cell apoptosis and rescues inefficient SNARE complex formation induced by α-syn fibrils in SH-SY5Y cells. However, these protective effects of CSPα were abolished by the L116del mutation. Collectively, these results indicate that L116 deletion in CSPα promotes α-syn pathology and neurotoxicity. Boosting CSPα may be therapeutically useful for treating synucleinopathies.

Pharmacodynamics of Cyclin D1 Degradation in Ovarian Cancer Xenografts with Repeated Oral SHetA2 Dosing.

SHetA2 is a promising, orally active small molecule with anticancer properties that target heat shock proteins. In this study, we aimed to investigate the pharmacodynamic (PD) effects of SHetA2 using preclinical in vitro and in vivo models of ovarian cancer and establish a physiologically based pharmacokinetic (PBPK)/PD model to describe their relationships with SHetA2 concentrations in mice. We found that daily oral administration of 60 mg/kg SHetA2 for 7 days resulted in consistent plasma PK and tissue distribution, achieving tumor drug concentrations required for growth inhibition in ovarian cancer cell lines. SHetA2 effectively induced cyclin D1 degradation in cancer cells in a dose-dependent manner, with up to 70% reduction observed and an IC50 of 4~5 µM. We identified cyclin D1 as a potential PD marker for SHetA2, based on a well-correlated time profile with SHetA2 PK. Additionally, we examined circulating levels of ccK18 as a non-invasive PD marker for SHetA2-induced apoptotic activity and found it unsuitable due to high variability. Using a PBPK/PD model, we depicted SHetA2 levels and their promoting effects on cyclin D1 degradation in tumors following multiple oral doses. The model suggested that twice-daily dosing regimens would be effective for sustained reduction in cyclin D1 protein. Our study provides valuable insights into the PK/PD of SHetA2, facilitating future clinical trial designs and dosing schedules.

Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities.

In search of novel multi-mechanistic approaches for treating Alzheimer's disease (AD), we have embarked on synthesizing single small molecules for probing contributory roles of the following combined disease targets: sigma-1 (σ-1), class IIb histone deacetylase-6 (HDAC-6), and oxidative stress (OS). Herein, we report the synthesis and partial evaluation of 20 amides (i.e., phenylacetic and Trolox or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid derivatives). Target compounds were conveniently synthesized via amidation by either directly reacting acyl chlorides with amines or condensing acids with amines in the presence of coupling agents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU) or 1,1'-carbonyldiimidazole (CDI). Overall, this project afforded compound 8 as a promising lead with σ-1 affinity (Ki = 2.1 µM), HDAC-6 (IC50 = 17 nM), and antioxidant (1.92 Trolox antioxidant equivalents or TEs) activities for optimization in ensuing structure-activity relationship (SAR) studies.

Biological Variations of Seven Clinical Chemistry Analytes and Trolox Equivalent Antioxidant Capacity within Salivary Constituents.

BACKGROUND: Data on biological variation in saliva samples are quite limited. This study aimed to obtain well-defined biological variation data for seven common clinical chemistry analytes and Trolox equivalent antioxidant capacity (TEAC) in saliva. METHODS: Unstimulated whole saliva and blood samples were collected from thirty-two healthy volunteers of both genders without any history of disease or metabolic syndrome under standard conditions at six different times within three weeks. The seven clinical chemistry analytes and TEAC, analyzed by photometric methods using automated analyzers, were planned for biological variation analysis. The components of nested analysis of variance were used to perform the biological variation data analysis. RESULTS: The within-subject and between-subject biological variations (CVG and CVI, respectively) for unstimulated whole saliva samples, respectively, were determined to be 19.3% and 25.1% for α-amylase, 25.1% and 51.1% for aspartate aminotransferase, 31.0% and 22.3% for lactate dehydrogenase, 19.0% and 20.8% for uric acid, 16.6% and 23.4% for total calcium, 12.9% and 13.7% for inorganic phosphate, 13.1% and 19.7% for total protein, and 14.9% and 20.0% for TEAC. In addition, the CVI and CVG were 3.4% and 6.3% for serum TEAC. CONCLUSIONS: Considering the evidence that saliva samples can be used to diagnose and monitor oral or non-oral diseases, these biological variation data will contribute to how to use subject-based reference values or population-based reference intervals of these analytes and TEAC.

Synthesis of Ester-Containing Chroman-4-Ones via Cascade Radical Annulation of 2-(Allyloxy)Arylaldehydes with Oxalates under Metal Free Conditions.

A convenient and practical method for the synthesis of bioactive ester-containing chroman-4-ones through the cascade radical cyclization of 2-(allyloxy)arylaldehydes and oxalates is described. The preliminary studies suggest that an alkoxycarbonyl radical might be involved in the current transformation, which was generated via the decarboxylation of oxalates in the presence of (NH4)2S2O8.

Gamma-Tocotrienol Modulates Total-Body Irradiation-Induced Hematopoietic Injury in a Nonhuman Primate Model.

Radiation exposure causes acute damage to hematopoietic and immune cells. To date, there are no radioprotectors available to mitigate hematopoietic injury after radiation exposure. Gamma-tocotrienol (GT3) has demonstrated promising radioprotective efficacy in the mouse and nonhuman primate (NHP) models. We determined GT3-mediated hematopoietic recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques divided into two groups received either vehicle or GT3, 24 h prior to TBI. Four animals in each treatment group were exposed to either 4 or 5.8 Gy TBI. Flow cytometry was used to immunophenotype the bone marrow (BM) lymphoid cell populations, while clonogenic ability of hematopoietic stem cells (HSCs) was assessed by colony forming unit (CFU) assays on day 8 prior to irradiation and days 2, 7, 14, and 30 post-irradiation. Both radiation doses showed significant changes in the frequencies of B and T-cell subsets, including the self-renewable capacity of HSCs. Importantly, GT3 accelerated the recovery in CD34+ cells, increased HSC function as shown by improved recovery of CFU-granulocyte macrophages (CFU-GM) and burst-forming units erythroid (B-FUE), and aided the recovery of circulating neutrophils and platelets. These data elucidate the role of GT3 in hematopoietic recovery, which should be explored as a potential medical countermeasure to mitigate radiation-induced injury to the hematopoietic system.

Functionalized Chromans from ortho-Quinone Methides and Arylallenes.

ortho-Quinone methides (o-QMs) underwent formal [4 + 2]-cycloaddition reactions with arylallenes regioselectively at the styrenyl olefin to furnish the corresponding 3-methylene-2-arylchromans in moderate to good yields (up to 88%). When R ≠ H, the reactions also proceeded with moderate stereoselectivity (up to 5:1) which was governed by the nature of the R group. The 3-methylene-2-arylchromans could serve as common intermediates for further functionalization including epoxidation, oxidative cleavage/Baeyer-Villiger oxidation, Riley oxidation, acid-catalyzed rearrangement, and Pd-catalyzed cross-coupling reactions to furnish the corresponding derivatives in moderate to good yields.

Metal-Free Synthesis of Carbamoylated Chroman-4-Ones via Cascade Radical Annulation of 2-(Allyloxy)arylaldehydes with Oxamic Acids.

An efficient and straightforward approach for the synthesis of carbamoylated chroman-4-ones has been well-developed. The reaction is triggered through the generation of carbamoyl radicals from oxamic acids under metal-free conditions, which subsequently undergoes decarboxylative radical cascade cyclization on 2-(allyloxy)arylaldehydes to afford various amide-containing chroman-4-one scaffolds with high functional group tolerance and a broad substrate scope.

Combination of Machine Learning and Analytical Correlations for Establishing Quantitative Compliance between the Trolox Equivalent Antioxidant Capacity Values Obtained via Electron Paramagnetic Resonance and Ultraviolet-Visible Spectroscopies.

Recent interest in the antioxidant capacity of foods and beverages is based on the established medical knowledge that antioxidants play an essential role in counteracting the damaging effects of free radicals, preventing human neurodegenerative diseases, cardiovascular disorders, and even cancer. At the same time, there is no "the method" that uniquely defines the antioxidant capacity of substances; moreover, the question of interrelation between results obtained by different experimental techniques is still open. In this work, we consider the trolox equivalent antioxidant capacity (TEAC) values obtained by electron paramagnetic resonance (EPR) spectroscopy and ultraviolet-visible (UV-vis) spectroscopy using the classic objects for such studies as an example: red, rosé, and white wine samples. Based on entirely different physical principles, these two methods give values that are not so simply interrelated; this creates a demand for machine learning as a suitable tool for revealing quantitative correspondence between them. The consideration consists of an approximate correlation-based analytical model for the key argument (i.e., TEACEPR) with subsequent adjustment by machine learning-based processing utilizing the CatBoost algorithm with the usage of auxiliary chemical data, such as the total phenolic content and color index, which cannot be accurately described by analytical expressions.

Electrochemical and Spectroscopic Characterization of Oxidized Intermediate Forms of Vitamin E.

Vitamin E, a collection of lipophilic phenolic compounds based on chroman-6-ol, has a rich and fascinating oxidative chemistry involving a range of intermediate forms, some of which are proposed to be important in its biological functions. In this review, the available electrochemical and spectroscopic data on these oxidized intermediates are summarized, along with a discussion on how their lifetimes and chemical stability are either typical of similar phenolic and chroman-6-ol derived compounds, or atypical and unique to the specific oxidized isomeric form of vitamin E. The overall electrochemical oxidation mechanism for vitamin E can be summarized as involving the loss of two-electrons and one-proton, although the electron transfer and chemical steps can be controlled to progress along different pathways to prolong the lifetimes of discreet intermediates by modifying the experimental conditions (applied electrochemical potential, aqueous or non-aqueous solvent, and pH). Depending on the environment, the electrochemical reactions can involve single electron transfer (SET), proton-coupled electron transfer (PCET), as well as homogeneous disproportionation and comproportionation steps. The intermediate species produced via chemical or electrochemical oxidation include phenolates, phenol cation radicals, phenoxyl neutral radicals, dications, diamagnetic cations (phenoxeniums) and para-quinone methides. The cation radicals of all the tocopherols are atypically long-lived compared to the cation radicals of other phenols, due to their relatively weak acidity. The diamagnetic cation derived from α-tocopherol is exceptionally long-lived compared to the diamagnetic cations from the other ß-, γ- and δ-isomers of vitamin E and compared with other phenoxenium cations derived from phenolic compounds. In contrast, the lifetime of the phenoxyl radical derived from α-tocopherol, which is considered to be critical in biological reactions, is typical for what is expected for a compound with its structural features. Over longer times via hydrolysis reactions, hydroxy para-quinone hemiketals and quinones can be formed from the oxidized intermediates, which can themselves undergo reduction processes to form intermediate anion radicals and dianions. Methods for generating the oxidized intermediates by chemical, photochemical and electrochemical methods are discussed, along with a summary of how the final products vary depending on the method used for oxidation. Since the intermediates mainly only survive in solution, they are most often monitored using UV-vis spectroscopy, FTIR or Raman spectroscopies, and EPR spectroscopy, with the spectroscopic techniques sometimes combined with fast photoinitiated excitation and time-resolved spectroscopy for detection of short-lived species.

HFIP-promoted halo-carbocyclizations of N- and O-tethered arene-alkene substrates to access all halo (X = Br, I, Cl)-functionalized tetrahydroquinoline and chroman cores.

A new method for the stereoselective metal-, additive- and oxidant-free Friedel-Crafts-type halo-carbocyclization of N- and O-tethered arene-olefin substrates is reported, involving reaction with a suitable electrophilic halogenating reagent (NXS/DCDMH) in hexafluoroisopropanol. All halo (X = Br, I, Cl)-functionalized tetrahydroquinolines and chromans were obtained in excellent yields and with high levels of diastereocontrol (dr = >99 : 1), and these products were successfully transformed into synthetically useful compounds such as dihydroquinolines and partial or full azahelicene compounds.

γ-Tocotrienol inhibits T helper 17 cell differentiation via the IL-6/JAK/STAT3 signaling pathway.

γ-Tocotrienol (GT3), a member of the vitamin E family, is well known for its medicinal value in clinical treatments. However, the role of GT3 in T helper 17 (Th17)/regulatory T cell (Treg) differentiation and function is not fully understood. Here, we demonstrated that GT3 suppressed Th17 differentiation in vitro by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation in the interleukin 6 (IL-6)/Janus kinase (JAK)/STAT3 signaling pathway. GT3 also inhibited HIF1A expression in Th17 metabolism. Additionally, we showed that GT3 treatment inhibited disease aggravation in an imiquimod (IMQ)-induced psoriasis-like mouse model by reducing the percentage of Th17 cells in the spleen in vivo. The findings of this study demonstrated the effects of GT3 on Th17 cells through the STAT3 signaling pathway.

Exploration of the Effects of TGF-ß Pathway-Based Pituitary Tumor of Rats on GH3 Cell Line after Intervention with Different Concentrations of TGZ.

The effect of the TGF-ß pathway-based pituitary tumor of rats on the GH3 cell line after intervention with different concentrations of troglitazone (TGZ) is explored. The CH3 cell line of 24 clean male SD rats with pituitary adenoma is selected. The cells are divided into a blank contrast set and an experimental set. The experimental set is divided into different TGZ concentration sets, including 1 × 10-3 TGZ set, 1 × 10-4 TGZ set, and 1 × 10-5 TGZ set. The cell proliferation is detected by the CCK-8 method, the protein expressions of CD147, TGF-ß1, and MMP-9 are detected by the western blot method, and the relative mRNA expressions of CD147, TGF-ß1, and MMP-9 are detected by the qRT-PCR method. The expression levels of CD147, TGF-ß1, and MMP-9 in CH3 cells of pituitary adenoma rats are notoriously lower, while the expression of CD147, TGF-31, and MMP-9 could be reduced by TGZ acting on the GH3 cell line. The specific mechanism of action of this effect on the invasive ability of GH3 cell lines is multifaceted, suggesting that peroxisome proliferator activator-receptor (PPAR-γ) agonists have good clinical application prospects in tumor therapy and can provide new targets and approaches for tumor drug therapy.

Enantioselective Michael/Hemiketalization Cascade Reactions between Hydroxymaleimides and 2-Hydroxynitrostyrenes for the Construction of Chiral Chroman-Fused Pyrrolidinediones.

In this paper, the organocatalytic asymmetric Michael addition/hemiketalization cascade reactions between hydroxymaleimides and 2-hydroxynitrostyrenes were developed, which provided a new protocol for building a chiral ring-fused chroman skeleton. This squaramide-catalyzed cascade reaction provided chiral chroman-fused pyrrolidinediones with three contiguous stereocenters in good to high yields (up to 88%), with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 96% ee) at −16 °C. Moreover, a scale-up synthesis was also carried out, and a possible reaction mechanism was proposed.