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Background and Objectives Inhibition of brain aminopeptidase A (APA), which converts angiotensin II into angiotensin III, has emerged as a novel antihypertensive treatment, as demonstrated in several experimental animal models. QGC001 (originally named RB150) is a prodrug of the specific and selective APA inhibitor EC33, and as such it is the prototype of a new class of centrally acting antihypertensive agents. Given by the oral route in hypertensive rats, it enters the brain and generates EC33, which blocks the brain renin–angiotensin system activity and normalises blood pressure. The aim of the present study was to evaluate the safety, pharmacokinetics and pharmacodynamic effects of QGC001 in humans. Design and Methods Fifty-six healthy male volunteers were randomly assigned to receive in double-blind and fasted conditions single oral doses of 10, 50, 125, 250, 500, 750, 1,000 and 1,250 mg of QGC001 ( n  = 6/dose) or placebo ( n  = 2/dose). We measured plasma and urine concentrations of both QGC001 and EC33 by liquid chromatography–tandem mass spectrometry, plasma renin concentrations (PRC), plasma and free urine aldosterone (PAldo and UAldo), plasma copeptine (PCop), and plasma and urine cortisol (PCort and UCort) concentrations, and supine systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) at various time points. Results All doses of QGC001 were clinically and biologically well-tolerated. Peak plasma concentrations ( C max ) of QGC001 and EC33 increased linearly with the dose, with a median time to reach C max ( t max ) of 1.5 h for QGC001 and 3.0 h for EC33. The median plasma elimination half-life of QGC001 was 1.6 h consistently throughout doses. Urinary excretion of QGC001 and EC33 was below 2 % of the administered dose. When compared with placebo, QGC001 did not significantly change PRC, PAldo, UAldo, PCop, PCort or UCort. No significant change was observed for supine HR, SBP and DBP in any treatment group. Conclusion Single oral administration of QGC001 up to 1,250 mg in healthy volunteers was well-tolerated. Following oral administration, QGC001 is absorbed via the gastrointestinal tract and converted partially into its active metabolite EC33 in plasma. As in animal experiments, in normotensive subjects QGC001 had no effect on the systemic renin–angiotensin–aldosterone parameters and on PCop concentrations, a marker of vasopressin release. In normotensive subjects, a single dose of QCG001 had no effect on SBP, DBP or HR. These data support further evaluation of multiple oral doses of QGC001 in human volunteers and its clinical efficacy in hypertensive patients.

Purpose This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC). Methods PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily ×5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥1,000 vs. <1,000 U/ml) and SUV values on PET scans (≥7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (>18 ng/ml) as an entry criteria after the first 17 patients were accrued. Results Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively. Conclusions Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

Summary Purpose This phase I trial assessed the safety, dose limiting toxicity (DLT) and pharmacodynamics of PX-12 in adult patients with advanced refractory cancers. Methods PX-12 was administered to sequential cohorts as a 72-h infusion utilizing a portable infusion pump on days 1, 2, and 3 of a 21-day cycle at a starting dose level of 300 mg/m 2 /day and escalating dose levels till DLT was observed. Plasma thioredoxin (Trx-1), vascular endothelial growth factor (VEGF) and FGF-2 (fibroblast growth factor) levels were measured predose and during infusion of PX-12. Results Patients ( n  = 14) were enrolled to the following dose cohorts, 300 mg/m 2 ( n  = 3), 400 mg/m 2 ( n  = 10) and 500 mg/m 2 ( n  = 1). Common grade 1/2 toxicities included fatigue, taste alteration and odor caused by expired drug metabolite. DLTs were one episode each of grade 3 hypoxia at the 400 mg/m 2 and grade 3 reversible pneumonitis at the 500 mg/m 2 dose levels. Best response was stable disease in a patient with rectal cancer. Predose Trx-1 levels ( n  = 12) ranged from 5.1 to 30.0 ng/mL (median 12.6 ng/mL). Conclusion PX-12 administered at 400 mg/m 2 /day by 72-hour infusion appears safe and tolerable. Inhibition of thioredoxin is a strategy worth evaluation with next generation of inhibitors.

Background: The blockade of the progression or onset of pathological events is essential for the homeostasis of an organism. Some common pathological mechanisms involving a wide range of diseases are the uncontrolled inflammatory reactions that promote fibrosis, oxidative reactions, and other alterations. Natural plant compounds (NPCs) are bioactive elements obtained from natural sources that can regulate physiological processes. Inflammation is recognized as an important factor in the development and evolution of chronic renal damage. Consequently, any compound able to modulate inflammation or inflammation-related processes can be thought of as a renal protective agent and/or a potential treatment tool for controlling renal damage. The objective of this research was to review the beneficial effects of bioactive natural compounds on kidney damage to reveal their efficacy as demonstrated in clinical studies. Methods: This systematic review is based on relevant studies focused on the impact of NPCs with therapeutic potential for kidney disease treatment in humans. Results: Clinical studies have evaluated NPCs as a different way to treat or prevent renal damage and appear to show some benefits in improving OS, inflammation, and antioxidant capacity, therefore making them promising therapeutic tools to reduce or prevent the onset and progression of KD pathogenesis. Conclusions: This review shows the promising clinical properties of NPC in KD therapy. However, more robust clinical trials are needed to establish their safety and therapeutic effects in the area of renal damage.

Breast cancer is the leading cause of cancer mortality among women globally, and drug resistance complicates treatment. Garlic-derived organosulfur compounds exhibit anticancer potential, but their multi-target activity against key breast cancer biomarkers remains unclear. This study utilized AutoDock Vina for molecular docking, OpenBabel for post-docking energy minimization, and employs SWISS-ADME and PreADMET platforms for ADMET profiling to assess six garlic compounds (Z-ajoene, allyl-methyl trisulfide, diallyl disulfide, diallyl sulfide, diallyl trisulfide, and S-allyl-L-cysteine) against clinically relevant breast cancer targets. Z-ajoene showed strong binding to Bcl-2, Topoisomerase II, and CDK-2, while S-allyl-L-cysteine targets five biomarkers. All compounds complied with Lipinski’s rule of five, indicating good oral bioavailability, and display favorable ADMET properties with no mutagenic or tumorigenic risks. Most compounds were predicted to inhibit P-glycoprotein, while only Z-ajoene showed potential inhibition of CYP2C9, suggesting possible drug-drug interactions. Despite moderate affinities, these compounds may serve as potential promising multi-target agents in breast cancer therapy. Our computational findings provide preliminary evidence that garlic-derived compounds warrant further in vitro and in vivo evaluation, particularly in the context of drug-resistant breast cancer.

American Oyster Defensin (AOD) is a marine peptide that is derived from North American mussels. It has been demonstrated to exhibit potent antimicrobial activity and high safety in both in vitro and in vivo models. In this study, to facilitate synthesis, mutants of AOD with fewer disulfide bonds were designed and subjected to structural, antimicrobial, and anti-biofilm analysis. The antimicrobial activity of AOD-derived peptides decreased after reduction in the disulfide bond, and among its three derivatives, only AOD-1 inhibited very few bacteria with a MIC value of 64 μg/mL, whereas the others had no inhibitory effect on pathogenic bacteria. The findings demonstrated that full disulfide bonds are indispensable for bactericidal activity, with the α-helix playing a pivotal role in inhibiting bacterial membranes. Furthermore, the results of the ATP, ROS, membrane potential, and membrane fluidity assays demonstrated that intracellular ATP, reactive oxygen species, and membrane fluidity were all increased, while membrane potential was reduced. This indicated that AOD resulted in the impairment of membrane fluidity and induced metabolic disorders, ultimately leading to bacterial death. The inhibitory effect of AOD on the biofilm of S. epidermidis G-81 was determined through the crystal violet and confocal microscopy. The results demonstrated that AOD exhibited a notable inhibitory impact on the biofilm of S. epidermidis G-81. The minimum biofilm inhibitory concentration of AOD on S. epidermidis G-81 was 16 μg/mL, and the minimum biofilm scavenging concentration was 32 μg/mL, which exhibited superior efficacy compared to that of lincomycin. The inhibitory effect on the primary biofilm was 90.3%, and that on the mature biofilm was 82.85%, with a dose-dependent inhibition effect. Concurrently, AOD cleared intra-biofilm organisms and reduced the number of biofilm-holding bacteria by six orders of magnitude. These data indicate that disulfide bonds are essential to the structure and activity of AOD, and AOD may potentially become an effective dual-action antimicrobial and anti-biofilm agent.

Diallyl disulfide (DADs), a natural organic compound, is extracted from garlic and scallion and has anti-tumor effects against various tumors. This study investigated the anti-tumor activity of DADs in human osteosarcoma cells and the mechanisms. MG-63 cells were exposed to DADs (0, 20, 40, 60, 80, and 100 μM) for different lengths of time (24, 48, and 72 h). The CCK8 assay results showed that DADs inhibited osteosarcoma cell viability in a dose-and time-dependent manner. FITC-Annexin V/propidium iodide staining and flow cytometry demonstrated that the apoptotic ratio increased and the cell cycle was arrested at the G2/M phase as the DADs concentration was increased. A Western blot analysis was employed to detect the levels of caspase-3, Bax, Bcl-2, LC3-II/LC3-I, and p62 as well as suppression of the mTOR pathway. High expression of LC3-II protein revealed that DADs induced formation of autophagosome. Furthermore, DADs-induced apoptosis was weakened after adding 3-methyladenine, demonstrating that the DADs treatment resulted in autophagy-mediated death of MG-63 cells. In addition, DADs depressed p-mTOR kinase activity, and the inhibited PI3K/Akt/mTOR pathway increased DADs-induced apoptosis and autophagy. In conclusion, our results reveal that DADs induced G2/M arrest, apoptosis, and autophagic death of human osteosarcoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway.

Garlic is a vegetable with numerous pro-health properties, showing high antioxidant capacity, and cytotoxicity for various malignant cells. The inhibition of cell proliferation by garlic is mainly attributed to the organosulfur compounds (OSCs), but it is far from obvious which constituents of garlic indeed participate in the antioxidant and cytotoxic action of garlic extracts. This study aimed to obtain insight into this question by examining the antioxidant activity and cytotoxicity of six OSCs and five phenolics present in garlic. Three common assays of antioxidant activity were employed (ABTS● decolorization, DPPH● decolorization, and FRAP). Cytotoxicity of both classes of compounds to PEO1 and SKOV-3 ovarian cancer cells, and MRC-5 fibroblasts was compared. Negligible antioxidant activities of the studied OSCs (alliin, allicin, S-allyl-D-cysteine, allyl sulfide, diallyl disulfide, and diallyl trisulfide) were observed, excluding the possibility of any significant contribution of these compounds to the total antioxidant capacity (TAC) of garlic extracts estimated by the commonly used reductive assays. Comparable cytotoxic activities of OSCs and phenolics (caffeic, p-coumaric, ferulic, gallic acids, and quercetin) indicate that both classes of compounds may contribute to the cytotoxic action of garlic.

Microbial volatile compounds (MVCs) significantly influence the growth of plants and phytopathogens. However, the practical application of MVCs at the field level is limited by the fact that the concentrations at which these compounds antagonize the pathogens are often toxic for the plants. In this study, we investigated the effect of dimethyl disulfide (DMDS), one of the MVCs produced by microorganisms, on the fitness of tomato plants and its fungicidal potential against a fungal phytopathogen, Sclerotinia minor . DMDS showed strong fungicidal and plant growth promoting activities with regard to the inhibition of mycelial growth, sclerotia formation, and germination, and reduction of disease symptoms in tomato plants infected with S. minor . DMDS exposure significantly upregulated the expression of genes related to growth and defense against the pathogen in tomato. Especially, the overexpression of PR1 and PR5 suggested the involvement of the salicylic acid pathway in the induction of systemic resistance. Several morphological and ultrastructural changes were observed in the cell membrane of S. minor and the expression of ergosterol biosynthesis gene was significantly downregulated, suggesting that DMDS damaged the membrane, thereby affecting the growth and pathogenicity of the fungus. In conclusion, the tripartite interaction studies among pathogenic fungus, DMDS, and tomato revealed that DMDS played roles in antagonizing pathogen as well as improving the growth and disease resistance of tomato. Our findings provide new insights into the potential of volatile DMDS as an effective tool against sclerotial rot disease.

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) have become a major global health burden, but the detailed pathogeneses of neurodegenerative diseases are still unknown, and current treatments are mainly aimed at controlling symptoms; there are no curative treatments for neurodegenerative diseases or treatments for the progressive cognitive, behavioral, and functional impairments that they cause. Studies have shown that some plant extracts with pungent flavor components have a certain neuroprotective effect in neurodegenerative diseases, and their mechanisms mainly involve inhibiting neuronal apoptosis, promoting neuronal regeneration, reducing mitochondrial degeneration, and reducing the production of oxides such as reactive oxygen species in cells, which are of great significance for exploring the treatment of neurodegenerative diseases. In this review, we searched the PubMed database for relevant literature collected in the past 15 years. Finally, we summarized the protective effects of pungent flavor components such as capsaicin, piperine, curcumin, cannabinoids, allicin, and nicotine on the nervous system, focusing on the molecular mechanisms and signaling pathways that they activate. In addition, we also compiled and summarized the laboratory experiments, preclinical experiments, and effects of various pungent flavor components in neurodegenerative diseases. The goal is to further explore their potential as effective drugs for the treatment of neurodegenerative diseases and provide new ideas for further research on the specific protective mechanisms of these substances for the treatment of neurodegenerative diseases and the targets of drug action in the future.