Search Results (219)

To explore the potential seed compounds from natural products as anticancer agents against small-cell lung cancer (SCLC), the underground parts of Agapanthus africanus, a plant commonly used for ornamental purposes, were investigated. Three spirostan-type steroidal glycosides (1–3) were isolated and identified by nuclear magnetic resonance spectral analysis. Compounds 1–3 exhibited cytotoxicity against SBC-3 human SCLC cells, with IC₅₀ values of 0.56, 1.4, and 7.4 µM, respectively. Compound 1, also known an agapanthussaponin A, demonstrated the most potent cytotoxicity among the isolated compounds and was evaluated for its apoptosis- and ferroptosis-inducing activities. Compound 1 arrested the cell cycle of SBC-3 cells in the G₂/M phase and induced apoptosis primarily via the mitochondrial pathway, characterized by caspases-3 and -9 activation, loss of mitochondrial membrane potential, and overproduction of reactive oxygen species. Additionally, 1 triggered ferroptosis via a dual mechanism consisting of enhanced cellular iron uptake through upregulation of transferrin and transferrin receptor 1 expression and impaired glutathione synthesis via downregulation of both xCT and glutathione peroxidase 4 expression. Compound 1 induces cell death via the apoptosis and ferroptosis pathways, suggesting its promise as a seed compound for the development of anticancer therapeutics against SCLC. Full article

Sitosterol (Sito) is a phytosterol with bioactive properties, including reducing atherosclerosis risk and anti-inflammatory and antitumoral effects. However, it can be oxidized by reactive oxygen species such as ozone (O₃), producing oxyphytosterols with harmful effects such as cytotoxicity, oxidative stress, and proatherogenicity. Ozone, a strong oxidant and common pollutant, can alter plant steroid compounds, raising concerns about dietary oxyphytosterol intake. Studies identify β-Secosterol (βSec) as the primary ozone-derived oxyphytosterol from Sito, exhibiting cytotoxic effects on HepG2 human liver tumor cells. This study investigated βSec’s biological effects on two rat liver cell lines: BRL-3A (immortalized) and HTC (tumoral), examining cell death, cell cycle progression, morphology, and cytoskeleton organization. While Sito influenced cell metabolic activity without affecting cell survival or morphology, βSec demonstrated significant cytotoxicity in both cell lines. It induced G0/G1 cell cycle arrest and disrupted cytoskeleton organization, with different implications: BRL-3A cells showed persistent cytoskeletal changes potentially linked to tumor induction, while HTC cells displayed chemoresistance, restoring cytoskeletal integrity and enhancing metastatic potential. These findings reveal βSec’s complex, context-dependent effects, suggesting it may promote tumor-like behavior in non-tumoral cells and resistance mechanisms in cancer cells, contributing to understanding oxyphytosterols’ implications for physiological and pathological conditions. Full article

Meloxicam (MLX), a member of the non-steroidal anti-inflammatory drugs (NSAIDs), is a preferential inhibitor of cyclooxygenase-2 (COX-2) responsible for the synthesis of pro-inflammatory prostaglandins. MLX, due to its inhibition of the COX-2 enzyme, which is overexpressed in many cancers, including melanoma, leading to rapid growth, angiogenesis, and metastasis, represents a potentially important compound with anticancer activity. This study aimed to investigate the potential anticancer activity of meloxicam against amelanotic C32 and melanotic COLO 829 melanoma cell lines. The objective was achieved by assessing cell metabolic activity using the WST-1 assay and analyzing mitochondrial potential, levels of reduced thiols, annexin, and caspases 3/7, 8, and 9 by imaging cytometry, as well as assessing reactive oxygen species (ROS) levels using the H₂DCFDA probe. The amelanotic melanoma C32 was more sensitive to MLX exposure, thus exhibiting antiproliferative effects, a disruption of redox homeostasis, a reduction in mitochondrial potential, and an induction of apoptosis. The results provide robust molecular evidence supporting the pharmacological effects of MLX, highlighting its potential as a valuable agent for in vivo melanoma treatment. Full article

Chlorella vulgaris, a unicellular microalga with broad industrial applications, is a valuable source of bioactive compounds, including proteins, pigments, and lipids. However, optimizing its growth and metabolite production remains a challenge. This study investigates the potential of angular 6/6/5/6-annelated pyrrolidine-2,3-diones—structurally complex small molecules resembling alkaloids and 13(14 → 8)abeo-steroids—as novel growth stimulants for C. vulgaris. A series of these compounds (20 structurally diverse derivatives, including 7 previously unreported ones) were synthesized and screened for their ability to enhance microalgal growth. Primary screening identified one compound as a promising candidate, significantly increasing algae cell concentration in microplate cultures. Subsequent validation in flask-scale experiments revealed that this candidate induced a 19% increase in protein content at 1 μmol/L, suggesting potential for protein enrichment in algal biomass. Stability studies of the candidate compound revealed its significant hydrolytic degradation in aqueous media. These findings highlight the potential of angular 6/6/5/6-annelated pyrrolidine-2,3-diones as modulators of microalgal metabolism, offering a new avenue for enhancing C. vulgaris biomass quality, particularly for protein-rich applications in the food and feed industries. Full article

Background/Objective: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity. Methods: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids. Results: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment. Conclusions: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment. Full article

An efficient protocol was developed for the microwave-mediated metallation of 5-(4-methoxycarbonylphenyl)-10,15,20-tris(pentafluorophenyl)porphyrin (P1) with bis(benzonitrile)platinum dichloride salt and subsequent 1,3-dipolar cycloaddition of the resulting PtP1 with an azomethine ylide to give two isomeric metallochlorins: PtC1 (main isomer) and PtC3. The methyl ester group of metalloporphyrin PtP1 and metallochlorin PtC1 was successfully hydrolysed in an alkaline medium to yield the corresponding derivatives PtP2 and PtC2 in moderate-to-good yields. As a proof of concept of the reactivity of the carboxy group in PtP2 and PtC2, these compounds were conjugated with a hydroxylated derivative of indomethacin, a known potent non-steroidal anti-inflammatory, obtaining the conjugates PtP2-Ind and PtC2-Ind. The obtained platinum(II) porphyrins and chlorins were characterized by UV-Vis, NMR spectroscopy and mass spectrometry. The structure of PtP1 was also confirmed by X-ray crystallography. Singlet oxygen generation studies were carried out, as well as theoretical calculations, which demonstrated that the prepared Pt(II) complexes can be considered potential photosensitizers for PDT. Full article

The efficacy of steroid pulse therapy for treating severe coronavirus disease (COVID-19) pneumonia remains unclear. This study aimed to determine the efficacy of steroid pulse therapy for severe COVID-19 pneumonia in patients who did not respond to conventional therapy, including steroids. We included 76 patients with severe COVID-19 pneumonia treated with steroids in this single-facility retrospective observational study. Severe COVID-19 pneumonia was defined as requiring high-concentration oxygen administration (oxygen mask with reservoir mask (RM) > 6 L/min), high-flow nasal cannula oxygen therapy, or ventilatory support for respiratory control. The patient characteristics at admission and changes in them over time were examined in (a) a survival vs. death group, and (b) a steroid pulse vs. non-steroid pulse therapy group. Steroid pulse therapy significantly improved the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen just after the therapy and after one week of therapy, but had no effect on the sequential organ failure assessment scores over time. Multivariate logistic regression analyses showed that remdesivir use was associated with better survival outcomes, while steroid pulse therapy was associated with poor outcomes. In conclusion, steroid pulse therapy did not improve the prognosis of patients with severe COVID-19 pneumonia any more effectively than conventional steroid therapy. Full article

Apricot bee pollen is an important natural product that exhibits antioxidant, anti-inflammatory, and antimicrobial properties. Deoxynivalenol (DON), one of the most prevalent mycotoxins produced by Fusarium fungi, poses risks to both human and animal reproductive systems. We observed that exposure to DON inhibited cell proliferation and induced apoptosis in bovine granulosa cells (bGCs), accompanied by a significant downregulation of PCNA expression and an upregulation of BAX expression. RNA sequencing analysis revealed that differentially expressed genes (DEGs) were primarily enriched in the oxidation-reduction process, oxidoreductase activity, and steroid biosynthesis. We further confirmed that DON exposure inhibited the production of estrogen and progesterone by decreasing the protein expression levels of CYP19A1 and StAR. Additionally, DON exposure increased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in a dose-dependent manner, suggesting that DON induced oxidative stress in bGCs. Importantly, we demonstrated that apricot bee pollen ethanol extract (ABPE) increased the cell viability of bGCs and alleviated the effects of DON-induced cell viability reduction and estrogen dysfunction. Furthermore, ABPE attenuated the DON-induced increase in ROS levels and upregulated the expression of antioxidant-related gene heme oxygenase-1 (HO-1). These results reveal the protective effects of ABPE against DON-induced cell viability reduction, estrogen disorder, and oxidative stress, providing new insights into the potential of bee pollen as a promising natural agent to improve mycotoxin contamination. Full article

Inflammation is a multifaceted biological response of the immune system against various harmful stimuli, including pathogens (such as bacteria and viruses), cellular damage, toxins, and natural/synthetic irritants. This protective mechanism is essential for eliminating the cause of injury, removing damaged cells, and initiating the repair process. While inflammation is a fundamental component of the body’s defense and healing process, its dysregulation can lead to pathological consequences, contributing to various acute and chronic diseases, such as autoimmune disorders, cancer, metabolic syndromes, cardiovascular diseases, neurodegenerative conditions, and other systemic complications. Generally, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), antihistamines, biologics, and colchicine are used as pharmacological agents in the management of inflammatory diseases. However, these conventional treatments often have limitations, including adverse side effects, long-term toxicity, and drug resistance. In contrast, enzyme-based therapeutics have emerged as a promising alternative due to their high specificity, catalytic efficiency, and ability to modulate inflammatory pathways with reduced side effects. These enzymes function by scavenging reactive oxygen species (ROS), inhibiting cytokine transcription, degrading circulating cytokines, and blocking cytokine release by targeting exocytosis-related receptors. Additionally, their role in tissue repair and regeneration further enhances their therapeutic potential. Most natural anti-inflammatory enzymes belong to the oxidoreductase class, including catalase and superoxide dismutase, as well as hydrolases such as trypsin, chymotrypsin, nattokinase, bromelain, papain, serratiopeptidase, collagenase, hyaluronidase, and lysozyme. Engineered enzymes, such as Tobacco Etch Virus (TEV) protease and botulinum neurotoxin type A (BoNT/A), have also demonstrated significant potential in targeted anti-inflammatory therapies. Recent advancements in enzyme engineering, nanotechnology-based enzyme delivery, and biopharmaceutical formulations have further expanded their applicability in treating inflammatory diseases. This review provides a comprehensive overview of both natural and engineered enzymes, along with their formulations, used as anti-inflammatory therapeutics. It highlights improvements in stability, efficacy, and specificity, as well as minimized immunogenicity, while discussing their mechanisms of action and clinical applications and potential future developments in enzyme-based biomedical therapeutics. Full article

Background: Accelerating recovery and preventing the progression to more severe outcomes for patients with coronavirus disease 2019 (COVID-19) is of paramount importance. Non-steroidal anti-inflammatory agents (NSAIDs) have been widely adopted in the international recommendations for non-severe COVID-19 management. Among NSAIDs, evidence about the efficacy of ketoprofen lysin salt (KLS) in the treatment of non-severe COVID-19 has not been reported. Methods: This retrospective study compared the outcomes of 120 patients with mild to moderate COVID-19 treated at home with KLS between March 2021 and May 2023 compared with the outcomes of 165 patients who received corticosteroids. The outcomes included hospitalization, the need for oxygen supplementation, clinical recovery from acute COVID-19, and time to negative swabs. Results: Symptoms persisted in a lower percentage of patients in the KLS group compared to the corticosteroids group (p < 0.0001) and for a shorter period (p = 0.046). We found 6 patients (5%) in the KLS group were hospitalized compared to 45 (27%) in the corticosteroids group (p < 0.001). A higher percentage of patients in the corticosteroids group require oxygen administration (p < 0.001). In addition, patients taking corticosteroids showed a longer viral shedding period compared to those taking KLS (p = 0.004). A final multivariate analysis suggests that KLS might reduce hospitalization risk, the need for oxygen supplementation, and the persistence of post-COVID-19 symptoms when compared to an oral corticosteroid after adjusting for significant co-variables. Conclusions: KLS might have a positive effect on clinical recovery in non-severe COVID-19 patients. A comparison with other NSAIDs in terms of difference in efficacy and safety should be investigated in further trials. Full article

The use of local anesthetics in dentistry is crucial for pain control. Their efficacy may be related to multiple factors, including gender, the clinical status of the patient, anatomical factors, the type of anesthetic, premedication treatment, and the experience of the professional. Aim: The objective of this study was to analyze whether premedication or the degree of patient anxiety influences the anesthetic efficacy of 4% articaine with epinephrine 1:100,000 and 0.5% bupivacaine with epinephrine 1:100,000 in patients undergoing root canal treatment for symptomatic irreversible pulpitis in the upper and lower molars. The null hypothesis (H0) of this study was that articaine and bupivacaine would have a similar anesthetic efficacy when used during the treatment of symptomatic irreversible pulpitis of the posterior mandibular and maxillary teeth, independent of non-steroidal anti-inflammatory drugs (NSAIDs) premedication or the patient’s anxiety levels. Methods: A total of 140 patients presenting with pulpitis in the upper and lower molars were randomly assigned to one of two anesthetics: articaine or bupivacaine. Before root canal treatment, patients completed the Modified Corah Dental Anxiety Scale (MDAS) and a Visual Analog Scale (VAS) for pain intensity. Inferior alveolar nerve block was performed for the lower molars and buccal infiltration for the upper molars, and the anesthetic efficacy was verified by the Endo Coldspray^® test. During the procedure, the patients’ heart rate and oxygen saturation were monitored using a pulse oximeter. The patients reported their pain levels using a VAS twenty-four hours postoperatively. Results: High levels of dental anxiety were significantly associated with higher pain scores (p = 0.000) for both groups. The hemodynamic changes during treatment remained within normal limits. The need for anesthetic reinforcement was higher in the bupivacaine group (p = 0.004). The patients in both groups reported low-intensity postoperative pain, although the pain level was slightly lower in the bupivacaine group. Conclusions: The anesthetic efficacy of articaine and bupivacaine in patients with irreversible pulpitis did not appear to be influenced by the degree of anxiety or the intake of AINEs as premedication. The intrinsic anesthetic efficacy was higher for articaine, which required less reinforcement than bupivacaine. Comparing the results obtained when performing buccal infiltration and inferior alveolar nerve block further highlighted the differences between the two anesthetics; these differences were more pronounced in the bupivacaine group, leading to rejection of the null hypothesis proposed at the beginning of the study. Full article

Background: Bronchiolitis accounts for a substantial number of pediatric hospitalizations and its epidemiology closely parallels that of respiratory syncytial virus (RSV), its principal etiological agent. International guidelines recommend supportive therapy based primarily on oxygen supplementation and hydration. Methods: This study aimed to assess, across three pediatric wards, the impact of internal monitoring and targeted educational interventions on adherence to bronchiolitis management guidelines. Focus was placed on evaluating the effectiveness of tailored strategies in enhancing the appropriateness of treatment practices. Each center independently developed an audit and feedback strategy aligned with local practices and available resources. In Center 1, monthly staff meetings included guideline refreshers throughout the epidemic season. Center 2 appointed two attending physicians to monitor treatment prescriptions and report deviations. Center 3 established an internal protocol through staff consensus, followed by monthly review sessions. In this retrospective analysis, all consecutive patients admitted with bronchiolitis during the winter seasons of 2022–2023 and 2023–2024 (Period 2) were compared with those admitted in 2021–2022 (Period 1). Results: A total of 623 infants under 24 months of age were included, 451 (72%) of whom tested positive for RSV. Their median length of hospital stay was 6 days; 26 infants (4%) required intensive care, and no deaths were recorded. A comparative analysis of the treatment modalities used—high-flow nasal cannula (HFNC) oxygen therapy, inhaled medications, corticosteroids, and antibiotics—revealed a reduced use of non-recommended therapies (e.g., nebulized β2-agonists, steroids, and antibiotics) in Period 2, alongside heterogeneous patterns in HFNC use. Center-specific strategies, tailored to team dynamics and resource availability, effectively promoted greater adherence to evidence-based guidelines. Conclusions: Our findings suggest that structured internal interventions can lead to more appropriate bronchiolitis management and the improved standardization of care. Full article

Sudden sensorineural hearing loss (SSHNL) is an abruptly appearing hearing loss. The etiology remains unclear, although vascular pathologies, viral infections, or autoimmune disease contribute to the understanding of this pathology. Systematic steroids are often used as the first-line treatment because of their anti-inflammatory effect. However, there remains controversy about the use of steroids and other alternative treatments, as hyperbaric oxygen therapy (HBOT), exploratory tympanotomy, prostaglandin, N-acetylcysteine, or defibrinogenation therapy. In this study, we aim to review the various treatment options currently available for sudden hearing loss, with the objective of advancing our understanding of this condition and clarifying information to guide future clinical practice guidelines. Full article

Background/Objectives: Sepsis continues to be a significant global health issue, with current treatments primarily focused on antibiotics, fluid resuscitation, vasopressors, or steroids. Recent studies have started to explore mitochondrial transplantation as a potential treatment for sepsis. This study aims to evaluate the effects of enhanced mitochondrial transplantation on sepsis. Methods: We examined various mitochondrial-targeting drugs (formoterol, metformin, CoQ10, pioglitazone, fenofibrate, and elamipretide) to improve mitochondrial function prior to transplantation. Mitochondrial function was assessed by measuring the oxygen consumption rate (OCR) and analyzing the expression of genes related to mitochondrial biogenesis. Additionally, the effects of enhanced mitochondrial transplantation on inflammation were investigated using an in vitro sepsis model with THP-1 cells. Results: Formoterol significantly increased mitochondrial biogenesis, as evidenced by enhanced oxygen consumption rates and the upregulation of mitochondrial-associated genes, including those related to biogenesis (PGC-1α: 1.56-fold, p < 0.01) and electron transport (mt-Nd6: 1.13-fold, p = 0.16; mt-Cytb: 1.57-fold, p < 0.001; and mt-Co2: 1.44-fold, p < 0.05). Furthermore, formoterol-enhanced mitochondrial transplantation demonstrated a substantial reduction in TNF-α levels in LPS-induced hyperinflammatory THP-1 cells (untreated: 915.91 ± 12.03 vs. formoterol-treated: 529.29 ± 78.23 pg/mL, p < 0.05), suggesting its potential to modulate immune responses. Conclusions: Mitochondrial transplantation using drug-enhancing mitochondrial function might be a promising strategy in sepsis. Full article

HIV-associated neurocognitive disorders are prevalent despite antiretroviral intervention. Some HIV virotoxins, such as the trans-activator of transcription (Tat), are not targeted by antiretrovirals, and their neurotoxic actions may be exacerbated by opioids. Both Tat and morphine disrupt mitochondrial function, which may promote neurotoxicity, but the mechanisms are poorly understood. Herein, we assess the capacity of HIV Tat and morphine to alter the fundamental ability of mitochondria to generate and transfer energy along the electron transport chain (ETC). We find that exposure to Tat inhibits mitochondrial respiration driven by ETC complexes I or II in a concentration-dependent manner. Findings were consistent across models of permeabilized neuroblastoma cells, murine-derived mitoplasts, and mitochondria derived from mice exposed to Tat in vivo. In cell culture models, Tat promoted Ca²⁺ influx and the generation of cytosolic reactive oxygen species (ROS). Acute exposure to morphine exerted no effect on mitochondrial respiration, but morphine modestly offset Tat-mediated effects on complex I and some effects for the generation of ROS. Morphine did not exert any protective effects when acutely administered in vivo. The mitoprotective steroid, allopregnanolone (AlloP), increased mitochondrial respiration in neuroblastoma cells (complex I) or mitoplasts (complex II) and attenuated Tat-mediated impairment of complexes I and II in neuroblastoma cells or mice exposed to Tat in vivo. AlloP further attenuated Tat-mediated intracellular Ca²⁺ influx and cytosolic ROS production. Taken together, these results suggest that HIV Tat compromises mitochondrial function through the impairment of respiratory complexes I and II and that physiological AlloP may exert protective effects. Full article