Antioxidant potentials of extracts from different parts of Clinacanthus nutans (Burm. f.) Lindau.

The research aimed to explore the antioxidant potential of extracts from different parts of Clinacanthus nutans growing in Vietnam, a member of the Acanthaceae family. The plant's roots, stem and leaves were extracted using 96% ethanol. The antioxidant actions of these extracts were evaluated by DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay on thin-layer plates and 96 well plates. The extract with the most potent activity was applied for distribution extraction with solvents with different polarities, including dichloromethane, ethyl acetate and water. Dry column vacuum chromatography was utilized to obtain the most antioxidant-potent extract fractions. The stem extract had the lowest IC50 value of 6.85µg/mL, showing the most potent antioxidant activity. The ethyl acetate fraction from the stem extract expressed the lowest IC50 value of 9.67µg/mL. Meanwhile, fraction 5, separated from the ethyl acetate fraction of the stem extract, had the lowest IC50 value of 9.89µg/mL. In conclusion, the extracts from different parts of Clinacanthus nutans all expressed antioxidant action at different levels, in which the stem extract, the ethyl acetate fraction and fraction 5 from the ethyl acetate fraction displayed the most effective actions. These findings highlight the promising potential of Clinacanthus nutans in treating oxidative stress-associated diseases, inspiring further research and exploration in this area.

The concentration of maternal sacubitril/valsartan transferred into human milk is negligible.

Background: Peripartum cardiomyopathy (PPCM) is a common cause of heart failure (HF) in the peripartum. Some medications are considered safe while breastfeeding. However, sacubitril/valsartan (Entresto), while efficacious, is not recommended in breastfeeding women due to concerns about adverse infant development, and no published data suggest otherwise. Objectives: This study aimed to assess the transfer of sacubitril/valsartan into human milk and evaluate the infant's risk of drug exposure. Methods: The InfantRisk Human Milk Biorepository released samples and corresponding health information from five breastfeeding maternal-infant dyads exposed to sacubitril/valsartan. Sacubitril, valsartan, and LBQ657 (sacubitril active metabolite) concentrations were determined using liquid chromatography-mass spectrometry (LC/MS/MS) from timed samples 0, 1, 2, 4, 6, 8, 10, and 12 h following medication administration at steady state conditions. Results: Valsartan levels were below the detection limit of 0.19 ng/mL in all milk samples. Sacubitril was measurable in all milk samples of the five participants, peaking 1 h after drug administration at a mean concentration of 1.52 ng/mL for a total infant dose of 0.00049 mg/kg/12 h and a relative infant dose (RID) calculated at 0.01%. The maximum concentration of its active metabolite LBQ657 in the milk samples was observed 4 h after medication administration and declined over the remaining 12-h dosing interval, for an average concentration of 9.5 ng/mL. The total infant dose was 0.00071 mg/kg/12 h, and the RID was 0.22%. Two mothers reported continuing to breastfeed while taking sacubitril/valsartan; both mothers stated observing no negative effects in their breastfed infants. Conclusion: The transfer of sacubitril/valsartan into human milk is minimal. These concentrations are unlikely to pose a significant risk to breastfeeding infants, with a combined calculated RID of <0.25%, which is far lower than the industry safety standards (RID <10%).

Solid dispersion systems for enhanced dissolution of poorly water-soluble candesartan cilexetil: In vitro evaluation and simulated pharmacokinetics studies.

BACKGROUND: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study. METHODS: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies. RESULTS: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C. CONCLUSION: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC.

Screening and separation of natural anticancer active ingredients related to phospholipase C.

Based on the specific binding of drug molecules to cell membrane receptors, a screening and separation method for active compounds of natural products was established by combining phospholipase C (PLC) sensitized hollow fiber microscreening by a solvent seal with high-performance liquid chromatography technology. In the process, the factors affecting the screening were optimized. Under the optimal screening conditions, we screened honokiol (HK), magnolol (MG), negative control drug carbamazepine, and positive control drug amentoflavone, the repeatability of the method was tested. The PLC activity was determined before and after the screening. Experimental results showed that the sensitization factors of PLC of HK and MG were 61.0 and 48.5, respectively, and amentoflavone was 15.0, carbamazepine could not bind to PLC. Moreover, the molecular docking results were consistent with this measurement, indicating that HK and MG could be combined with PLC, and they were potential interacting components with PLC. This method used organic solvent to seal the PLC greatly ensuring the activity, so this method had the advantage of integrating separation, and purification with screening, it not only exhibited good reproducibility and high sensitivity but was also suitable for screening the active components in natural products by various targets in vitro.

Sacubitril-valsartan vs ACE/ARB in pediatric heart failure: A retrospective cohort study.

BACKGROUND: The first angiotensin receptor/neprilysin inhibitor on the market, sacubitril-valsartan, has shown marked improvements in death and hospitalization for heart failure among adults, and is now approved for use in pediatric heart failure. While the ongoing PANORAMA-HF trial is evaluating the effectiveness of sacubitril-valsartan for pediatric patients with a failing systemic left ventricle, the enrollment criteria do not include the majority of pediatric heart failure patients. Additional studies are needed. METHODS: Using the TriNetX database, we performed a propensity score matched, retrospective cohort study to assess the incidence of a composite of all-cause mortality or heart transplant within 1 year. The 519 patients who received sacubitril-valsartan were compared to 519 matched controls who received an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB). RESULTS: There was no significant difference in the incidence of the composite outcome with sacubitril-valsartan over an ACE/ARB (13.3% vs 13.2%, p = 0.95), or among the components of mortality (5.0% vs 5.8%, p = 0.58) or heart transplantation (8.7% vs 7.5%, p = 0.50). Patients who were receiving full goal-directed medical therapy (14.4% vs 16.0%, p = 0.55) also showed no difference in the composite outcome. We observed a significantly increased incidence of hypotension (10% vs 5.2%, p = 0.006) and a trend toward reduced number of hospitalizations per year (mean (SD) 1.3 (4.4) vs 2.0 (9.1), p = 0.09). CONCLUSIONS: Sacubitril-valsartan is not associated with a decrease in the composite of all-cause mortality or heart transplantation within 1 year. Future studies should evaluate the possible reduction in hospitalizations and optimal dosing to minimize hypotension.

Effect of employing different extraction techniques and solvents on the total phenolic content and antioxidant properties of an Iranian endemic species Zeravschania khorasanica (Apiaceae).

Zeravschania khorasanica, a species endemic to the eastern part of Iran, possesses distinct characteristics that distinguish it from its two closely related species. This research employed five different extraction techniques to identify the active components, total phenolic content and in vitro antioxidant activity of the extract. Furthermore, hydro-distillation was utilized for GC/MS analysis to determine the composition of the essential oil. The total phenolic content was estimated using the Folin-Ciocalteu assay and the antioxidant capacity was evaluated using the DPPH radical scavenging test. The findings revealed that ethanolic Soxhlet extraction yielded the highest efficiency in extracting total phenolic content (88.19 ±1.99 gallic acid mg/100g). In contrast, water maceration extraction demonstrated the highest antioxidant activity (68.1 ±5.4%). Interestingly, the study uncovered that there is no significant positive correlation between the phenolic content and the antioxidant activity of the plant. Additionally, HPLC analysis identified three phenolic constituents in the extract. The Soxhlet extraction method yielded the highest levels of chlorogenic acid (5.8 ppm), caffeic acid (4.1 ppm) and salicylic acid (10.3 ppm). As per the GC/MS analysis, a total of eleven compounds were identified. The predominant compounds were elemicin at 58.19% and trans--bergamotene at 25.78%.

Evaluating the impact of Sacubitril/valsartan on diastolic function in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: Heart failure is a common and severe condition, often complicated by diastolic dysfunction. Current standard therapies such as ACEIs and ARBs have limited efficacy in managing diastolic function. Sacubitril/Valsartan, an emerging therapy, warrants rigorous investigation to elucidate its impact on diastolic function in heart failure patients. METHODS: This systematic review and meta-analysis were conducted adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and utilized the PICO schema. Searches were performed on 4 databases-PubMed, Embase, Web of Science, and Cochrane Library-without temporal restrictions. Inclusion and exclusion criteria were strictly defined, and quality assessments were conducted using the Cochrane Collaboration Risk of Bias tool. Both fixed-effects and random-effects models were used for statistical analysis, depending on inter-study heterogeneity assessed by I2 statistics and Chi-square tests. RESULTS: Out of 1129 identified publications, 8 studies met the criteria and were included in the meta-analysis. These studies consisted of both randomized controlled trials and cohort studies and featured diverse global populations. Significant reductions were found in the echocardiographic parameter E/e' ratio and LAVi upon treatment with Sacubitril/Valsartan compared to standard therapies, with mean differences of -1.38 and -4.62, respectively, both with P values < .01. CONCLUSIONS: This meta-analysis demonstrates that Sacubitril/Valsartan significantly improves diastolic function parameters in heart failure patients compared to standard treatments. These findings underscore the potential benefits of Sacubitril/Valsartan in the management of heart failure, particularly for patients with diastolic dysfunction.

Fast and safe clinical response to sonidegib in a 98-year old woman affected by locally advanced basal cell carcinoma.

A 98-year-old woman presented with histologically confirmed locally advanced basal cell carcinoma of the face. A multidisciplinary approach excluded surgery because of the site near sensitive organs, extension, age, and comorbidities. Patient and caregivers declined radiotherapy considering the necessity of multiple hospital appointments. The patient was then placed on therapy with sonidegib, an oral inhibitor of the Hedgehog signaling pathway. There was a very rapid clinical response after only 28 days of treatment. The basal cell carcinoma improved progressively, with no adverse events reported. This case illustrates the efficacy and safety of this treatment in an advanced age patient. This treatment had a remarkably positive impact on quality of life, including that of the caregivers.

Drug development blossoms for rare, fatal bone disease.

Five drugs are now approved or in trials for genetic condition that triggers misplaced bone growth.

Sacubitril/valsartan ameliorates cardiac function and ventricular remodeling in CHF rats via the inhibition of the tryptophan/kynurenine metabolism and inflammation.

Sacubitril/valsartan has been highly recognized as a treatment for Chronic heart failure (CHF). Its potential cardioprotective benefits and mechanisms, however, remain to be explored. Metabolomics can be used to identify the metabolic characteristics and related markers, as well as the influence of drugs, thereby opening up the new mechanism for sacubitril/valsartan therapy in CHF disease. In this study, the ligation of left anterior descending and exhaustive swimming were used to induce a rat model of CHF after myocardial infarction. The efficacy was appraised with echocardiography, serum NT-proBNP, and histopathologica. UPLC-Q/TOF-MS combined with multivariate statistical analysis approach were used to analyze the effect of sacubitril/valsartan on CHF rats. RT-qPCR and western blot were performed to investigate the tryptophan/kynurenine metabolism pathway. Accordingly, the basal cardiac function were increased, while the serum NT-proBNP and collagen volume fraction decreased in CHF rats with sacubitril/valsartan. Sacubitril/valsartan regulated the expression of kynurenine et.al 8 metabolomic biomarkers in CHF rats serum, and it contributed to the cardioprotective effects through tryptophan metabolism pathway. In addition, the mRNA and protein expression of the indoleamine 2,3-dioxygenase (IDO) in the myocardial tissue of CHF rats, were down-regulated by sacubitril/valsartan, which was the same with the IL-1ß, IFN-γ, TNF-α, COX-2, and IL-6 mRNA expression, and IL-1ß, IFN-γ, and TNF-α expression in serum. In conclusion, sacubitril/valsartan can ameliorate cardiac function and ventricular remodeling in CHF rats, at least in part through inhibition of tryptophan/kynurenine metabolism.

Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson's disease models.

BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

Identification of Novel Peptides in Distillers' Grains as Antioxidants, α-Glucosidase Inhibitors, and Insulin Sensitizers: In Silico and In Vitro Evaluation.

Distillers' grains are rich in protein and constitute a high-quality source of various bioactive peptides. The purpose of this study is to identify novel bioactive peptides with α-glucosidase inhibitory, antioxidant, and insulin resistance-ameliorating effects from distiller's grains protein hydrolysate. Three novel peptides (YPLPR, AFEPLR, and NDPF) showed good potential bioactivities, and the YPLPR peptide had the strongest bioactivities, whose IC50 values towards α-glucosidase inhibition, radical scavenging rates of 2,2'-azino-bis (3-ethylbenzothiazoline-6- sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) were about 5.31 mmol/L, 6.05 mmol/L, and 7.94 mmol/L, respectively. The glucose consumption of HepG2 cells treated with YPLPR increased significantly under insulin resistance condition. Moreover, the YPLPR peptide also had a good scavenging effect on intracellular reactive oxygen species (ROS) induced by H2O2 (the relative contents: 102.35% vs. 100%). Molecular docking results showed that these peptides could stably combine with α-glucosidase, ABTS, and DPPH free radicals, as well as related targets of the insulin signaling pathway through hydrogen bonding and van der Waals forces. This research presents a potentially valuable natural resource for reducing oxidative stress damage and regulating blood glucose in diabetes, thereby increasing the usage of distillers' grains peptides and boosting their economic worth.

Mitigating gut microbial degradation of levodopa and enhancing brain dopamine: Implications in Parkinson's disease.

Parkinson's disease is managed using levodopa; however, as Parkinson's disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson's disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson's disease patients have varying levels of these bacteria. Thus, decreasing bacterial metabolism is a promising therapeutic approach to enhance the bioavailability of levodopa in the brain. In this work, we show that Mito-ortho-HNK, formed by modification of a naturally occurring molecule, honokiol, conjugated to a triphenylphosphonium moiety, mitigates the metabolism of levodopa-alone or combined with carbidopa-to dopamine. Mito-ortho-HNK suppresses the growth of E. faecalis, decreases dopamine levels in the gut, and increases dopamine levels in the brain. Mitigating the gut bacterial metabolism of levodopa as shown here could enhance its efficacy.

The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI.

Nonphytotoxic and pH-responsive ZnO-ZIF­8 loaded with honokiol as a "nanoweapon" effectively controls the soil-borne bacterial pathogen Ralstonia solanacearum.

The development of intelligently released and environmentally safe nanocarriers not only aligns with the sustainable agricultural strategy but also offers a potential solution for controlling severe soil-borne bacterial diseases. Herein, the core-shell structured nanocarrier loaded with honokiol bactericide (honokiol@ZnO-ZIF-8) was synthesized via a one-pot method for the targeted control of Ralstonia solanacearum, the causative agent of tobacco bacterial wilt disease. Results indicated that honokiol@ZnO-ZIF-8 nanoparticles induced bacterial cell membrane and DNA damage through the production of excessive reactive oxygen species (ROS), thereby reducing bacterial cell viability and ultimately leading to bacterial death. Additionally, the dissociation mechanism of the nanocarriers was elucidated for the first time through thermodynamic computational simulation. The nanocarriers dissociate primarily due to H+ attacking the N atom on imidazole, causing the rupture of the Zn-N bond under acidic conditions and at room temperature. Furthermore, honokiol@ZnO-ZIF-8 exhibited potent inhibitory effects against other prominent Solanaceae pathogenic bacteria (Pseudomonas syringae pv. tabaci), demonstrating its broad-spectrum antibacterial activity. Biosafety assessment results indicated that honokiol@ZnO-ZIF-8 exhibited non-phytotoxicity towards tobacco and tomato plants, with its predominant accumulation in the roots and no translocation to aboveground tissues within a short period. This study provides potential application value for the intelligent release of green pesticides. ENVIRONMENT IMPLICATION: The indiscriminate use of agrochemicals poses a significant threat to environmental, ecological security, and sustainable development. Slow-release pesticides offer a green and durable strategy for crop disease control. In this study, we developed a non-phytotoxic and pH-responsive honokiol@ZnO-ZIF-8 nano-bactericide based on the pathogenesis of Ralstonia solanacearum. Thermodynamic simulation revealed the dissociation mechanism of ZIF-8, with different acidity controlling the dissociation rate. This provides a theoretical basis for on-demand pesticide release while reducing residue in the. Our findings provide strong evidence for effective soil-borne bacterial disease control and on-demand pesticide release.

Honokiol and magnolol: A review of structure-activity relationships of their derivatives.

Honokiol (HK) and magnolol (MAG) are typical representatives of neolignans possessing a wide range of biological activities and are employed as traditional medicines in Asia. In the past few decades, HK and MAG have been proven to be promising chemical scaffolds for the development of novel neolignan drugs. This review focuses on recent advances in the medicinal chemistry of HK and MAG derivatives, especially their structure-activity relationships. In addition, it also presents a comprehensive summary of the pharmacology, biosynthetic pathways, and metabolic characteristics of HK and MAG. This review can provide pharmaceutical chemists deeper insights into medicinal research on HK and MAG, and a reference for the rational design of HK and MAG derivatives.

Extraction of Antioxidants from Brown Macroalgae Fucus spiralis.

In this study, different extraction methods and conditions were used for the extraction of antioxidants from brown macroalgae Fucus spiralis. The extraction methodologies used were ultrasound-assisted extraction (ultrasonic bath and ultrasonic probe), extraction with a vortex, extraction with an Ultra-Turrax® homogenizer, and high-pressure-assisted extraction. The extracts were analyzed for their total phenolic content (TPC) and their antioxidant activity, and evaluated through the 2,2-difenil-1-picrilhidrazil (DPPH) free radical scavenging method and ferric reducing antioxidant power (FRAP) assay. Ultrasonic probe-assisted extraction yielded the highest values of TPC (94.78-474.16 mg gallic acid equivalents/g extract). Regarding the antioxidant activity, vortex-assisted extraction gave the best DPPH results (IC50 1.89-16 µg/mL), while the highest FRAP results were obtained using the Ultra-Turrax® homogenizer (502.16-1188.81 µmol ascorbic acid equivalents/g extract). For each extraction method, response surface methodology was used to analyze the influence of the experimental conditions "extraction time" (t), "biomass/solvent ratio" (R), "solvent" (S, water % in water/ethanol mixture), and "pressure" (P) on TPC, DPPH, and FRAP of the F. spiralis extracts. In general, higher TPC content and higher antioxidant capacity (lower IC50 and higher FRAP) were obtained with higher R, t, and P, and lower S (higher ethanol %). The model regarding the combined effects of independent variables t, R, and S on the FRAP response values for vortex-assisted extractions best fitted the experimental data (R2 0.957), with optimal extraction conditions of t = 300 s, R = 50 g, and S = 25%.

Discovery of novel biphenyl derivatives as androgen receptor degraders for the treatment of enzalutamide-resistant prostate cancer.

Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.

Bicyclol mitigates lipopolysaccharide-induced acute lung injury through myeloid differentiation factor 88 inhibition.

Acute lung injury (ALI) remains a significant clinical challenge due to the absence of effective treatment alternatives. This study presents a new method that employs a screening platform focusing on MyD88 affinity, anti-inflammatory properties, and toxicity. This platform was used to evaluate a 300-compound library known for its anti-inflammatory potential. Among the screened compounds, Bicyclol emerged as a standout, exhibiting MyD88 binding and a significant reduction in LPS-stimulated pro-inflammatory factors production in mouse primary peritoneal macrophages. By targeting MyD88, Bicyclol disrupts the MyD88/TLR4 complex and MyD88 polymer formation, thereby mitigating the MAPKs and NF-κB signaling pathways. In vivo experiments further confirmed Bicyclol's efficacy, demonstrating alleviated ALI symptoms, decreased inflammatory cytokines level, and reduced inflammatory cells presence in lung tissues. These findings were associated with a decrease in mortality in LPS-challenged mice. Overall, Bicyclol represents a promising treatment option for ALI by specifically targeting MyD88 and limiting inflammatory responses.

Semisynthesis and biological evaluation of novel honokiol thioethers against colon cancer cells HCT116 via inhibiting the transcription and expression of YAP protein.

Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC50 value of 6.1 µmol/L, superior to the reference drug 5-fluorouracil (IC50: 9.63 ± 0.27 µmol/L). The structure-activity relationships (SARs) indicated that the introduction of -(4-NO2)Ph, 3-pyridyl, -(2-F)Ph, -(4-F)Ph, -(3-F)Ph, -(4-Cl)Ph, and -(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates.