Potent Effects Research Articles

UPLC-MS/MS-based metabolomics combined to chemometrics reveal the anti-inflammatory metabolites of African Marigold (Tagetes erecta L.) flowers

African Marigold (Tagetes erecta L.) is widely recognized for its ornamental value and therapeutic properties, particularly its anti-inflammatory potential. This study employs UPLC-MS/MS-based metabolomics combined with chemometric analysis to identify bioactive metabolites contributing to the anti-inflammatory effects of T. erecta flowers. The flowers were fractionated using hexane, methylene chloride, ethyl acetate, and butanol, and a total of 79 metabolites were identified across the fractions, including flavonoids, phenolic acids, tannins, quinic acids, terpenoids, alkaloids, and amino acids. The anti-inflammatory efficacy of each fraction was assessed in vitro by evaluating their impact on the expression of four pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and IFN-γ) in LPS-stimulated leukocytes using PCR. Orthogonal Projections to Latent Structures was employed to determine the key metabolites contributing to the observed bioactivity. The analysis revealed that the methylene chloride and ethyl acetate fractions exhibited the most potent anti-inflammatory effects, primarily due to the presence of flavonoids and phenolic acids. Notably, disyringic acid hexoside, ellagic acid, gallic acid, p-coumaric acid, and quercetagetin dimethyl ether were identified as major anti-inflammatory agents based on their high correlation coefficients with cytokine inhibition and their substantial concentrations within the active fractions. These findings underscore the importance of selecting appropriate extraction solvents to isolate specific bioactive compounds and provide a deeper understanding of the metabolite profiles that contribute to the anti-inflammatory properties of T. erecta flowers.

Synthesis of new 1,4-benzodioxin derivatives containing thiazolidin-4-one skeleton, molecular modelling and docking as antibacterial agents

In this study, we synthesized a variety of 1,4-benzodioxin derivatives containing the thiazolidin-4-one skeleton and evaluated their antimicrobial properties. Several of the newly synthesized compounds exhibited potent inhibitory effects against the Gram-negative bacteria Escherichia coli. By conducting molecular docking simulations and molecular dynamics with the fatty acid synthesis enzyme FabH, we unveiled the potential antimicrobial activity of these compounds, suggesting they interfered with fatty acid biosynthesis pathways. Additionally, we optimized compound 3b and assessed its ability to disrupt biofilms using live/dead cell staining techniques. The results highlighted significant biofilm disruption, enhancing the compounds' antimicrobial efficacy. These findings provided valuable insights for the development of novel antimicrobial agents and presented a promising avenue for addressing antimicrobial resistance through innovative therapeutic approaches.

Paeoniflorin mitigates insulin-like growth factor 1-induced lipogenesis and inflammation in human sebocytes by inhibiting the PI3K/Akt/FoxO1 and JAK2/STAT3 signaling pathways.

Insulin-like growth factor-1 (IGF-1) is considered as a pathogenic factor contributing to sebaceous gland dysfunction, which leads to acne vulgaris. Paeoniflorin (Pae), a bioactive monomer derived from total glycosides of paeony, has shown potential in treating various diseases. However, its anti-acne effects on human sebocytes are not well understood. In this study, we investigated the effects of Pae on acne development induced by IGF-1 in SZ95 sebocytes. Following IGF-1 stimulation, SZ95 sebocytes were exposed to Pae and then determined for proliferation, cell cycle, apoptosis, lipogenesis and pro-inflammatory cytokine secretion. We also analyzed the expression of proteins involved in the PI3K/Akt/FoxO1 and JAK2/STAT3 pathways. In vitro experiments demonstrated that Pae significantly inhibited colony formation, induced G1/S cell cycle arrest, promoted apoptosis, inhibited lipogenesis and cytokine synthesis in IGF-1-treated SZ95 sebocytes. Furthermore, Pae suppressed the phosphorylation of Akt, FoxO1, JAK2, and STAT3. Importantly, the sebo-suppressive and anti-inflammatory effects of Pae were enhanced by blocking PI3K and JAK2. In summary, our findings suggest that Pae has potent anti-proliferative and pro-apoptotic effects in SZ95 sebocytes. Additionally, Pae effectively protects against IGF-1-induced lipogenesis and inflammation by targeting the PI3K/Akt/FoxO1 and JAK2/STAT3 signaling pathways.

Discovery of E0199: A novel compound targeting both peripheral NaV and KV7 channels to alleviate neuropathic pain

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both NaV1.7, NaV1.8, and NaV1.9 and KV7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited NaV1.7, NaV1.8, and NaV1.9 channels with a particularly low half maximal inhibitory concentration (IC50) for NaV1.9 by promoting sodium channel inactivation, and also effectively increased KV7.2/7.3, KV7.2, and KV7.5 channels, excluding KV7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent anti-tumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

Efficacy of Adding Sitagliptin to Ongoing Metformin on Metabolic Profile, Triglyceride-Glucose Index, Vitamin D3, and Liver Tests in Patients Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease: A Double-Blind Randomized Clinical Trial

IntroductionDipeptidyl peptidase-4 inhibitors (DPP-4i) provide potent anti-diabetic effects in patients with type 2 diabetes mellitus (T2DM), but their role in the presence of nonalcoholic fatty liver disease (NAFLD) is not well-known. The aim of this clinical trial was to evaluate the effects of sitagliptin on the metabolic profile and liver tests in metformin-treated T2DM patients with NAFLD. Patients-MethodsThis was a prospective, 12-week, single-center, comparative randomized clinical trial (RCT) enrolling 66 adult T2DM patients with NAFLD (diagnosed by ultrasound). Patients were randomly assigned to either metformin (2000 mg/day, n=33) or sitagliptin + metformin (100 and 2000 mg/day, respectively, n=33), administered orally. Certain metabolic parameters, i.e., fasting blood sugar (FBS), hemoglobin A1c (Hb1A1c), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), vitamin D3 (vitD3), alkaline phosphatase (ALP), alanine aminotransferase (SGPT) and aspartate aminotransferase (SGOT) were measured at baseline and after 12 weeks. Triglyceride-glucose (TG-G) index was also calculated. ResultsAll biochemical variables decreased by a greater extent in the sitagliptin+metformin group compared with the metformin group with differences in FBS (p=0.030), TC (p=0.017), TG (p=0.008), SGPT (p=0.018) and vitD3 (p=0.001) reaching statistical significance. Furthermore, the mean reduction of the TG-G index was significantly greater in the sitagliptin+metformin vs. metformin group (0.67 vs. 0.21, respectively; p=0.017). ConclusionSitagliptin+metformin therapy led to significantly greater improvements in FBS, TC, TG, SGPT, vitD3 and TG-G compared with the metformin monotherapy group. Other biomarkers also decreased more in the sitagliptin+metformin vs. metformin group, but these differences did not reach statistical significance. The present findings should be interpreted with caution but there are indicating certain metabolic benefits after sitagliptin addition in metformin-treated T2DM patients with NAFLD. Further studies are required to elucidate these effects and provide strong evidence for safe conclusions.

Phenolic Bisabolane Sesquiterpene Derivatives from an Arctic Marine-derived Fungus Aspergillus sydowii MNP-2

Background:: Filamentous fungi in the genus Aspergillus are well known for their important roles in production of bioactive secondary metabolites with diversely chemical structures and potential application in pharmaceutical industry. Objective:: The present study aimed to investigate the phenolic bisabolane sesquiterpene (PBS) derivatives from an Arctic marine-derived fungus Aspergillus sydowii MNP-2. Methods:: In this study, antimicrobial activities were carried out according to the broth microdilution assay, nitric oxide (NO) production in mouse macrophages (RAW264.7) and BV2 microglial cells was used to detect the inhibitory effect of compounds in inflammatory reactions, and in vitro inhibitory cell proliferation activity was determined by the cell counting kit-8 (CCK-8) assay. Results:: In this work, chemical investigation of an Arctic marine-derived strain A. sydowii MNP-2 led to the isolation of 11 PBSs (1-11) using various chromatographic methods. Their chemical structures were unambiguously determined by 1H NMR spectroscopy and mass spectrometry analyses as well as comparison with literature data. It is noteworthy that compounds 1, 7 and 11 were firstly obtained from A. sydowii. Antimicrobial assay showed that these chemicals had no potent inhibitory effect on Staphylococcus aureus, Escherichia coli, and Candida albicans with MIC values > 16 μg/mL. Additionally, the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)- induced inflammation in mouse macrophages (RAW264.7) and BV2 microglial cells were all below 10% for compounds 4-6 and 8, indicating almost negligible anti-inflammatory efficacy. Among the tested compounds 4-6 and 8 for tumor-cell proliferation inhibition activities, compound 5 demonstrated the strongest inhibitory effect against human acute promyelocytic leukemia cells (HL-6) with a 44.76% inhibition rate. Conclusion:: In the present study, 11 PBS derivatives were purified and characterized from the solidand liquid-state fermentations of the Arctic marine-derived fungus A. sydowii MNP-2. Unfortunately, none of these metabolites had significant antimicrobial, anti-inflammatory, or tumor-cell proliferation inhibition activities.

Exploring of Chemical Profile and Biological Activities of Three Ocimum Species From Comoros Islands: A Combination of In Vitro and In Silico Insights.

Ocimum species have a great interest in different traditional medicinal systems. This study examined the chemical composition, antioxidant properties, enzyme inhibitory effects, and antibacterial and antifungal activities of the aerial parts of Ocimum gratissimum, Ocimum americanum, and Ocimum basilicum from the Comoros Islands. The extracts were analyzed using high-performance liquid chromatography-mass spectrometry (HPLC-MS) to determine their chemical composition. Antioxidant activity was assessed using 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), chelating ability, and phosphomolybdenum radical scavenging assays. Enzyme inhibitory activities against acetylcholinesterase (AChE), butrylcholinesterase (BChE), tyrosinase, amylase, and glucosidase were evaluated using spectrophotometric methods. Antibacterial and antifungal activities were tested using the broth microdilution method against selected pathogenic microorganisms. The selected enzymes and proteins were evaluated using in silico methods with biomolecules from these plants. In addition, 111 different metabolites were identified in the tested extracts using advanced HPLC/MS techniques. The most significant number of detected compounds were derivatives of hydroxycinnamic acids, followed by flavonoid glycosides and aglycones and derivatives of hydroxybenzoic acids. All three Ocimum species exhibited significant antioxidant activities, O. gratissimum exhibited the best-reducing abilities in CUPRAC and FRAP assays. In addition, enzyme inhibitory assays revealed that O. americanum had the most potent inhibitory effect on tyrosinase (48.01 ± 3.89 mg kojic acid equivalent [KAE]/g), and amylase (1.08 ± 0.02 mmol acarbose equivalent [ACAE]/g). Antibacterial and antifungal tests demonstrated that the extracts possess broad-spectrum activity. Molecular docking results showed that compounds exhibited remarkable binding energies with target enzymes and proteins. The molecular dynamics simulations identified chicoric acid with MurE of Staphylococcus aureus complex as the most promising drug candidate. These findings support their traditional medical and nutraceutical uses and suggest possibilities for natural functional applications.

Chronic pregabalin treatment reduced anxiety, and acute pregabalin treatment increased depression-like behaviors in rats

BackgroundPregabalin is an antiepileptic drug that binds to the alpha-2/delta unit at presynaptic voltage-dependent calcium channels. We aimed to investigate the effect of acute and chronic pregabalin administration on anxiety and depression-like behaviors.MethodsFifty-six male Wistar albino rats were divided into seven groups: control, vehicle, and five different dose groups (5, 10, 30, 60, and 100 mg/kg). Pregabalin was administered for two weeks. Depression-like behaviors were evaluated by Forced swimming test. Anxiety-like behavior (ALB) was evaluated by Open field test (OFT), Elevated Plus Maze (EPM), and light-dark box. Subjects underwent the forced swimming test (FST) after the first dose, while the open field test (OFT), elevated plus maze (EPM), and light-dark box (LDB) were performed after two weeks of treatment. Further sucrose preference test was conducted to evaluate anhedonia until the end of the experiment.ResultsIn the forced swimming test, depression-like behaviors increased after acute single-dose administration of 10, 30, 60, 100 mg/kg pregabalin. According to OFT results, chronic 100 mg/kg pregabalin showed anxiolytic effects by decreasing grooming, and freezing behaviors. In addition, 100 mg/kg chronic pregabalin administration significantly increased the time spent in the central region, the number of entries to the center, and the unsupported rearing number without causing any change in locomotor activity. According to EPM results, both chronic 60 and 100 mg/kg pregabalin treatments showed anxiolytic effects by increasing open arm time and head dipping behavior. In addition, 60 and 100 mg/kg chronic pregabalin administration significantly decreased stretch attend posture. All pregabalin administrations between 5 and 100 mg/kg displayed anxiolytic effects in the LDB. Sucrose preference was above 65% for the duration of all experiments and subjects did not show anhedonia.ConclusionAcute pregabalin treatment triggered depression-like behaviors. Anhedonia, which may be associated with depression, was not observed during chronic treatment. Moreover, chronic treatment with pregabalin revealed potent anxiolytic effects in different behavior patterns and doses for all tests of unconditional anxiety. In particular, 100 mg/kg chronic pregabalin administration decreased anxiety-like behaviors in all experiment setups. Although the anxiolytic effect was demonstrated in chronic treatment, acute treatment of pregabalin induced depression-like behaviors, and thus in clinical practice should be done with caution, especially in patients with anxiety-depression comorbidity.

Triple-regulated conditionally replicating adenovirus for effective and safer treatment of peritoneal carcinomatosis

There is no effective therapy for peritoneal carcinomatosis derived from gastric cancer. An ideal conditionally replicating adenovirus (CRA) that selectively replicates in and kills cancer cells has not been developed for gastric cancer-derived peritoneal carcinomatosis. Using our platform technology of CRA regulated and treating tumors with multiple factors (m-CRA), we generated two types of survivin-responsive m-CRAs, Surv.m-CRA-CMVp and Surv.m-CRA-CEAp, consisting of E1A downstream of the survivin promoter, and the mutated E1B gene downstream of the human cytomegalovirus immediate early gene enhancer/promoter and carcinoembryonic antigen promoter, respectively. Survivin mRNA was expressed at high and undetectable levels in two gastric cancer cells and eleven normal cells, respectively. Carcinoembryonic antigen was expressed at high and very low levels in MKN-45 gastric cancer and normal PrEC cells, respectively, and was not detected in other cell types. While both Surv.m-CRA-CEAp and Surv.m-CRA-CMVp exhibited potent cytotoxic effects on MKN-45 cells in vitro, Surv.m-CRA-CEAp significantly reduced cytotoxicity to normal cells compared to Surv.m-CRA-CMVp. Control mice that received an intraperitoneal injection of MKN-45 cells gradually lost body weight and died of peritoneal carcinomatosis within 98 days. In contrast, all mice receiving Surv.m-CRA-CEAp or Surv.m-CRA-CMVp-infected MKN-45 cells increased their body weight and survived 120 days. In conclusion, the triple-regulated Surv.m-CRA-CEAp enhances cancer specificity (i.e., safety) without reducing the potent therapeutic effect for carcinoembryonic antigen-positive gastric cancer-derived peritoneal carcinomatosis. The modified E1B promoter strategy of CRA facilitates the development of novel CRAs for the effective and safe treatment of a variety of refractory cancers.

Unveiling Potent Anti-Asthmatic Effect of Curcumin in Combination with Salmeterol in Swiss Albino Mice

Background: Asthma is a long-term inflammatory respiratory condition marked by alterations in the airways and an increase in inflammatory cell infiltration. It has been observed that Curcumin possesses immune-modulating, anti-inflammatory, and relaxing properties for smooth muscle in the airways. Salmeterol is believed to ease the smooth muscles of the airways. Objective: Swiss Albino mice were used in the research to examine the combination anti-asthmatic effects of Curcumin and Salmeterol in asthma produced by ova albumin and milk induced eosinophilia and leucocytosis. Methods: The mice received pre-treatment with Curcumin (10 mg/kg, 20 mg/kg intraperitoneally) as well as Salmeterol (5 mg/kg) after being stimulated with an Ovalbumin (OVA) challenge and milk. After the induction period, various hematological, biochemical, molecular (ELISA), and histological analyses were performed. Results: The findings demonstrated that the combined treatment decreased the animal’s overall leukocyte and eosinophil numbers in a manner that was dose-dependent. Additionally, the therapy reduced albumin and overall protein amount in serum, BALF and lung tissues, facilitated changes in haematological parameters, and reduced the rise of Th2 cytokines (IL-4, TNF-α, IL-13) levels that is induced by OVA in lungs and BALF, total IgE level in serum. The combined action of Curcumin and Salmeterol reduced OVA-induced inflammatory influx and ultrastructural abnormalities, according to histopathological evaluation. Conclusion: The findings of this investigation demonstrate that curcumin and salmeterol together possess anti-asthmatic effects through suppressing Th2 triggered immune response and possessing an anti-inflammatory effect and anti-allergic effect. Thus combination of treatments might be a novel technique for managing asthma.

Interactions of novel 1,3-diaryltriazene-sulfamethazines with carbonic anhydrases: Kinetic studies and in silico simulations

Sulfonamides, recognized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, are crucial in treating diverse diseases, including epilepsy, glaucoma, bacterial infections, and various pathological processes, e.g., high blood pressure, rheumatoid arthritis, ulcerative colitis, pain, and inflammation. Additionally, therapeutically, 1,3-diaryl-substituted triazenes and sulphamethazines (SM) are integral components in various drug structures, and the synthesis of novel compounds within these two categories holds substantial significance. Herein, ten 1,3-diaryltriazene-substituted sulphamethazine derivatives SM(1-10), which were created by reacting the diazonium salt of sulphamethazine with substituted aromatic amines, were synthesized and the physiologically and pharmacologically relevant human (h) isoforms hCA I and II, cytosolic isozymes, were included in the study. The synthesized compounds showed excellent inhibition versus hCAs; the 4-butoxy (SM7, KI of 5.69 ± 0.59 nM) compound exhibited a potent inhibitory effect against the hCA I compared with the reference drug acetazolamide (AAZ, KI of 116.00 ± 8.48 nM). The 4-cyano (SM4, KI of 5.87 ± 0.57 nM) compound displayed higher potency than AAZ (KI of 57.25 ± 4.15 nM) towards hCA II. Meanwhile, among the synthesized molecules, the 3,4-dimethoxy (SM9, KI of 74.98 ± 10.49 nM, SI of 9.94) compound (over hCA I) displayed a noticeable selectivity for hCA isoform II. The target compounds in the molecular docking investigation were determined to take part in various hydrophilic and hydrophobic interactions with nearby amino acids and fit nicely into the active sites of the hCAs. This research has yielded compounds displaying varying affinity toward hCA isoenzymes, ultimately serving as potent and selective hCA inhibitors. Given its substantial biological inhibitory potency, this particular derivative series is determined to hold the potential to serve as a promising lead compound against these hCAs.

Reveal the potent antidepressant effects of Zhi-Zi-Hou-Pu Decoction based on integrated network pharmacology and DDI analysis by deep learning

Reveal the potent antidepressant effects of Zhi-Zi-Hou-Pu Decoction based on integrated network pharmacology and DDI analysis by deep learning

Potent Biological Activity of Fluorinated Derivatives of 2-Deoxy-d-Glucose in a Glioblastoma Model.

One defining feature of various aggressive cancers, including glioblastoma multiforme (GBM), is glycolysis upregulation, making its inhibition a promising therapeutic approach. One promising compound is 2-deoxy-d-glucose (2-DG), a d-glucose analog with high clinical potential due to its ability to inhibit glycolysis. Upon uptake, 2-DG is phosphorylated by hexokinase to 2-DG-6-phosphate, which inhibits hexokinase and downstream glycolytic enzymes. Unfortunately, therapeutic use of 2-DG is limited by poor pharmacokinetics, suppressing its efficacy. To address these issues, we synthesized novel halogenated 2-DG analogs (2-FG, 2,2-diFG, 2-CG, and 2-BG) and evaluated their glycolytic inhibition in GBM cells. Our in vitro and computational studies suggest that these derivatives modulate hexokinase activity differently. Fluorinated compounds show the most potent cytotoxic effects, indicated by the lowest IC50 values. These effects were more pronounced in hypoxic conditions. 19F NMR experiments and molecular docking confirmed that fluorinated derivatives bind hexokinase comparably to glucose. Enzymatic assays demonstrated that all halogenated derivatives are more effective HKII inhibitors than 2-DG, particularly through their 6-phosphates. By modifying the C-2 position with halogens, these compounds may overcome the poor pharmacokinetics of 2-DG. The modifications seem to enhance the stability and uptake of the compounds, making them effective at lower doses and over prolonged periods. This research has the potential to reshape the treatment landscape for GBM and possibly other cancers by offering a more targeted, effective, and metabolically focused therapeutic approach. The application of halogenated 2-DG analogs represents a promising advancement in cancer metabolism-targeted therapies, with the potential to overcome current treatment limitations.

Discovery of novel quinazoline derivatives as tubulin polymerization inhibitors targeting the colchicine binding site with potential anti-colon cancer effects

Tubulin is a critical target for cancer therapy, with colchicine binding site inhibitors (CBSIs) being the most extensively researched. A series of quinazoline derivatives designed to target the colchicine binding site of tubulin were synthesized and evaluated for their biological activities. The antiproliferative effects of these compounds were tested against six human cancer cell lines, and compound Q19 demonstrated potent antiproliferative activity against the HT-29 cell line, with an IC50 value of 51 nM. Additionally, further investigation revealed that Q19 effectively inhibited microtubule polymerization by binding to the colchicine binding site on tubulin. Furthermore, compound Q19 arrested the HT-29 cell cycle at the G2/M phase, induced apoptosis in these cells, and disrupted angiogenesis. Finally, compound Q19 exhibited potent inhibitory effects on tumor growth in HT-29 xenografted mice while demonstrating minimal toxic side effects and acceptable pharmacokinetic properties. These findings suggested that Q19 hold promise as a potential candidate for colon cancer therapy targeting tubulin.

Multifunctional Microneedle Patch with Diphlorethohydroxycarmalol for Potential Wound Dressing.

Treatment of skin wounds with diverse pathological characteristics presents significant challenges due to the limited specific and efficacy of current wound healing approaches. Microneedle (MN) patches incorporating bioactive and stimulus materials have emerged as a promising strategy to overcome these limitations and integrating bioactive materials with anti-bacterial and anti-inflammatory properties for advanced wound dressing. We isolated diphlorethohydroxycarmalol (DPHC) from Ishige okamurae and assessed its anti-inflammatory and anti-bacterial effects on macrophages and its antibacterial activity against Cutibacterium acnes. Subsequently, we fabricated polylactic acid (PLA) MN patches containing DPHC at various concentrations (0-0.3%) (PDPHC MN patches) and evaluated their mechanical properties and biological effects using in vitro and in vivo models. Our findings demonstrated that DPHC effectively inhibited nitric oxide production in macrophages and exhibited rapid bactericidal activity against C. acnes. The PDPHC MN patches displayed potent antibacterial effects without cytotoxicity. Moreover, in 2,4-Dinitrochlorobenzene-stimulated mouse model, the PDPHC MN patches significantly suppressed inflammatory response and cutaneous lichenification. The results suggest that the PDPHC MN patches holds promise as a multifunctional wound dressing for skin tissue engineering, offering antibacterial properties and anti-inflammatory properties to promote wound healing process.

New Acetophenone Scaffolds: Synthesis, Antifungal Activities, Biocompatibility, Molecular Docking, ADMET Analysis, and Dynamic Simulations

In this work, the chemical reactivity of 2-cyano-N'-(1-phenylethylidene)acetohydrazide (3) towards different aldehydes is utilized to synthesize binary and fused heterocyclic compounds, including arylidenes 6, 7, 12, 13, 14, 18a-c, 19a,b, 20, chromone 23, and chromene derivatives 24, 26a-c, 29, and 30. The capability of newly synthesized compounds to inhibit fungal growth of Aspergillus niger ATCC 16404, A. flavus ATCC 9643, Penicillium chrysogenum ATCC 10106, and Rhizopus oryazae ATCC 96382 are assessed. It is observed that compound 29 had strong antifungal activity against all fungi with MFIC values varying from 250 to 1000 μg/ml, while compound 18a demonstrated potent antifungal effect against A. niger and A. flavus. In addition, it is found that compound 29 was cytotoxic to Vero cells at doses of 1000-500 μg/ml; however, no discernible variation was observed between the concentrations of 250-31.25 μg/ml. Moreover, the interactions between the promising compounds 18a, 19b, and 29 and antifungal target proteins are assessed using molecular docking. The results of the docking simulations demonstrated that these compounds demonstrated optimal binding energies and effectively engaged with the active sites of FDC1 protein in A. niger, UDP-N-acetylglucosamine in A. fumigatus, Adenosine 5′-phosphosulfate kinase in P. chrysogenum, and protease in Rhizopus oryazae. These interactions involved various types of molecular interactions, indicating that these compounds have the ability to impede enzymes and exhibit strong antimicrobial effects. Furthermore, the in-silico ADMET profiles of compounds 18a, 19b, and 29 reveal that they adhere to the Lipinski rules, suggesting favorable physicochemical properties. Also, MD simulations revealed stable complexes of 29 with anti-fungal receptors including fdc1, UDP-N-acetylglucosamine, APS kinase, and protease with RMSD (0.1-0.8, 0.19-0.25, 0.20-0.30, and 0.20-0.35 nm), RMSF (0.1-0.8 nm), SASA (140-155, 130-140, 135-145, and 120-130 nm2), and Rg (1.90-2.00, 1.80-1.90, 2.40-2.50, and 2.10-2.20 nm) respectively. Our results provide potential and promising compounds for fungal infection diseases.

RNAs associated with oxidative stress and apoptosis show anticancer effects of Flos Sophorae flavonoids extract on human hepatoma cells

Flos Sophorae, a traditional Chinese medicinal herb and health tea, consists of the dried flowers and buds of the Sophora japonica L. (Leguminosae). This study assesses the in vitro anticancer efficacy of Flos Sophorae flower extract (FSFE) against the human hepatocarcinoma cell line HepG2, juxtaposed with its effects on normal human liver L02 cells. Cell viability was assessed using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay to evaluate the effects of fruit skin flavonoid extract (FSFE) on cellular proliferation. The results indicated that FSFE significantly inhibited the proliferation of HepG2 liver cancer cells, with an inhibitory concentration (IC50) of 117.98 μg/mL, while having minimal effects on normal liver L02 cells. HPLC analysis identified rutin and quercetin as components of FSFE, both recognized for their antioxidant properties. The flavonoids in Flos Sophorae exhibit potent inhibitory effects on liver cancer cells, indicating potential as a natural anticancer agent. The findings support the continued development and research into the therapeutic applications of these compounds.

A nanoprodrug derived from branched poly (ethylene glycol) recognizes prostate-specific membrane antigen to precisely suppress prostate cancer progression

Prostate-specific membrane antigen (PSMA) is overexpressed in 80–90 % of prostate cancers (PCa) and is widely used as a diagnostic and therapeutic biomarker. Docetaxel (DTX), an FDA-approved anti-microtubule drug, is commonly employed to manage metastatic castration-resistant PCa; however, DTX therapy is often associated with severe side effects. One promising strategy to mitigate these side effects is the development of nanomedicine by loading small molecules into biocompatible vectors. Poly (ethylene glycol) (PEG) has been extensively used in clinical settings for this purpose, with PEGylated drugs demonstrating significant success. Compared to linear PEG, branched PEG (multi-arm PEG) provides enhanced stability for nanomedicines. In this study, we developed a novel nanoprodrug 4armPEG-Docetaxel DCL (4armPEG-DD) by conjugating a 4-arm PEG with DTX via a reduction-sensitive disulfide bond and further modifying it with 2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid (DCL), a PSMA-targeting ligand. Both in vitro and in vivo results demonstrated that the designed nanoprodrug specifically recognized PSMA-positive PCa cells and effectively released DTX in response to the intracellular reducing environment, leading to potent cytotoxic effects on PSMA-positive prostate tumors. Importantly, 4armPEG-DD exhibited improved in vivo safety compared to small-molecule DTX. Thus, we propose that 4armPEG-DD represents a promising candidate for the clinical treatment of PSMA-positive PCa.

Bioactive constituents from Clerodendrum trichotomum and their α-glucosidase inhibitory and PPAR-γ agonist activities

Three new neoclerodane diterpenoids (1–3), two new steroids (4–5), one new monoterpene (6), one new derivative of benzaldehyde (7) and one new iridoid glycoside (8), along with 19 known phenolic compounds, were isolated from Clerodendrum trichotomum. Their structures were established by a combination of detailed spectroscopic analyses (1D and 2D NMR) and high resolution electrospray ionization mass spectroscopy (HRESIMS). The isolated compounds were screened on α-glucosidase inhibitory and the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activities, and the results showed that three phenylethanoid glycosides, verbascoside (9), leucosceptoside a (10), and isoacteoside (13), and two flavonoids, apigenin (22) and luteolin (26) showed potent inhibitory effects against α-glucosidase, with IC50 values in the range from 15 to 700 μM. In addition, four flavonoids apigenin 7-O-β-D-glucuronide (19), apigenin (22), luteolin (26), and quercetin (27) exhibited significant PPAR-γ agonistic activities with EC50 values in the range 2.3–24.9 μM.