Current pharmaceutical design最新文献

Recent research suggests that targeting ferroptosis exhibits promise as a potent treatment approach for breast carcinoma. Specific subtypes of tumor cells exhibit heightened vulnerability to ferroptosis-inducing chemicals, which selectively trigger tumor stem cells' demise, enhance tumor cells' sensitivity to chemotherapeutic drugs, and eliminate cancerous cells. Ferroptosis plays a dual role in breast cancer progression, emerging as both a stimulating and inhibitory component. Ferroptosis is effective in treating cancer cells (mesenchymal breast), identified by their ability to undergo Epithelial-mesenchymal Transition (EMT) and their resistance to conventional therapies. Pharmaceutical drugs that hinder the activity of enzymes known as kinases, which are involved in the AKT/mTOR/PI3K signaling pathway, have shown significant potential in the treatment of breast carcinoma. This review investigates the molecular mechanisms of different signaling pathways implicated in ferroptosis in breast carcinoma, with specific emphasis on metastasis, invasion, and proliferation. Our study contributes to understanding a potentially important target that could be used in developing therapeutic strategies for breast cancer treatment.

Pyrido[2,3-d]pyrimidine and its derivatives have garnered significant attention due to their potential biological and pharmacological activities. Research has demonstrated their significant potential for antitumor and antibacterial applications. Over the years, pyrido[2,3-d]pyrimidine derivatives have remained a research focus for scientists, with numerous synthetic methods and reaction conditions reported. This review comprehensively summarizes the fast, facile, and economical synthetic methods for pyrido[2,3- d]pyrimidine derivatives over the past years, which are categorized based on different synthetic precursors, and evaluates their antitumor and antibacterial activities, aiming to make them better serve the cause of human health.

Thrombomodulin (TM) is a single-chain transmembrane glycoprotein with anticoagulant effects. TM has two forms: membrane type existing on the cell surface and blood type free in plasma and urine. TM functions as an anticoagulant cofactor for thrombin activation of protein C on the surface of vascular endothelial cells. Due to the excellent anti-coagulant effects in modulating the coagulation and fibrinolytic system, the recombinant human soluble TM (rhsTM) has been used for the treatment of disseminated intravascular coagulation (DIC). In addition to anti-coagulation, many studies have shown that TM can also exert anti-inflammatory and anti-tumor effects. TM has a lectin-like domain at its N-terminus that has been shown to exhibit direct anti-inflammatory functions. At the same time, due to its special structure, thrombomodulin plays an important role in vascular-related mechanistic diseases by participating in the regulation of inflammatory pathways, complement, HMGB1, etc. In this article, changes in TM expression in the body after injury, composition of TM structural domains, anticoagulant, anti-inflammatory, and antitumor effects, and related mechanisms of TM were systematically reviewed, to provide a theoretical basis and reference for the potential clinical implications of TM in treating various diseases.

Nanogels (NGs) are presently the focus of extensive research because of their special qualities, including minimal particle size, excellent encapsulating efficacy, and minimizing the breakdown of active compounds. As a result, NGs are great candidates for drug delivery systems. Cross-linked nanoparticles (NPs) called stimulus-responsive NGs are comprised of synthetic, natural, or a combination of natural and synthetic polymers. These NPs can swell in response to large amounts of solvent, but their structural makeup prevents them from dissolving. Furthermore, in response to (i) physical stimuli like temperatures, ion strength, and magnetized or electrical fields; (ii) chemical stimuli like the pH level, molecules, or ions; (iii) biological stimuli like the enzymatic substrate or affinity ligand, they transform into a hard particle (collapsed form) from a polymer solution (swell form). Over the past decade, there has been a major advancement in the creation of "smart" NGs in applications related to therapeutics and diagnosis, involving nucleic acid and intracellular drug delivery, photodynamic/photothermal treatment, biological imaging, and its detection. The nanogels reviewed in this article rely only on temperatures, pH, light, magnetic fields, and combinations of those variables. Developing a targeted delivery vehicle will greatly benefit from the presented information, especially when used for Core-shell multi-sensitive photo-sensitive nanogels.

Introduction: The objective of the present study was to improve the anti-inflammatory and antibacterial activities of mastic gum resin (MGR). MGR was loaded into a phospholipid nanocarrier with or without partially hydrolyzed ginsenoside, followed by dispersion into distilled water.

Method: The phospholipid nanocarrier dispersion showed significantly enhanced in-vitro release, porcine skin/ intestine permeation, and retention. When the ratio of the MGR versus partially hydrogenated ginsenoside reached 1:1 w/w in the nanocarrier composition, the in-vitro release increased 54.8-fold compared to the MGR powder suspended in the release media.

Results: Permeation of the nanocarrier dispersion through the porcine skin and intestine increased 160-fold and 42-fold, respectively, compared to permeation of the MGR powder suspension. Furthermore, the nanocarrier dispersion reduced NO production and iNOS mRNA expression in the LPS-stimulated RAW264.7 cells. MIC and MBC of the nanocarrier dispersion against P. gingivalis were 4.11 ± 1.17 and 8.22 ± 2.35 μg/mL, respectively.

Conclusion: In conclusion, the anti-inflammatory and antibacterial activities of MGR were remarkably enhanced when the MGR was loaded into the nanocarrier with partially hydrolyzed ginsenoside.

Schizophrenia is a heterogeneous neuropsychological disorder characterized by three distinct sets of symptoms: positive, negative, and cognitive. It carries significant public health implications and is estimated to affect up to 1% of the population. Despite extensive research, the underlying mechanisms of schizophrenia are not entirely understood, and existing antipsychotic treatments have notable limitations. Firstly, these treatments are effective for only approximately half of the patients. Secondly, they primarily alleviate positive symptoms such as misperceptions and thought disorders, which are core to the illness, while neglecting the negative symptoms like flat affect and social withdrawal, as well as cognitive symptoms such as learning and attention difficulties. Thirdly, these treatments come with significant neurofunctional and metabolic side effects, and in some cases, they can lead to issues like sexual dysfunction or agranulocytosis (in the case of Clozapine (CLZ)). In this review, we delve into currently available treatments for schizophrenia, with the utilization of Deep brain stimulation techniques to overcome the limitations of antipsychotics. We also discuss the major clinical trials for schizophrenia along with deep brain stimulation intervention.

Backgrounds: Renal interstitial fibrosis (RIF) constitutes the ultimate pathological alteration in nearly all chronic kidney diseases (CKD). Mesenchymal stem cell conditioned medium (MSC-CM) exhibits an alleviating impact on renal fibrosis; however, the underlying mechanism remains unclear. The objective of this study was to explore whether MSC-CM regulates the expression of α-smooth muscle actin (α-SMA), Transforming growth factor-β1 (TGF-β1), Hypoxia-inducible factor-1α (HIF-1α), Nuclear receptor coactivators (NCOA1), and SRY-related high mobility (Sox9).

Methods: Rat renal tubular epithelial cells (RTECs), NRK-52E, were treated with diverse concentrations of Cobalt chloride (CoCl2) for 24 hours. The survival rate and protein expression of NRK-52E cells exposed to different concentrations of CoCl2 were determined to identify the final concentration. Three groups of NRK-52E cells were employed in the experiment: the normal control group, the 400 μM CoCl2 group, and the MSC-CM + 400 μM CoCl2 group. The cell morphology was observed by an inverted phase contrast microscope and scanning electron microscope, and the protein expressions of α-SMA, TGF-β1, HIF-1α, NCOA1, and Sox9 were detected.

Result: The microscopic findings demonstrated that MSC-CM was able to decrease the degree of cytochemical hypoxia damage in NRK-52E cells induced by CoCl2. Immunofluorescence and Western blot analyses also affirmed a similar tendency. The upregulation of α-SMA, TGF-β1, HIF-1α, NCOA1, and Sox9 triggered by CoCl2 could be inhibited following MSC-CM intervention.

Conclusion: Our findings indicate that MSC-CM exerts a protective effect on RTECs by down-regulating α-SMA, TGF-β1, HIF-1α, NCOA1, and Sox9.

Introduction: Brain ischemia-reperfusion can cause serious and irreversible health problems. Recent studies have suggested that certain flavonoids may help stabilize the correctly folded structure of the visual photoreceptor protein rhodopsin and offset the deleterious effect of retinitis pigmentosa mutations.

Objective: The current study aimed to determine the effect of 3',4'-Dihydroxyflavonol (DiOHF) supplementation for 1 week on lipid peroxidation in the retina tissue following focal brain ischemia-reperfusion in rats.

Methods: This study was carried out on male Wistar-albino rats. A total of 28 rats were used in the research, and four groups were formed: Control group: no anesthesia or surgical procedure was applied to the animals in this group, Sham group: after general anesthesia was established in the animals in this group, the carotid artery areas were opened and closed, and the 1 ml vehicle was applied for 1 week, Ischemia-Reperfusion (I/R) group: after the carotid arteries were isolated in rats under general anesthesia, ischemia was performed by ligating them for 30 minutes, and then reperfusion was applied for 1 week, and Ischemia-Reperfusion + DiOHF group: under general anesthesia, ischemia was developed in the carotid arteries of the rats by ligation for 30 minutes, and then DiOHF was applied along with reperfusion for 1 week. At the end of the study, retinal tissue taken from animals sacrificed under general anesthesia was analyzed for MDA and GSH. Retinal tissue was also examined for histology and neurogenesis.

Results: The highest MDA value was determined in the ischemia group, and the lowest value in the control and sham groups. In group 4, this parameter was found to be significantly lower than in the I/R group. Retinal GSH was very low in the I/R group. However, 1-week DiOHF treatment increased the GSH values. Deteriorations also occurred in the histological structure of the retinal tissue, and neurogenesis was inhibited. However, treatment improved retinal damage and neurogenesis.

Conclusion: The results of the current study showed that focal brain ischemia in rats caused significant retinal lipid peroxidation. However, 1-week DiOHF treatment suppressed the increased lipid peroxidation by increasing GSH levels. Moreover, treatment improved retinal damage and neurogenesis.

Objective: This study aimed to evaluate the effectiveness and safety of Altibrain® in combination with standard Autism Spectrum Disorder (ASD) treatment compared to standard ASD treatment alone in individuals diagnosed with ASD.

Method: A randomized, open-label trial was conducted involving 120 participants aged 3 to 17 years, randomly assigned to either the Standard ASD Treatment group or the Altibrain® + Standard ASD Treatment group. Sixty patients were randomly allocated to each Standard ASD Treatment group or the Altibrain® + Standard ASD Treatment group. participant allocation was done by computer-generated randomization. Participants had confirmed ASD diagnoses based on DSM-IV or ICD-11 criteria and demonstrated moderate to severe core ASD symptoms. Informed consent was obtained from caregivers. A total number of 120 subjects were included, consisting of 71 male and 49 female patients. Participants received either standard ASD treatment alone or Altibrain® in addition to standard ASD treatment orally once daily for 24 weeks. A total of 7 study visits/24 weeks to analyze the intervention efficacy of the Standard ASD Treatment group or the Altibrain ® + Standard ASD Treatment group. Primary outcomes included changes in core ASD symptoms measured by the Autism Diagnostic Observation Schedule (ADOS) and safety assessments. Secondary outcomes included alterations in social communication skills, reduction in repetitive behaviors, overall functional improvements, and safety and tolerability of Altibrain®.

Results: Altibrain® significantly improved qualitative deficits in social interaction and repetitive behaviors compared to standard ASD treatment alone (p < 0.0001). The Altibrain® + Standard ASD Treatment group demonstrated significant improvements in social functioning, social awareness, cognition, communication, and motivation compared to the Standard ASD Treatment group (p < 0.0001). Additionally, Altibrain® showed superior efficacy in reducing hyperactivity/noncompliance, inappropriate speech, irritability, lethargy/ social withdrawal, stereotypic behavior, and aberrant behavior compared to standard treatment alone (p < 0.0001). Additionally, Altibrain® exhibited a favorable safety profile as per the 4-week post-treatment safety follow-up.

Conclusion: Further research is warranted to confirm and expand upon these results, including longer-term studies with larger cohorts and investigations into underlying mechanisms. Overall, Altibrain® holds promise as a valuable therapeutic option for individuals with ASD and their families. Limitations of the study include neuroimaging and biomarkers analysis.

Introduction: Fungal endophytes have mutualistic associations with the plant's host, communicating through genetic and metabolic processes. As a result, they gain the ability to generate therapeutically effective metabolites and their derivatives.

Methods: The current study aims to assess antioxidant potential along with the identification of robust metabolites within the crude extract of a potent endophytic fungus Xylaria ellisii isolated from leaf tissues of the Acorus calamus Linn plant.Four endophytic fungi were obtained from leaf tissues of Acorus calamus Linn., and identified morphologically and molecularly as distinct species. Each ethyl acetate extract of the isolated fungi exhibited a unique chemical profile in the HPTLC fingerprint at various wavelengths. The ethyl acetate (EA) extract from the fungal strain ACL-4 (Xylaria ellisii) demonstrated the strongest antioxidant activity among the four fungal endophytes examined, with an EC50 value of 292.64 ± 3.558 μg/mL. Remarkably, fungal endophyte ACL-4 extract exhibited superior antimicrobial activity at the less concentrations compared to ACL-ME extract of leaf crude.

Results: The extract of ACL-ME-treated HEK 293T cells exhibited significant toxicity, with an IC50 value of 1481.74 ± 23.772 μg/mL, compared to fungal strain ACL-4-treated HEK 293T cells, which had an IC50 value greater than 2000 μg/mL. Consequently, the crude extract of ACL-4 and ACL-ME along with the standard drug methotrexate exhibited cytotoxic activity against cancer cell line MDA-MB-231 with IC50 concentrations of 146.65 ± 0.394 μg/mL, 528.46 ± 10.912 μg/mL, and 134.11 ± 3.446 μg/mL, respectively. A total of 2,255 compounds were detected through LC-HRMS-based metabolomics in the crude metabolites of Xylaria ellisii, with certain compounds identified in multiple instances. Among this repertoire, 62 robust bioactive compounds were identified through meticulous screening, guided by existing literature. Comparative HPTLC fingerprint analysis, along with antioxidant efficacy assays of ethyl acetate extracts of Xylaria ellisii derived from Acorus calamus leaves and Cassia fistula twigs revealed the host-specific production of bioactive chemicals.

Conclusion: The top-scoring Keap1 inhibitors derived from Xylaria ellisii, including Pregabalin (-6.083 Kcal/mol), Ferulic acid (-5.434 Kcal/mol), (R)-Piperidine-2-carboxylic acid (-5.31 Kcal/mol), Genipin (-5.197 Kcal/mol), and Brivaracetam (-5.17 Kcal/mol), respectively were considered as Keap 1 inhibitors, potentially mitigate oxidative stress.