Current pharmaceutical biotechnology最新文献

Background: The combination of Gardeniae Fructus (ZZ) and Scutellariae Radix (HQ) is a traditional Chinese medicine used for Alzheimer's disease (AD). However, the molecular mechanisms underlying its anti-dementia effects, particularly its multi-component synergy and pathway modulation, remain poorly understood.

Objective: Our study employed an integrated systems pharmacology approach to mechanistically decode the anti-AD properties of ZZ-HQ, combining network pharmacology predictions, molecular docking simulations, and experimental validation to identify critical bioactive components, molecular targets, and therapeutic pathways.

Methods: A comprehensive network pharmacology analysis was performed to identify bioactive compounds within the ZZ-HQ complex and their potential protein targets associated with AD. Molecular docking was utilized to predict and assess the binding interactions between key bioactive compounds and AD-related protein targets. Experimental validation focused on baicalin, a major active compound in the ZZ-HQ complex, evaluating its effects on cell viability, apoptosis regulation, oxidative stress reduction, and the activation of the PI3K/Akt signaling pathway.

Results: Fifty-four bioactive compounds were identified in the ZZ-HQ complex, interacting with 258 AD-associated proteins. Key compounds, such as baicalein and norwogonin, demonstrated strong binding affinities with pivotal proteins, including SRC and PIK3R1. Experimental studies further confirmed that baicalin significantly improved cell viability by activating the PI3K/Akt pathway, reducing apoptosis, and alleviating oxidative stress.

Conclusion: Our study uncovered the therapeutic potential of the ZZ-HQ combination in addressing AD through multi-target mechanisms, particularly via modulation of the PI3K/Akt pathway and oxidative stress. These findings provide a scientific basis for the pharmacological effects of ZZ-HQ and offer valuable insights for further research on its potential application in AD treatment.

Rare diseases, defined as conditions affecting fewer than 200,000 people in the United States or less than 1 in 2,000 people in Europe, pose significant challenges for healthcare systems and pharmaceutical research. This comprehensive review examines the evolving landscape of orphan drug development, analyzing scientific, economic, and regulatory challenges while highlighting recent technological breakthroughs and innovative approaches. We explore how artificial intelligence, next-generation sequencing, and personalized medicine are revolutionizing rare disease research and treatment development. The review details key advances in therapeutic approaches, including gene therapy, cell-based treatments, and drug repurposing strategies, which have led to breakthrough treatments for previously untreatable conditions. We analyze the impact of international collaborations, such as the International Rare Diseases Research Consortium, and discuss how regulatory frameworks worldwide have evolved to accelerate orphan drug development. The paper highlights the growing market for orphan drugs, projected to reach $242 billion by 2024 while examining the complex challenges of ensuring treatment accessibility and economic sustainability. We assess innovative clinical trial designs, patient registry development, and emerging strategies in personalized medicine that are transforming the field. Despite notable advancements, significant gaps remain in diagnosis, treatment accessibility, and sustainable funding for rare disease research. The review concludes by proposing specific actions for enhancing international collaboration, improving patient registries, and aligning incentives to address the unmet medical needs of rare disease patients, emphasizing the critical role of continued public-private partnerships and technological innovation in advancing orphan drug development.

Owing to the lack of appropriate selective treatments, hepatocellular carcinoma (HCC) remains one of the major reasons of cancer associated death. Chronic liver failure nearly always accompanies HCC, and doctors usually detect it only after the disease has progressed beyond the point where curative therapies are possible. Despite the fact that HCC has distinct morphological and phenotypic patterns, therapeutic options are limited to comparatively homogeneous drugs such as multi-targeted tyrosine kinase blockers and immune checkpoint blockers. Multiple studies evaluating the effectiveness of different medications have yielded disappointing findings, indicating that HCC has poor immunity to chemotherapy, which is exacerbated by multidrug resistance. As a result, more successful therapies addressing HCC's disordered metabolic and molecular pathways are needed. The quite often change in sequence of genes and molecular targets in HCC patients are telomerase reverse transcriptase, Wnt/-catenin signaling pathway oncogene (CTNNB1), and the TP53 gene, according to integrated genomic profiling. Furthermore, new approaches like genome-scale metabolic replicas may be utilized to explicate the basic cancer specific metabolism, allowing for such exploration of promising biomarkers and drug candidates. The clinical implications of metabolic network driven heterogeneity of HCCcaseson the basis of redox response, metabolite use, and subtype specific pathways could help accelerate the advancement of personalised medicine. Another interesting strategy is microRNA- based therapy which involves miRNA antagonists to block oncogenic miRNAs and miRNA substitution, which entails reintroducing a tumor-suppressor miRNA to restore function following a functional impairment. The existing and evolving clinical purpose in context of molecular targets and metabolic network-based approaches are summarised in this review, paving the way for successful HCC patient care.

Background: Oropharyngeal candidiasis (OPC), a fungal infection affecting the mouth and throat, imposes a substantial burden on vulnerable populations such as HIV/AIDS patients, cancer treatment recipients, and the elderly. Conventional antifungal medications are encountering increasing resistance and side effects, necessitating the exploration of novel therapeutic approaches.

Objectives: This review proposes a comprehensive strategy for developing a novel natural product- based antifungal formulation targeting OPC. The approach involves harnessing promising natural compounds with established antifungal properties and employing advanced delivery systems like mucoadhesive microemulsions to improve efficacy and minimize adverse effects. Additionally, the review explores the integration of computational methods to expedite the identification and development of potent antifungal agents.

Methods: A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Web of Science. Search terms included combinations of "oropharyngeal candidiasis," "natural antifungal agents," "flavonoids," "mucoadhesive microemulsions," "computational drug discovery," and "in vitro/in vivo studies." Priority was given to studies published within the last ten years.

Results: The review identifies promising natural compounds with antifungal activity against Candida species commonly associated with OPC. Additionally, several studies highlight the potential of computational tools such as molecular docking and in silico ADMET for rapidly identifying natural compounds with potent antifungal activity and favorable pharmacokinetic and safety profiles. A brief overview of in vitro and in vivo experiments is provided, emphasizing their role in validating the safety and efficacy of the proposed natural product-based antifungal formulation. Formulation and analytical aspects are also discussed.

Conclusion: The multidisciplinary approach outlined, incorporating natural products, computational methods, advanced preclinical in vitro and in vivo experiments, and advanced delivery systems, offers promise for the rapid, cost-effective development of safe and effective optimized formulations to address the growing challenge of OPC, particularly in vulnerable populations.

Background: The inherent limitation of ocular dosage forms is decreased precorneal residence time which affects the bioavailability and therapeutic efficacy.

Objective: The objective of the current research was to sustain drug release and enhance precorneal drug residence time by formulating lipidic core-shell nanoparticles of Dexamethasone Sodium Phosphate and loading them in ion-sensitive in situ gel for corneal neovascularization.

Methods: Polymeric nanoparticles were formulated using Eudragit L100-55 and PVA by twostep solvent diffusión nanoprecipitation method and coated by a lipidic film of Soya phosphatidylcholine with Cholesterol. The optimized lipidic core-shell nanoparticles were transformed into in situ gel using Gellan gum. The lipidic core-shell nanoparticles were evaluated for particle size, zeta potential, entrapment efficiency, in vitro reléase and in situ gel was evaluated for in vitro gelling time, pH, drug content, HETCAM studies, etc Results: The Core-shell lipid nanoparticles exhibited a particle size of 368.00±0.54 nm and zeta potential -13.3±2.0 mV respectively. The lipidic core-shell nanoparticles were found to show a sustained drug release when compared to the drug solution. The optimized in situ gel was found to show a gelation time of 39.59±2.49 seconds and was found to be non-irritant.

Conclusion: A decline in ex vivo drug permeation was observed through an aqueous suspension of core-shell polymeric nanoparticles and core-shell LPN loaded in situ gel thus confirming sustained release for the drug Dexamethasone Sodium Phosphate.

Introduction: Hydroxysafflor Yellow A (HSYA), known for its anti-inflammatory effects in cardiovascular diseases, has also been shown to reduce adiposity and improve metabolic disorders in diet-induced obese (DIO) mice. However, the molecular mechanisms underlying its anti-obesity effects, particularly whether they are mediated through immune-inflammatory pathways, remain unclear. This study aims to identify the key molecular mechanisms involved in HSYA's anti-obesity action.

Methods: Male C57BL/6J mice were divided into three groups: Standard Feed (SF), High-Fat Diet (HFD), and HFD with HSYA treatment (250 mg/kg/day for 9 weeks). Whole transcriptome sequencing of White Adipose Tissue (WAT) identified Differentially Expressed Genes (DEGs), which were integrated with network pharmacology predictions to identify key molecular targets of HSYA. RT-qPCR in WAT, 3T3-L1 adipocytes, and RAW264.7 macrophages validated the core genes, and molecular docking assessed HSYA's binding affinity with these targets.

Results: HSYA treatment significantly reduced body weight (35.27 ± 1.27g vs. 45.46 ± 1.68g, p < 0.05) and WAT mass (3.38±0.21g vs. 1.86±0.27g, p < 0.05) in DIO mice and ameliorated glucose and lipid metabolism abnormalities. Transcriptome analysis revealed 739 DEGs, with 21 overlapping genes identified between sequencing and network pharmacology analyses. Experimental validation highlighted Prkcd, Btk, and Vav1 as core genes within immune-inflammatory pathways, including chemokine and B cell receptor signaling, which are implicated in obesityrelated inflammation. RT-qPCR confirmed the downregulation of Prkcd, Btk, and Vav1 after HSYA treatment, consistent with transcriptomic findings. Molecular docking analysis demonstrated strong binding affinities between HSYA and VAV1 (-8.5 kcal/mol), BTK (-6.9 kcal/mol), and PRKCD (-6.6 kcal/mol).

Conclusion: HSYA demonstrates the therapeutic potential for obesity by modulating immuneinflammatory pathways in WAT, specifically targeting Prkcd, Btk, and Vav1 in mice. Given its clinical use in cardiovascular disease, these findings suggest that HSYA may offer broader therapeutic benefits, including obesity management, though further studies are needed to clarify the mechanisms and assess its applicability to humans.

Aims: This study investigates causal relationships between gut microbiota (GM), plasma metabolites, and cerebral small vessel disease (CSVD), with a focus on identifying GM taxa and metabolites that mediate disease risk.

Methods: Summary data from genome-wide association studies on GM (MiBioGen), 1,400 plasma metabolites, and CSVD were analyzed using a two-step Mendelian randomization (MR) approach. The primary analysis utilized inverse-variance weighting, complemented by weighted median, weighted mode, and MR-Egger methods for robustness.

Results: The MR analysis identified 12 GM taxa associated with CSVD risk, including 7 taxa linked to increased risk (Veillonellaceae, Hungatella, Ruminococcus2, Lachnospiraceae UCG010, Streptococcus, Cyanobacteria, Verrucomicrobia) and 5 taxa linked to decreased risk (Faecalibacterium, Alphaproteobacteria, Eubacterium nodatum group, Fusicatenibacter, Rhodospirillales). Additionally, 10 plasma metabolites were causally associated with CSVD risk, with sphingomyelin (d18:2/14:0, d18:1/14:1), nicotinamide, and 3-ethylcatechol sulfate (2) linked to increased risk, while phosphate-to-uridine ratio, adenosine 5'-diphosphate (ADP)-toflavin adenine dinucleotide (FAD) ratio, arginine, caffeine-to-theobromine ratio, N-succinylphenylalanine, sphingosine, and phenylpyruvate-to-4-hydroxyphenylpyruvate ratio were linked to decreased risk. Mediation analysis identified 8 causal pathways through which plasma metabolites connect GM taxa to CSVD.

Conclusion: These findings underscore the substantial influence of GM and plasma metabolites on CSVD risk, highlighting potential therapeutic targets. Further investigation is needed to elucidate the biological mechanisms underlying these associations.

Objective: Through comprehensive transcriptome sequencing of liver RNA in mice induced with streptozotocin (STZ) to develop hyperglycemia, we uncovered crucial genes associated with hyperglycemic processes, shedding light on their respective functions. Furthermore, we delved deeply into a discussion surrounding the mechanism behind plasma glucagon-like peptide 1 (PGLP-1) and its role in inhibiting gluconeogenesis.

Methods: Liver tissues from mice induced with STZ to develop hyperglycemia (M group), as well as those treated with PGLP-1 (P11 group) and Exendin-4 (E group), were collected. RNA extraction was performed for comprehensive transcriptome sequencing. Differentially expressed mRNA, microRNA (miRNA), and long-chain non-coding RNA (lncRNA) were identified and subjected to analysis of their respective GO and KEGG pathways. An association network involving mRNA-miRNA-lncRNA was constructed to pinpoint target molecules associated with gluconeogenesis. Furthermore, personalized analysis focused on eight gluconeogenesis-related signal pathways obtained from KEGG.

Results: A total of 289 differentially expressed mRNA (dif-mRNA), 21 differentially expressed miRNA (dif-miRNA), and 463 differentially expressed lncRNA (dif-lncRNA) were screened from the M group and P11 group. 182 dif-mRNA, 239 dif-miRNA, and 384 dif-lncRNA were screened from the M group and E group. A total of 427 dif-mRNA, 261 dif-miRNA, and 525 diflncRNA were screened from the E group and the P11 group. Among them, mRNA was enriched to the PI3K-Akt signaling pathway, Type ll diabetes mellitus, the Insulin signaling pathway, and the PPAR signaling pathway, while lncRNA was mainly enriched in PI3K-Akt signaling pathway. Similar to the whole transcriptome sequencing, the results of gluconeogenesis personalized analysis showed that the PI3K-Akt signaling pathway was the key pathway, and Gck and Cyp7a1 were highly expressed after PGLP-1 was administered.

Conclusions: According to our findings, we believe that PGLP-1 is a potential regulator of noncoding RNAs, including miRNAs and lncRNAs. Additionally, it modulates the PI3K-Akt signaling pathway, resulting in the upregulation of GcK and Cyp7a1. In this way, it effectively inhibits gluconeogenesis.

Cardiovascular diseases (CVDs) have the highest mortality rates worldwide. To reduce the risk of CVDs, dietary interventions are a potential approach. This review explores the potential of mycoprotein, a fungal-derived protein, as a dietary approach for maintaining cardiovascular health. A comprehensive literature search was conducted using various databases (Web of Science, Medline, Scopus, Google Scholar, EBSCO, PubMed) and government websites (WHO, CDC) to identify relevant studies. Mycoprotein provides essential amino acids with high bioavailability (0.996) while containing minimal saturated fat (1.5 grams) and high fiber (6 grams). Clinical studies have shown that mycoprotein consumption reduces cholesterol, improves lipid profiles, and potentially lowers blood pressure, possibly due to its impact on gut microbiota (GM) and short-chain fatty acids (SCFAs) production. The intestinal fermentation of mycoprotein fiber increases the abundance of beneficial gut bacteria, binds to Gprotein coupled receptors like GPR41 and 43 to promote vasodilation, inhibits the angiotensinconverting enzyme, and reduces hepatic cholesterol production. Chitin and beta-glucan, the primary fiber of mycoprotein, exhibit anti-inflammatory properties that may contribute to overall cardiovascular health. The study concludes that mycoprotein is a sustainable and nutritious alternative, and its consumption promotes cardiovascular health and reduces CVD risks.

Background: Hesperidin is a flavonoid found in citrus fruits, particularly in the peel and pulp of oranges and lemons. By encapsulating drugs or bioactive compounds within NPs, it's possible to enhance their stability, solubility, and bioavailability. The current investigation aims to optimize hesperidin nanoparticles (Hes-NPs) and evaluate their hepatoprotective and antioxidant effects in paracetamol-intoxicated mice.

Methods: The characteristics of Hes-NPs were elucidated, including morphology, particle size, zeta potential, UV-vis, entrapment efficiency, and FT-IR spectra. Hes-NPs were also tested for their hepatoprotective and antioxidant effects in paracetamol-treated mice. Safety and toxicity assessments are crucial before pharmacological studies. In addition, liver enzymes, oxidative stress, inflammatory biomarkers, and gene expression of CYP2E1 and CYP3A11 were measured. Furthermore, the study examined the molecular docking of hesperidin with the CYP2E1 and CYP3A11 proteins.

Results: The synthesized Hes-NPs were uniform, spherically shaped, and well dispersed, with no aggregation noted, with a size range of 155.12 ± 14.13 nm. The measured zeta potential value of Hes-NPs was -21.57 ± 0.8 mV with a polydispersity index (PDI) of 0.49. Also, the UV spectra of hesperidin are at 220 and 279 nm, and Hes-NPs have strong absorption at 225 and 280 nm. Also, the LD50 of Hes-NPs was 1137.5 mg/kg b.w. Moreover, administering paracetamol-intoxicated mice with Hes-NPs resulted in improved plasma lipid profile &#40;TC, TG, and HDL-C&#41; and liver enzymes (ALT, AST, ALP, and LDH) as well as oxidative stress (GSH, SOD, CAT, Pr-SHs, and MDA) and inflammatory (TNF-α) biomarker levels, as well as attenuated CYP2E1, and CYP3A11 gene expression. In-silicon results proved that hesperidin showed a stronger estimated binding affinity with a ∆G of -8.6 and -10.5 kcal/mol. towards CYP2E1, and CYP3A11 activity, respectively. Our results showed that hesperidin forms hydrogen bonds with amino acid residues through the 9 and 12 bonds of CYP2E1 and CYP3A11, respectively.

Conclusion: Hes-NPs could offer several advantages. It can be designed to specifically target liver cells, minimizing off-target effects, enhancing bioavailability, and shielding hesperidin from degradation in the body. The current results suggest that Hes-NPs may enhance antioxidant defenses and protect against oxidative stress in paracetamol-intoxicated mice.