Effective Drug Research Articles

CaMKII Exacerbates Doxorubicin‐Induced Cardiotoxicity by Promoting Ubiquitination Through USP10 Inhibition

ABSTRACTBackgroundDoxorubicin (DOX) is an effective anticancer drug, but it has a problem of cardiotoxicity that cannot be ignored. Ca2+/calmodulin‐dependent protein kinase II (CaMKII) is tightly associated with the pathological progression of DOX‐induced cardiotoxicity. Ubiquitin‐specific protease 10 (USP10) plays an important role in many biological processes and cancers. However, its association with DOX‐induced cardiotoxicity and CaMKII remains unclear.MethodsH9C2 cells, HL‐1 cells and C57BL/6 mice were used to establish the DOX‐induced cardiotoxicity model, and the CaMKII‐specific inhibitor KN‐93 and USP10 specific inhibitor Spautin‐1 were used to observe the CaMKII and USP10 effect. In cell experiments, CCK‐8 method was used to assess cell viability, LDH kit was used to assess lactate dehydrogenase expression, DCFH‐DA staining was used to observe changes in active oxygen content, TUNEL staining was used to observe cell apoptosis, and Western blotting method was used to detect relevant protein markers. The expression of p‐CaMKII and USP10 was assessed by immunofluorescence staining. In animal experiments, mouse echocardiograph was used were used to evaluate cardiac function, and HE staining and Masson staining were used to evaluate myocardial injury. Cardiomyocyte apoptosis was detected by TUNEL staining. Western blotting method was used to detect relevant protein markers.ResultsOur results demonstrated that activation of CaMKII and inhibition of USP10 pathway related to DOX‐induced cardiotoxicity. Inhibition of CaMKII with KN‐93 ameliorated DOX‐induced cardiac dysfunction and cytotoxicity. In addition, CaMKII inhibition prevented DOX‐induced apoptosis and ubiquitination. Furthermore, CaMKII inhibition increased USP10 expression in DOX‐treated mouse hearts, H9C2 cells and HL‐1 cells. At last, the USP10 inhibitor, Spautin‐1, blocked the regulatory effect of CaMKII inhibition on apoptosis and ubiquitination in DOX‐induced cardiotoxicity.ConclusionOur findings revealed that DOX‐induced myocardial apoptosis and activated CaMKII through cellular and animal levels, while providing a novel probe into the mechanism of CaMKII action: promoting ubiquitination by inhibiting USP10 aggravated apoptosis.

New vatalanib analogs: Design, synthesis, in silico study and biological evaluation for anticancer activity

In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs. Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT‐116) using vatalanib as a positive control. The new candidates showed promising anticancer activity against two tested cancer cell lines with IC50 values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 µM, in particular compounds 11b and 11c which were more potent than vatalanib. The most potent was the 4-benzoylquinoxaline derivative 11b (IC50 = 6.04 ± 0.19 µM and 15.58 ± 0.58 µM) compared to vatalanib (IC50 of 25.27 ± 0.84 µM and 43.91 ± 1.64 µM) against HepG2 and HCT116, respectively. The selectivity indices of 11b were found to be approximately 14 and 5 towards HepG2 and HCT116, respectively. While vatalanib showed selectivity indices of about 5 and 3 towards HepG2 and HCT116, respectively. The most promising compound 11b was further investigated in HepG‐2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death. It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC50 of 0.918 ± 0.033 µM compared to vatalanib (IC50 of 0.265 ± 0.009 µM). Deep computational studies were created for the designed compounds including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates. The results of the docking study were consistent with biological testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib. So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead molecules for development of new effective anticancer drugs.

Biogenic silver nanoparticles synthesized using rose petals: Potential to inhibit multidrug-resistant bacterial pathogens in disabled patients

BackgroundDrug resistant bacterial infections can be fatal for disabled people needing multiple medications and new effective antibacterial drugs such as biosynthesized nanoparticles are needed. A cost-effective and green method was studied for the biosynthesis of silver nanoparticles using pink rose petals. Materials and methodsSilver nanoparticles (AgNP) were synthesized using the petals of pink rose flowers. The AgNPs were characterized using FITR, SEM, XRD, and EDS analyses. The antibacterial activity of the AgNPs against multidrug-resistant bacterial pathogens Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, and colistin-resistant Klebsiella pneumoniae were studied using the microplate method. ResultsTh AgNPs had a spherical shape and an average size of 26 nm. XRD analysis showed that the nanoparticles were Ag0. Antibacterial activity was the highest against the multidrug-resistant S. aureus the minimum inhibitory concentration (MIC) being 400 µg/ml AgNPs. The multidrug-resistant E. coli, multidrug-resistant A. baumannii, and colistin-resistant K. pneumoniae MICs were 800 µg/ml, 3200 µg/ml, and 1600 µg/ml, respectively. ConclusionThe green synthesized of AgNPS using pink rose petals and their antibacterial effects offer material for the treatments of common multidrug-resistant bacterial pathogens.

Application of Box-Behnken design in the optimization and development of albendazole-loaded zein nanoparticles as a drug repurposing approach for colorectal cancer management

Colorectal cancer (CRC) is the second cancer worldwide representing a major global health challenge. Numerous effective anticancer drugs have been developed in the last decade, yet the problem remains due to their low therapeutic index and nonspecificity. A new anticancer therapeutic paradigm is based on repurposing and nanoformulating drugs. Albendazole (ALB), a popular anthelmintic agent, was recently repurposed against CRC cells. In this study zein, an amphiphilic protein, was used to formulate nanoparticles (NPs) loaded with ALB. Box-Behnken design was selected to optimize the loaded NPs, the concentrations of polyvinyl alcohol, acetic acid, and the weight of zein were the independent variables. The dependent variables were the particle size, polydispersity index, and zeta potential. The optimized formula displayed a size of 84.3 ± 0.41 nm, PDI 0.13 ± 0.012, and a zeta potential of 42.5 ± 2.35 mV. ALB was successfully encapsulated into zein NPs and the release study revealed a desirable pH-responsive drug release behavior, that was negligible discharge during the first 2 h at pH 1.2 and progressive in the simulated colon environment reaching 71.1 ± 0.34 % at 6 h and 92.4 ± 1.11 % at 24 h. The anticancer effect of the loaded NPs on the human HCT116 cells showed favorable effects at 1 μM concentrations with a significant decrease in the IC50 at days 2 and 3 upon loading albendazole into zein NPs. ZNPs proved to be prospective nanocarriers that could be used for the delivery of repurposed drugs in CRC treatment.

Intratumoral lactic acid neutralization strategy for boosting chemoimmunotherapy using liposomal sodium bicarbonate

Glycolysis-related lactic acid overproduction creates an “ion-trapping” barrier and immunosuppressive tumor microenvironment that compromise effective intratumoral drug delivery and therapy. Therefore, normalization of tumor microenvironment via lactic acid neutralization can be a promising avenue for overcoming this therapeutic hurdle. In this study, the flexible liposomes loaded with sodium bicarbonate (NaHCO3@Flip) were used as a nano-adjuvant to boost chemoimmunotherapy. Their effects on assisting DOXIL and anti-PD-1 therapy were investigated. NaHCO3@Flip achieved deep tumor penetration, with the ability to neutralize lactic acid and normalize the acidic tumor microenvironment. NaHCO3@Flip is biosafe and can enhance cellular uptake efficiency of doxorubicin (DOX) by overcoming the ion-trapping barrier and amplify immunogenic cell death induced by DOX. The combination therapy of liposomal DOX and NaHCO3@Flip demonstrated enhanced inhibition of tumor growth. NaHCO3@Flip can also synergize with PD-1 antibody therapy. NaHCO3@Flip has the potential to serve as a therapeutic adjuvant for boosting chemoimmunotherapy by overcoming the ion-trapping effect and normalizing the tumor microenvironment.

Sinensetin inhibits the movement ability and tumor immune microenvironment of non-small cell lung cancer through the inactivation of AKT/β-catenin axis.

Although current treatment strategies have improved clinical outcomes of non-small cell lung cancer (NSCLC) patients, side effect and prognosis remain a hindrance. Thus, safer and more effective therapeutical drugs are needed for NSCLC. Sinensetin (Sin) is a flavonoid from citrus fruits, which exhibits antitumor effect on diverse cancers. However, the effect and mechanism of Sin on NSCLC remain unknown. In this study, NSCLC cell lines, and tumor-bearing mice were treated with Sin. The effect and mechanism of Sin were addressed using cell counting kit-8, transwell, enzyme-linked immunosorbent assay, hematoxylin and eosin, immunohistochemistry, and western blot analysis assays in both cell and animal models. Sin reduced the cell viability of A549 and H1299, with the IC50 of 81.46 µM and 93.15 µM, respectively. Sin decreased invaded cell numbers, the expression of N-cadherin and vascular endothelial growth factor A (VEGFA), while increased the E-cadherin level, the cytotoxicity of CD8+ T cells, and the concentration of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) in NSCLC cells. Mechanistically, Sin declined the expression of protein kinase B (AKT)/β-catenin pathway, which was restored with the application of SC79, an activator of AKT. The inhibitory role of Sin in NSCLC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and immune escape was reversed by the management of SC79. In vivo, Sin reduced tumor size and weight, and the expression of N-cadherin, VEGFA, and AKT/β-catenin pathway, but enhanced the level of E-cadherin and IFN-γ. Taken together, Sin suppressed cell growth, invasion, EMT and immune escape via AKT/β-catenin pathway in NSCLC.

A long chain fatty acid receptor signaling as a new therapeutic target for stress-induced chronic pain

Psychological and social stresses are known to be risk factors for psychiatric disorders, including depression and anxiety. On the other hand, exposure to these stresses can also cause prolonged and severe pain. However, the pathological mechanism for stress-induced chronic pain is complex, and there are many unresolved aspects, and no effective therapeutic drugs have been established. Since the discovery of the long-chain fatty acid receptor GPR40/FFAR1 about 20 years ago, research on the mechanism that promotes insulin secretion in the pancreas has progressed. Previously, we have worked to elucidate the physiological effects of GPR40/FFAR1 in the central nervous system and has found that it is involved in the regulation of pain and emotion. Based on these findings, they are now investigating the involvement of fatty acid receptors signaling in the development of stress-related chronic pain. In this review, we discuss the status of psychological stress-related chronic pain and the GPR40/FFAR1-mediated and -striking regulatory mechanisms of stress-induced chronic pain, based on our findings using a mouse model of chronic pain created by loading postoperative pain to a social defeat stress model mouse that mimics psychosocial stress. We summarized about the involvement of fatty acid receptor signaling as a new therapeutic candidate for chronic pain in this review.

Unveiling Wide Spectrum Therapeutic Implications and Signaling Mechanisms of Valsartan in Diverse Disorders: A Comprehensive Review.

Valsartan is an orally active non-peptide angiotensin receptor antagonist, an effective and well-tolerated anti-hypertensive drug. Besides its antihypertensive action, it has clinical implications in many other disorders, like heart failure (HF), arrhythmia, chronic kidney disease (CKD), diabetic complications (DM), atherosclerosis, etc. Besides angiotensin receptor blocking activity, valsartan reduces circulating levels of biochemical markers, such as hs-CRP, which is responsible for its anti-inflammatory and anti-oxidant activity. Moreover, valsartan also acts by inhibiting or inducing various signalling pathways, such as inducing autophagy via the AKT/mTOR/S6K pathway or inhibiting the TLR/NF-kB pathway. The current review exhaustively discusses the therapeutic implications of valsartan with specific emphasis on the mechanism of action in various disorders. The article provides a detailed spectrum of the therapeutic profile of valsartan and will likely be very useful to researchers working in the relevant research areas.

Hotspots and Trends in Global Antiviral Herbal Basic Research: A Visualization Analysis

Introduction: Viral infections can become public health emergencies due to the possibility of the wide transmission of their associated pathogens and their rapid variation. Moreover, most viruses lack effective therapeutic drugs and vaccines. Herbal medicines have been clinically validated for their broad-spectrum antiviral properties and their ability to leverage their complex compositions to target multiple levels, pathways, and channels. In this study, we seek to assess the current global research landscape and identify current and future directions for research on antiviral herbal medicines to guide future pharmacological developments. Methods: Bibliometric and visualization methods were used to analyze 2134 Chinese-language and 4600 English-language journal articles published between 2017 and 2022 from both Chinese and international databases, and the theme words and foci of highly cited papers were analyzed. Results: It was found that coronaviruses (especially severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), the influenza virus, the hepatitis B virus, and the human immunodeficiency virus were the primary targets for antiviral herbal medicines. Key herbs included Glycyrrhiza glabra, Lonicera japonica, Scutellaria baicalensis, Ephedra sinica, Forsythia suspensa, Agastache rugosa, Astragalus membranaceus, and Poria cocos. The primary active compounds known to be responsible for these antiviral effects are alkaloids, bioflavonoids, flavonoids, sterols, and polyphenols, including curcumin, quercetin, kaempferol, wogonin, stigmasterol, β-glutosterol, luteolin, coumarins, naringenin, gallic acid, berberine, and andrographolide. These compounds work through mechanisms such as inhibiting viral replication, blocking virus–receptor interactions, destroying viruses, regulating the immune response, oxidative stress induction, and cytokine response suppression. Conclusions: The research foci included the pharmacodynamic foundations, molecular dynamics simulation, and virtual screening of active components in herbs use for the treatment of viral diseases such as SARS-CoV-2 using bioinformatics, macromolecular docking, and network pharmacology. Significant gaps remain in interdisciplinary collaboration, especially regarding herb cultivation, processing, sustainable harvesting, and potential drug interactions.

Histidine-derived carbon dots for redox modulation and gut microbiota regulation in inflammatory bowel disease therapy

Inflammatory bowel disease (IBD) is a chronic inflammation of the colon that is becoming increasingly prevalent. As a result, there is a growing demand for safe, effective, and non-addictive drugs. Herein, we are inspired by using carbon dots-based nanomedicines to regulate redox balance and alleviate inflammatory diseases. Specifically, histidine-derived carbon dots (His-CDs) with antioxidant and multi-enzyme (superoxide dismutase, catalase) activities are synthesized, which not only improve intestinal redox balance, but also demonstrate promising potential in modulating gut microbiota for the treatment of IBD. To understand that underlying activities mechanisms of His-CDs, their precursors, structures, and band gaps are carefully analyzed. Our investigations show that His-CDs effectively reduce oxidative damage to cells and nematodes by scavenging free radicals. Furthermore, we confirm the anti-IBD effects of His-CDs at both cellular and mouse levels. Importantly, our research reveal that His-CDs restore intestinal homeostasis in colitis by regulating the gut microbiota. We further validate this finding through fecal microbiota transplantation, which demonstrate an increase in the abundance of beneficial bacteria in the intestinal tract following the administration of His-CDs. This investigation not only expands the knowledge of nanozymes, but also offers a promising nanomedicine approach for IBD therapy.

Nanotechnology in Drug Delivery: Overcoming Poor Solubility Challenges through Nanoformulations

Abstract: The pharmaceutical sector continues to face difficulties with poorly soluble drug solubility. Insufficiently soluble drugs have low bioavailability, and their effectiveness is frequently affected. Numerous approaches have been developed in response to this challenge, including using various dosage forms, solid dispersions, nano-suspensions, self-emulsifying drug delivery systems, and cyclodextrin complexes. By improving drug dissolving, decreasing drug particle size, and increasing drug dispersion, these dosage forms seek to increase drug solubility. Nanotechnology is one of the latest advances that has the potential to revolutionize the delivery of drugs and significantly improve the solubility of drugs that are now poorly soluble. Since they have a larger surface area and can pass through biological barriers, nanoparticles are particularly well suited for the delivery of drugs. These technologies can potentially enable the development of more effective and efficient drug formulations for the treatment of various diseases. In addition, the review highlights recent advances in the field, including emerging technologies such as nanotechnology, which can revolutionize drug delivery and significantly improve the solubility of poorly soluble drugs with their potential applications.

Research Progress of Natural Products with the Activity of Anti-nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), a multi-target disease, is becoming a global epidemic. Although several anti-NASH drug candidates are being evaluated in late-stage clinical trials, none have been approved by the FDA to date. Given the global prevalence of the disease, the lack of effective drugs, and the very limited therapeutic efficacy of most of the existing synthetic drugs focusing on a single target, there is an urgent need to continue to develop new therapeutic agents. In contrast, many natural products, including pure compounds and crude extracts, possess hepatoprotective activities. Usually, these natural components are characterized by multi-targeting and low side effects. Therefore, natural products are important resources for the development of new anti- NASH drugs. In this paper, we focus on reviewing the anti-NASH potential, structure, and some of the side effects of natural products based on structural classification. We hope this mini-review will help researchers design and develop new anti-NASH drugs, especially based on the structure of natural products.

AI-assisted autonomous manufacturing of tailored drug-loaded nanoparticles by multi-step continuous-flow platform

In the development of highly effective drug delivery systems (DDS), autonomous multi-step manufacturing of tailored nanoparticles in size and drug loading was achieved by seamlessly integrating combinatorial synthesis of drug-loaded nanoparticles, rapid flow-dialysis to purify them, followed by real-time characterization of size and encapsulation efficiency (EE) in a continuous-flow manner. To accomplish this, a newly developed ultrafast flow-dialysis module with multiple buffer injectors for efficient removal of impurities within 10 min was utilized. These integrated multi-step flow processes were autonomously controlled by leveraging a multi-objective Bayesian optimization (MOBO) algorithm. Consequently, this artificial intelligence (AI)-assisted rapid screening of multi-step parameters accomplished the swift manufacturing of both Doxorubicin (DOX)-loaded liposomes and polymeric nanoparticles, customized in terms of size and drug loading within 6 h for each. This AI-based autonomous platform envisions accelerating the development timeline for bespoke DDS applications, addressing diverse therapeutic needs in the field of nanomedicine.

Targeting MurG Enzyme in Klebsiella pneumoniae: An In Silico Approach to Novel Antimicrobial Discovery

Antibiotic resistance poses a global crisis fuelled by widespread antibiotic use, particularly against Gram-negative bacteria like Klebsiella pneumoniae, a leading cause of hospital-acquired infections with high mortality rates. Urgent identification of effective drug targets is imperative, with a focus on metabolic pathways to inhibit bacterial growth. Targeting the crucial metabolic pathways of K. pneumoniae would be a more efficient way to prevent its growth and the diseases that it causes. The present study focused on inhibiting the UDP-N-acetylglucosamine--N-acetylmuramyl-(pentapeptide)pyrophosphoryl-undecaprenol N-acetylglucosamine transferase (MurG) enzyme, which is a key enzyme in peptidoglycan synthesis pathway. A high throughput virtual screening was used to find possible lead molecules from Enamine -High-Throughput Screening Centre library. The resulting high binding affinity ligands were further assessed for their drug-likeness and other pharmacokinetic properties. Based on these analyses, the three ligands Z95813755_1, Z324718246_1 and Z324718246_2 were selected for further molecular dynamic simulation studies. The molecular dynamic simulation results and MM/PBSA analysis predicted that both Z95813755_1 and Z324718246_2, molecules show higher affinity towards MurG. For the first time we are reporting potential inhibitors against MurG from K. pneumoniae, providing new insights in management of multi drug resistant K. pneumoniae infections.

The heterogeneity of breast cancer metastasis: a bioinformatics analysis utilizing single-cell RNA sequencing data.

Breast cancer is a common malignancy in women, and its metastasis is a leading cause of cancer-related deaths. Single-cell RNA sequencing (scRNA-seq) can distinguish the molecular characteristics of metastasis and identify predictor genes for patient prognosis. This article explores gene expression in primary breast cancer tumor tissue against metastatic cells in the lymph node and liver using scRNA-seq. Breast cancer scRNA-seq data from the Gene Expression Omnibus were used. The data were processed using R and the Seurat package. The cells were clustered and identified using Metascape. InferCNV is used to analyze the variation in copy number. Differential expression analysis was conducted for the cancer cells using Seurat and was enriched using Metascape. We identified 18 distinct cell clusters, 6 of which were epithelial. CNV analysis identified significant alterations with duplication of chromosomes 1, 8, and 19. Differential gene analysis resulted in 17 upregulated and 171 downregulated genes for the primary tumor in the primary tumor vs. liver metastasis comparison and 43 upregulated and 4 downregulated genes in the primary tumor in the primary tumor vs lymph node metastasis comparison. Several enriched terms include Ribosome biogenesis, NTP synthesis, Epithelial dedifferentiation, Autophagy, and genes associated with epithelial-to-mesenchymal transitions. No single gene or pathway can clearly explain the mechanisms behind tumor metastasis. Several mechanisms contribute to lymph node and liver metastasis, such as the loss of differentiation, epithelial-to-mesenchymal transition, and autophagy. These findings necessitate further study of metastatic tissue for effective drug development.

Non-local impact of distal airway constrictions on patterns of inhaled particle deposition.

Airway constriction and blockage in obstructive lung diseases cause ventilation heterogeneity and create barriers to effective drug deposition. Established computational particle-deposition models have not accounted for these impacts of disease. We present a new particle-deposition model that calculates ventilation based on the resistance of each airway, such that ventilation responds to airway constriction. The model incorporates distal airway constrictions representative of cystic fibrosis, allowing us to investigate the resulting impact on patterns of deposition. Unlike previous models, our model predicts how constrictions affect deposition in airways throughout the lungs, not just in the constricted airways. Deposition is reduced in airways directly distal and proximal to constrictions. When constrictions are clustered together, central-airways deposition can increase significantly in regions away from constrictions, but distal-airways deposition in those regions remains largely unchanged. We use our model to calculate lung clearance index (LCI), a clinical measure of ventilation heterogeneity, after applying constrictions of varying severities in one lobe. We find an increase in LCI coinciding with significantly reduced deposition in the affected lobe. Our results show how the model provides a framework for development of computational tools that capture the impacts of airway disease, which could significantly affect predictions of regional dosing.

Structural characterization and anti-hyperuricemic effect of a mannogalactan from Armillariella tabescens mycelium

Hyperuricemia and its complications caused by purine metabolism disorder continue to occur, which require effective drug treatment with fewer side effects. This study explored the positive effects of a natural homogeneous polysaccharide (AT-W) from the mycelium of Armillariella tabescens in a mouse hyperuricemia model. Structural characterization showed that the average molecular weight of AT-W is 25.6 kDa, and it is composed of mannose, galactose, arabinose, and fucose, with molar percentages of 11.46:70.9:4.96:12.67. The main backbone of AT-W is composed of partially 3-O-methylated →6)-α-Galp-(1→, and the branches are mainly composed of α-Manp-(1→, →3)-α-Fucp-(1→. In vivo bioactivity evaluation showed AT-W could not only reduce serum uric acid levels by inhibiting the activity of xanthine oxidase, upregulating the expression of ABCG2 and OAT1, and downregulating the expression of URAT1 but also have a significant protective effect on renal damage caused by hyperuricemia. These findings indicate that AT-W has therapeutic potential for hyperuricemia diseases.

A theranostic photosensitizer-conjugated albumin co-loading with resiquimod for cancer-targeted imaging and robust photo-immunotherapy

Cancer immunotherapy remains a low immune response rate in clinic because of dominant immunosuppressive tumor microenvironment (TME) and lack of effective drug to specifically remodel the TME. In this work, we introduced a tumor-seeking human serum albumin (HSA) based delivery platform by covalently conjugating with a tumor-targeting near-infrared (NIR) photosensitizer (IR-DBI) and non-covalently loading of immune modulator Resiquimod (R848). HSA exhibited tumor-preferential accumulation after covalent conjugation with IR-DBI. Meanwhile, HSA restricted the rotation of IR-DBI, narrowed the HOMO-LUMO energy gap, significantly enhanced fluorescent intensity and dual-modal phototherapy (PTT/PDT). The enhanced phototherapeutic effect further induced robust ICD effect. More importantly, non-covalent loading of R848 could be released from HSA at tumor sites by laser irradiation-induced heat. The in-situ release of R848 in TME efficiently promoted the maturation of DC cells and repolarized M2 macrophages to M1 macrophages. Consequently, robust photo-induced antitumor immunity was triggered in the different mice models bearing primary and distant tumors or lung metastasis, which was further enhanced by combining with CTLA-4 blockade therapy. Taken together, this work may present a versatile albumin composite which exhibits tumor-preferential accumulation and imaging-guided PDT/PTT/immunotherapy.

Design Formulation of Nanospanlastic Novel Carriers as a Promising Approach to Enhanced Bioavailability in Intranasal Drug Delivery for Sinusitis: Statistical Optimization and In vitro and In vivo Characterization

Background: Most new biologically active chemicals require better water solubility and slower dissolution rates. Cefdinir (CFD) has a very low bioavailability in its crystalline form and is poorly soluble in water. Objective: By preparing cefdinir's spanlastic nanovesicles (SNVs) using the ethanol injection method, the current study has attempted to enhance the drug's solubility and bioavailability using a statistical design approach. Methods: Independent variables, including the nonionic surfactant concentration, edge activator (EA), sonication time, SNVs entrapment efficiency, particle size, zeta potential, PDI, and in vitro release, have been evaluated. The best CFD-SNVs were positioned within in situ gel with muco-adhesive properties made of hydroxypropyl methylcellulose and deacetylated gellan gum. By contrasting intranasal injection of the produced gel with an IV solution, animal models have been used to investigate CFD's systemic and cerebral dynamics. Results: Statistical analysis has suggested an ideal SNVs formulation with nonionic surfactant (65 mg), EA (15 mg), and sonication (3 min). The sol-gel temperature for forming the mucoad-hesive in situ gel containing SNVs has been found to be 34.03°C, and 18.36 minutes has been the extended mucociliary transit time. Following intranasal injection, compared to SNV dispersion, the gelling system has exhibited higher brain bioavailability (2251.9 ± 75 vs. 5281.6 ± 51%, re-spectively). The gel has also demonstrated effective drug targeting of the brain with higher direct transport percentage indices. Conclusion: Mucoadhesive in situ gel with CFD-loaded SNVs can be administered via the in-tranasal route. To enhance bioavailability in the brain and drug targeting from the nose to the brain, nasal in situ gel loaded with CFD-SNVs could be a new carrier to be employed in sinusitis.

Qihuang Zhuyu Formula Modulates Mitochondrial Function to Inhibit Platelet Activation via Endocannabinoid Signaling Mediated by the SIRT1/PPARα Pathway

Ethnopharmacological relevanceDeveloping effective drugs is urgent for preventing platelet activation and atherosclerotic disease. Qihuang Zhuyu Formula (QHZYF) is a curative medical plants formula in clinic while its molecular mechanism remains to be further elucidated. Aim of the studyTo investigate how QHZYF, via the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor alpha (PPARα) pathway, mediates the endocannabinoid system, regulates mitochondrial function, and inhibits platelet activation, thereby offering novel strategies for the prevention and treatment of cardiovascular diseases. MethodsThe chemical constituents of QHZYF were characterized by ultra-performance liquid chromatography tandem with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS). For the in vivo experiments, an atherosclerosis rat model was developed. Platelet activation and endocannabinoid levels were assessed by ELISA, while the expression of PPARα was evaluated by immunofluorescence. Additionally, the expression of endocannabinoid-degrading enzymes was analyzed by Western blotting. In the in vitro studies, the protein-protein interaction between SIRT1 and PPARα was initially investigated using co-immunoprecipitation (Co-IP). Thereafter, platelets were co-cultured with human umbilical vein endothelial cells (HUVECs) stimulated by oxidized low-density lipoprotein (ox-LDL). The mitochondrial function of platelets was examined by flow cytometry. Platelet activation and endocannabinoid levels were quantified using ELISA, and the expression of PPARα and endocannabinoid-degrading enzymes was determined by Western blotting. Subsequently, QHZYF was incorporated into the aforementioned system, and the entire experimental protocol was replicated to explore how QHZYF influences platelet activation through the SIRT1/PPARα pathway-mediated endocannabinoid system. ResultsIn the in vivo experiments, it was observed that QHZYF significantly augmented the levels of SIRT1 and PPARα, concurrently with a decrease in the expression of endocannabinoid-degrading enzymes. This was paralleled by a rise in endogenous cannabinoid levels and a reduction in platelet activation, a process that was found to be regulated by SIRT1. The co-immunoprecipitation (Co-IP) analysis substantiated the cooperative interaction between SIRT1 and PPARα, underscoring their role in mediating the endocannabinoid system, regulating mitochondrial function, and consequently influencing platelet activation. In the in vitro studies, a co-culture system involving platelets and HUVECs stimulated with ox-LDL was employed. It was noted that the SIRT1/PPARα pathway mediates the endocannabinoid system in regulating mitochondrial function, which in turn affects platelet activation. The incorporation of QHZYF-containing serum into this system produced outcomes consistent with those observed in the in vivo experiments. These findings suggest that QHZYF operates by modulating the endocannabinoid system via the SIRT1/PPARα pathway, thereby controlling mitochondrial function and inhibiting platelet activation. ConclusionSIRT1 may mediate endogenous cannabinoid signaling through its interaction with PPARα, regulating mitochondrial function and subsequently influencing platelet activation. QHZYF effectively modulates the endocannabinoid system via the SIRT1/PPARα pathway, thereby inhibiting platelet activation.