Current pharmaceutical design最新文献

Background: Clinical Hereditary Hemolytic Anemia (HAA) particularly Hereditary Spherocytosis (HS) encompasses diverse genetic disorders causing premature red blood cell destruction and intrinsic RBC defects. There's a pressing need for standardized diagnostic protocols tailored to the Asian population, particularly in Saudi Arabia, underscoring the significance of thorough blood biochemistry analysis.

Materials and methods: A case-control prospective study was conducted at King Abdulaziz University, samples were obtained from King Fahad, hospital Jeddah, Saudi Arabia, serving a significant population, and blood samples from 27 patients meeting ethical criteria for HHA and HS. Inclusion criteria included diagnosed patients of any age and sex, while exclusion criteria encompass chronic infections, metabolic diseases, pregnancy, and lactation. Blood profiling was conducted following strict protocols, aiming to glean insights into patients' management and therapeutic strategies. Despite an intended larger sample size, limitations in availability led to the inclusion of 27 patient analyses.

Results: Among 27 participants, males comprised 59.3%, females 40.7%. Anemia types indicated 22.2% Type 1 (HHA) and 77.8% Type 3 (HS). Age groups (<30, 31-59, ≥60 years) highlighted HS prevalence, notably in older individuals. Blood pressure analysis revealed age-related increases, especially in those over 60 with systolic BP (147.33 ± 9.86 mm/Hg) (p≤0.02) and diastolic BP (85.67 ± 9.01 mm/Hg) (p≤0.03) emphasizing agespecific monitoring. Temperature variations were noted across ages, significant in patients over 60 (35.93 ± 1.100C) (p≤0.09), indicating potential clinical relevance. Iron levels showed no age-related differences, while Blood Urea Nitrogen (BUN) levels rose with age, particularly in those over 60 (35.83 ± 16.67 mm/dL) (p≤0.04), suggesting age-related influence. Alkaline Phosphatase levels increased with age, especially in patients aged 31 to 59 (205.80±123.17IU/L)(p≤0.001), warranting further investigation. Similarly, Aspartate Transferase levels rose with age, especially in patients aged 31 to 59 (134.69 ± 284.58 U/L) (p≤0.01),), underlining age-specific considerations. Notable differences in BUN (15.03 mm/dL and 29.06 mm/dL)and Aspartate Transferase (33.01 U/L and 115.66 U/L) levels were observed among different anemia types with no major significant alteration in LDH.

Conclusion: The results suggest unique biochemical signatures with potential renal and hepatic implications, underscoring the importance of biochemical assessment in managing hereditary hemolytic anemias, particularly HS.

Objective: The present study delves into the exploration of diagnostic biomarkers linked with ferroptosis in the context of diabetic nephropathy, unraveling their underlying molecular mechanisms.

Methods: In this study, we retrieved datasets GSE96804 and GSE30529 as the training cohort, followed by screening for Differentially Expressed Genes (DEGs). By intersecting these DEGs with known ferroptosisrelated genes, we obtained the differentially expressed genes related to ferroptosis (DEFGs). Subsequently, Weighted Correlation Network Analysis (WGCNA) was carried out to identify key modules associated with Diabetic Nephropathy (DN), culminating in the identification of a significant gene. Enrichment analysis and Gene Set Enrichment Analysis (GSEA) were then carried out on the DEFGs and genes linked to the significant gene. To validate our findings, we employed cohorts GSE30528 and GSE43950, utilizing ROC curve analysis to assess diagnostic efficacy for DN, as measured by the area under the curve (AUC). Immune cell infiltration was analyzed and compared between groups using the CIBERSORT algorithm. Bayesian colocalization analysis was performed to examine the co-location of DEFGs and DN. Finally, to validate the hub genes identified, we conducted quantitative real-time polymerase chain reaction (qRT-PCR) experiments in vitro.

Results: FUZ, GLI1, GLI2, GLI3, and DVL2 were identified as the hub genes. Functional enrichment analysis demonstrated that ferroptosis and immune response play an important role in DN. ROC analysis showed that the identified genes had good diagnostic efficiency in DN. The results of the immune infiltration analysis showed that there may be crosstalk between ferroptosis and immune cells in DN. Bayesian co-localization analysis revealed the genetic correlation between the hub genes and DN. The outcomes of the qRT-PCR analyses corroborated the reliability of the identified hub genes as robust molecular markers for targeted therapy in DN.

Conclusion: The interplay between immune inflammatory reactions and ferroptosis emerges as a crucial pathogenic mechanism, offering novel insights into the molecular therapy of DN. Furthermore, the identification of FUZ, GLI1, GLI2, GLI3, and DVL2 as potential targets holds promise for future therapeutic interventions aimed at treating DN.

Introduction: Most Breast Cancer (BC) patients undergoing Radiotherapy (RT) are potentially susceptible to skin toxicity and prone to clinical symptom complaints. This study aimed to investigate the effect of oral Atorvastatin (ATV) administration on skin toxicity in BC patients undergoing RT.

Methods: One hundred BC patients were randomly assigned to oral ATV (40 mg) or placebo tablets two days before beginning the RT until the eighth week of the RT regimen was completed. Radiation-induced dermatitis was classified according to the Radiation Therapy Oncology Group (RTOG) criteria for eight weeks of treatment. In addition, during the eight weeks of RT, the clinical symptoms, such as pain, itching, burning, and sensitivity, were scored by patients in both groups according to the Visual Analogue Scale (VAS).

Results: Ninety-four BC patients were analyzed in this study. At the end of the seventh week of RT, the between- group analysis showed a statistically significant reduction of 20.7% in the ATV group (1.693 ± 0.846) compared to the placebo group (1.900 ± 0.986, P=0.036). However, the comparison of the dermatitis grade in the ATV and placebo groups showed a reduction of 54.5% in the ATV group; this difference was not statistically significant (p = 0.072). The results of VAS regarding the clinical symptoms of patients showed pain, itching, burning, and sensitivity to touch to be clinically decreased in the ATV group compared to the placebo group in the 8 weeks, but these differences were not statistically significant.

Conclusion: According to the results of this clinical study, the oral administration of ATV at a dose of 40 mg during RT regimens can effectively reduce skin RT-induced toxicity and improve the self-report clinical symptoms among BC patients.

The increasing global prevalence of obesity (OB) calls for the development of effective treatments. Traditional Chinese Medicine (TCM) offers a promising approach by modulating gut microbiota (GM) to enhance the production of short-chain fatty acids (SCFAs). Research has demonstrated that SCFAs can regulate appetite and energy expenditure via the Central Nervous System (CNS), underscoring the role of the gut-brain axis in maintaining energy balance. A comprehensive review of the literature was conducted using databases, such as ScienceDirect, Google Scholar, and PubMed. The focus was on the impact of TCM on SCFA production and its influence on appetite regulation and energy expenditure through the CNS. This review indicates that TCM enhances the production of SCFAs, which suppress appetite and increase energy expenditure through their interaction with the CNS, particularly the gut-brain axis. TCM demonstrates promise as a therapeutic strategy for obesity by enhancing the production of SCFAs and regulating energy balance. This approach presents a novel avenue for obesity treatment through the modulation of the microbiome.

Intrauterine Adhesions (IUAs) are characterized by endometrial damage due to endometritis or curettage. Currently, the gold standard for IUA treatment is hysteroscopy, which enables the dissolution of IUA through mechanical or electrosurgical energy. Common strategies to prevent recurrence include the insertion of a balloon catheter or IUD in the uterus. Although hysteroscopy and postoperative strategies improve the uterine cavity's morphology and menstrual flow in some patients, infertility and adhesion recurrence rates are among the problems that persist. Mesenchymal Stem Cells (MSCs) are ideal for tissue regeneration due to their self-renewal and immunomodulatory characteristics. MSCs also exert anti-fibrotic properties in IUA treatment. However, the clinical application of stem cells is limited due to safety concerns and cost. In this review, we have summarized the recent advances in the application of MSCs in IUA treatment.

Exosomes are small extracellular vesicles secreted by various cell types, playing a crucial role in intercellular communication by carrying proteins, lipids, and nucleic acids, thus holding significant potential in diagnostics and therapeutics. Accurate labeling of exosomes is vital for studying their biogenesis, trafficking, and functional properties, enabling precise tracking and manipulation. This review examines current labeling techniques, including metabolic glycan labeling, chemical tagging, membrane fluorescent dyes, bio-conjugation, non-covalent labeling, and cell-engineering approaches. Each method is analyzed for its efficiency, specificity, and practicality, with attention to potential artifacts and challenges. Advancements in these techniques are essential for improving our understanding of exosome biology and developing exosome-based diagnostic and therapeutic strategies, providing researchers with valuable insights into state-of-the-art techniques and their applications in exosome research.

Background: Patients with hepatic encephalopathy (HE) have many triggers and a high mortality rate. The protective effect of existing therapeutic drugs on the liver is weak. We found that Danggui Shaoyao Powder can improve the symptoms of HE and may have a better liver protection effect. And the mechanism of it is unclear.

Objective: The research explores the mechanism of Danggui Shaoyao Powder for the treatment of HE through network pharmacology, molecular docking and molecular dynamics.

Methods: Targets of Danggui Shaoyao Powder were screened from Traditional Chinese Medicine System Pharmacology Platform (TCMSP), SwissTargetPrediction, and Uniport. GeneCards was used to gain targets of HE. Further, core targets and ingredients were screened by protein-protein interaction network (PPI) and herbs-compounds-targets network. Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were completed to screen relative sites and signaling pathways. Molecular docking and dynamics were used to show the stability of ligand-receptor complexes.

Results: IL6, SRC and kaempferol, beta-sitosterol were screened as the top two core targets and ingredients. Dendrites, dendritic trees, and membrane sides were defined as the main sites of action. Core signaling pathways were screened such as: PI3K-Akt and MAPK. Molecular docking shows well-defined binding sites and the stability of the binding is demonstrated by molecular dynamics.

Conclusion: Through this study, Danggui Shaoyao Powder may act on IL6, SRC, and other targets through ingredients such as kaempferol and beat-sitosterol and regulate signaling pathways such as PI3K-Akt, MAPK and NF-κB to the treatment of HE.

Introduction: Datura stramonium (DS) possesses strong medicinal and therapeutic potential but has been rarely evaluated in this context.

Methods: The present study was intended to evaluate the antioxidant, hepatoprotective, and nephroprotective potential of the crude methanolic leaf extract and ethyl acetate, chloroform, n-hexane, and aqueous fractions of DS in paracetamol-intoxicated rabbits. Paracetamol (2 g/Kg BW) was applied to induce liver and kidney injury in rabbits while the methanolic extract and fractions of DS were applied in the dose range of 150 mg/Kg to 300 mg/Kg body weight for 21 days. Histopathology of the liver, and kidney and analysis of ALT (Alanine Transaminase), ALP (Alkaline Phosphatase), total bilirubin, serum urea, serum creatinine, and serum uric acid were carried out. In-vitro antioxidant potential of the extract and fractions of DS was carried out through DPPH (1,1-diphenyl 2-picrylhydrazyl) free radical scavenging assays.

Results: The hepatoprotective and nephroprotective potential of the extract and fractions of DS at the dose level of 300 mg/Kg BW was highly significant (P ˂ 0.01). ALT was found elevated in the paracetamol-treated group (117.3 ± 1.61 U/L) compared to the group treated with methanolic extract of DS, (57.3 ± 0.87 U/L) and normal control group (60.6 ± 1.58 U/L) at 300 mg/kg BW. Elevated levels of ALP (120 ± 1.58 U/L) and Bilirubin (1.6 ± 0.32 mg/dl) were found in the paracetamol-treated group compared with the group treated with methanolic extract of DS (67.5 ± 1.35 U/L; 0.2 ± 1.0 mg/dl) and normal control group (70.1 ± 1.53 U/L; 0.4 ± 0.16 mg/dl) respectively at 300 mg/kg BW. The methanolic extract of DS produced a marked scavenging activity of the DPPH free radicals (88.2 ± 0.006 %) followed by the fractions of DS compared to ascorbic acid (95.5 + 0.003 %) at a concentration of 1000 μg/ml. The effects were comparable to those produced by ascorbic acid. Liver and kidney histology of the rabbits treated with extract, fractions, and ascorbic acid of DS caused reductions in the pathological features compared to the paracetamol-treated animals. The histological observations and chemical pathological alterations demonstrated the significant hepatoprotective and nephroprotective benefits of the DS extract and its fractions.

Conclusion: It has been concluded that the methanolic extract and fractions of DS possess antioxidant, hepatoprotective, and nephroprotective properties in paracetamol-intoxicated rabbits.

Amyotrophic Lateral Sclerosis (ALS), is a progressive neurodegenerative disease characterized by motor symptoms, and cognitive impairment. The complexity in treating ALS arises from genetic and environmental factors, contributing to the gradual decline of lower and upper motor neurons. The anticipated pharmaceutical market valuation for ALS is projected to reach $1,038.94 million by 2032. This projection underscores the escalating impact of ALS on global healthcare systems. ALS prevalence is expected to surge to 376,674 cases by 2040. In 2022, India ranked among the top 3 Asian-Pacific nations, while North America dominated the global ALS market. Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese Medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management.

Aim: The aim of the current study was to explore nano-formulation for effective neuroprotection by auranofin.

Background: Currently, the treatment options for various CNS disorders, particularly neurodegenerative disorders, are greatly constrained. A significant obstacle in this pursuit is the blood-brain barrier, a shielding covering that hinders the route of numerous biochemical treatments into the brain. To overcome this problem, nanoformulation- based approaches are gaining interest, increasing the compound's BBB penetrability.

Objective: The objective of this study was to evaluate whether nanoparticles fabricated from poly(lactic-co-glycolic acid) encapsulated with auranofin could oppose aluminium chloride-induced Alzheimer's disease.

Method: Auranofin-encapsulated PLGA nanoparticles were prepared, and their particle size, Entrapment Efficiency (EE), distribution of particles, morphological surface charge, and structural characteristics were characterized. During the in vivo study, rats were orally administered AlCl3 at 100 mg/kg for 21 days. Meanwhile, auranofin and auranofin nanoparticles were orally administered at doses of 5 and 10 mg/kg and 2.5 and 5 mg/kg, respectively, within 2 weeks. After the course therapy, the rats were decapitated, and the hippocampus was collected for the estimated biochemical and neuroinflammatory markers.

Results: The auranofin nanoparticles were characterized, revealing % entrapment efficiency (98%) and % loading dose (76%). The nanoparticles exhibited a morphological surface charge of 27.5 ± 5.10 mV, a polydispersity index of 0.438 ± 0.12, and a mean particle size of 101.5 ± 10.3 nm. In the in vivo study, administering a gold compound (auranofin) and formulation (auranofin nanoparticles) resulted in a significant improvement in cognitive deficits, changes in biochemical parameters, and markers of neuroinflammation triggered with aluminium chloride.

Conclusion: The results have suggested that auranofin nanoparticles demonstrate abilities to protect neurons compared to auranofin alone. The noticed therapeutic benefits of the auranofin-encapsulated PLGA nanoparticles can be attributed to modulation in particle size with antioxidative and anti-inflammatory impacts of auranofin. Consequently, the outcome of the research has revealed that gold compound nanoparticles hold the potential to be a promising option for altering the therapeutic course of Alzheimer's disease.