Current pharmaceutical design最新文献

Background: Triple-negative breast cancer (TNBC) is characterized by the absence of HER2 expression, progesterone receptor (PR), and estrogen receptor (ER). TNBC has a poor prognosis and limited therapy options due to its lack of specific targets and aggressive behavior.

Aim: This review demonstrates the therapeutic efficacy and mechanisms of natural compounds in targeting key molecular pathways involved in the development and progression of TNBC, investigating their interaction with oncogenic signaling pathways.

Methods: A thorough literature review was conducted using databases such as PubMed, Scopus, and Web of Science to identify studies assessing the anti-TNBC properties of natural compounds.

Results: Natural bioactive compounds like curcumin, resveratrol, quercetin, EGCG, berberine, and thymoquinone have demonstrated promising anticancer properties in TNBC models. These limit metastasis, induce apoptosis, inhibit proliferation, and reverse chemoresistance by altering vital pathways like PI3K/AKT/ mTOR, MAPK/ERK, NF-κB, JAK/STAT, and Wnt/β-catenin. For example, quercetin inhibits NF-κB signalling and increases the cytotoxicity of doxorubicin, but curcumin decreases AKT phosphorylation. Furthermore, natural compounds may enhance immune response in BRCA-mutated TNBC by modifying immunological checkpoints, including PD-L1, when combined with PARP inhibitors.

Conclusion: Natural compounds are a promising supplementary method for TNBC therapy due to their ability to target unregulated pathways and overcome therapeutic resistance. Nevertheless, challenges such as pharmacokinetics, limited bioavailability, and a lack of clinical validation persist. Future research should focus on combinatorial regimens, nanocarrier-based delivery technologies, and biomarker-guided clinical trials to develop successful TNBC treatments.

Cytokine Release Syndrome (CRS) is a hyperinflammatory condition triggered by infections, immunotherapies, and systemic immune dysregulation. PANoptosis, a unique form of programmed inflammatory cell death that integrates pyroptosis, apoptosis, and necroptosis, has emerged as a key contributor to CRS pathogenesis. This review explores the mechanistic role of PANoptosis in CRS, with particular emphasis on immunotherapy-induced toxicity and viral infections such as SARS-CoV-2 and influenza. PANoptosis exacerbates cytokine storms through ZBP1, NLRP3, and CASP8-mediated pathways, creating a pathological feedback loop that intensifies inflammation and promotes multi-organ damage. Current evidence suggests that modulating PANoptotic pathways, including targeting TNF-α, IFN-γ, and inflammasome components, may mitigate cytokine-driven tissue injury. Despite growing interest, the therapeutic potential of PANoptosis remains underexplored. Advancing our understanding of PANoptosis and its interaction with cytokine signaling will be critical for developing effective interventions for CRS and improving outcomes in patients undergoing immunotherapy or battling severe infections.

Objectives: The delivery of healthcare services via information and communication technology, or telemedicine, has grown to be an essential part of modern medicine. This study explores the evolving role of telemedicine, focusing on its expansion into the Metaverse, and evaluates its potential to improve healthcare accessibility, patient engagement, and medical outcomes.

Methods: A comprehensive analysis of the literature was conducted, evaluating studies investigating the efficacy of telemedicine in different medical fields, notably mental health, chronic disease management, and postsurgical follow-ups. This study assessed the impact of emerging technologies, specifically virtual reality (VR) and augmented reality (AR), on telemedicine, emphasizing their applications within the Metaverse. Furthermore, ethical considerations, insurance limitations, and technological disparities were assessed.

Results: Telemedicine has significantly enhanced healthcare access, especially in remote and underserved regions. Patient satisfaction and purpose to continue with telemedicine services are elevated, particularly in specialized areas like Tele-stroke and mental health counseling.

Discussion: The Metaverse has the potential to transform telemedicine through the establishment of immersive and interactive healthcare settings. VR and AR have the potential to facilitate virtual consultations, enhancing the interaction between patients and healthcare professionals. Additionally, the integration of data may lead to improvements in diagnostic accuracy and treatment planning. However, issues such as data privacy, cybersecurity hazards, and the digital gap must be addressed to provide adequate access.

Conclusion: Telemedicine has demonstrated significant utility within modern healthcare, and its incorporation with the Metaverse offers novel prospects for improving patient care, advancing medical education, and facilitating collaborative research. Despite the promising benefits, it is crucial to address technological, ethical, and regulatory challenges to ensure widespread adoption and successful implementation.

Introduction: Disorders of mood and post-traumatic stress disorder (PTSD) are common after major trauma, and one of the treatments used is Tricyclic Antidepressants (TCA). These medications work by inhibiting the re-uptake of neurotransmitters like serotonin and noradrenaline. Serotonin is known to have measurable effects on bone tissue due to the presence of specific receptors on bone cells. However, there are conflicting reports about how serotonin signaling affects bone tissue and the process of fracture healing. This study aimed to evaluate the effect of TCAs on fracture healing.

Method: Twelve skeletally mature Wistar rats were used in the study. All rats underwent intra-medullary pinning of the right tibia, and a complete mid-diaphyseal fracture was created. The rats were then randomly split into two groups: a control group and a study group. For twenty-eight days, the study group received a daily dose of 10 mg/kg of amitriptyline via intraperitoneal infusion, while the control group received an equal volume of plain saline via the same route. On day twenty-eight, five hours after the final dose, all rats were euthanized to assess fracture healing using radiological, microscopic, and histological methods.

Results: The study found a significant difference in the total volume of new bone formation between the two groups on day twenty-eight. The control group had a mean bone formation volume of 1.077 mm³, whereas the amitriptyline-treated group had a significantly higher mean volume of 1.824 mm³ (p<0.01).

Discussion: The results suggest that TCAs positively influence the early phases of fracture healing. The increased new bone formation observed in the amitriptyline group indicates a potential therapeutic benefit beyond their known psychiatric effects. This finding adds to the existing literature on the complex relationship between serotonin signaling and bone metabolism, providing evidence that this class of antidepressants may enhance the process of bone repair.

Conclusion: Tricyclic Antidepressants, specifically amitriptyline, significantly increase new bone formation in the early stages of fracture healing in Wistar rats.

Cataract remains one of the leading causes of blindness worldwide. Studies have shown that its onset is predominantly age-related, particularly affecting the elderly. According to the latest report by the World Health Organization (WHO), more than fifty percent of global blindness cases are attributed to cataracts alone. If timely and appropriate measures are not implemented, this percentage is projected to double in the coming decades. Therefore, there is an urgent need to develop alternative approaches to manage cataracts more effectively, beyond the current reliance on surgical intervention. In recent years, researchers have been actively exploring simpler, non-surgical treatment options that could potentially dissolve cataracts in their early stages. The successful development of such therapies would mark a significant breakthrough and offer immense benefits to humanity. This article highlights the evolution of surgical techniques used in cataract management, from traditional practices to modern innovations, while also discussing emerging non-invasive strategies such as lanosterol-based pharmacotherapy, nanomedicine-driven drug delivery systems, and regenerative approaches like stem cell therapy. These advances signal a promising future for safer, more accessible, and more effective cataract care.

Introduction: The Xianlinggubao capsule (XLGB), a traditional Chinese medicine formulation approved by the China Food and Drug Administration, has been effectively used to treat two common medical conditions: osteoarthritis (OA) and osteoporosis (OP). However, due to the complex ingredients, the molecular mechanisms underlying its therapeutic effects for OA and OP remain unknown.

Methods: This study identified XLGB-related therapeutic target genes and pathways for OA and OP by using bioinformatics and network pharmacology. Molecular docking assessed the interactions between core genes and compounds, while quantitative real-time PCR and Western blotting analyses validated the mRNA and protein expression of key target genes.

Results: Bioinformatics analysis identified 473 unique genes common to OA and OP. Network pharmacology analysis identified 30 intersecting genes as the principal target genes for anti-OA and anti-OP effects. Ten hub genes were identified using protein-protein interaction as potential therapeutic targets. These genes were related to transcription regulation and enriched in certain signaling pathways, such as interleukin-17 and tumor necrosis factor. Molecular docking analysis revealed danshenxinkun B to exhibit a strong affinity for Ptgs2, Fos, and Tnfaip3, while miltirone displayed a strong affinity for Ptgs2. The experimental results have been verified using cellular experiments.

Discussion: This study showed Ptgs2, Fos, and Tnfaip3 to be mainly enriched in interleukin-17 and tumor necrosis factor signaling pathways. Moreover, danshenxinkun B and miltirone significantly modulated the expression levels of these genes.

Conclusion: This study has demonstrated that danshenxinkun B and miltirone may be pivotal agents in treating OA and OP by down-regulating the expressions of Ptgs2, Fos, and Tnfaip3.

Introduction: Increasing anion gap (AG) correlates with both short- and long-term mortality in intensive care unit (ICU) patients with acute kidney injury (AKI). However, the relationship between AG fluctuations and AKI prognosis has been understudied. This study aims to evaluate the predictive value of AG fluctuations within the first 48 hours after ICU admission for renal recovery and 30-day all-cause mortality in AKI patients.

Methods: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC-IV, v2.2) database, including AKI patients aged 18 and older. A multifactorial Cox regression model was employed to assess the impact of AG fluctuations within 48 hours of ICU admission on mortality, adjusted using five models. Kaplan-Meier survival curves and curve-fitting analysis were used to illustrate the relationship between AG fluctuations and mortality risk.

Results: A total of 15,438 patients with AKI were included, 57.0% of whom were male. The 30-day all-cause mortality rate was 19.19%. Patients were categorized into three groups based on AG fluctuations within the first 48 hours: <3 mmol/L, 3-5 mmol/L, and >5 mmol/L. Cox regression and survival analysis indicated a significantly higher 30-day mortality rate in the >5 mmol/L group (HR = 1.63; 95% CI = 1.50-1.77, P < 0.001), with the worst prognosis. Restricted cubic spline analysis revealed a nonlinear relationship between AG fluctuations and 30-day mortality risk.

Discussion: The findings suggest that AG fluctuations during the first 48 hours of ICU admission are closely associated with adverse outcomes in AKI patients. Monitoring AG dynamics may aid clinicians in identifying high-risk patients and enhancing patient management by allowing for timely interventions that may improve prognosis.

Conclusion: AG fluctuations within the first 48 hours of ICU admission are a key predictor of renal recovery and 30-day mortality in AKI patients. AG fluctuations greater than 5 mmol/L are significantly associated with increased mortality risk.

Introduction: Hepatitis C virus (HCV) remains a major global health challenge, driving chronic hepatitis C (CHC) progression to severe liver diseases, including hepatocellular carcinoma (HCC). Directacting antivirals (DAAs) have transformed HCV treatment by achieving high sustained virological response (SVR) rates. However, limitations such as resistance, reinfection, and restricted accessibility emphasize the urgent need for novel therapeutic approaches. Among HCV therapeutic targets, the NS3/4A protease is critical for viral replication and immune evasion, positioning it as a prime focus for innovative drug discovery.

Methods: A comprehensive computational approach was adopted to evaluate flavonoids, natural compounds with known antiviral and anticancer properties, as potential inhibitors of the HCV NS3/4A protease. A curated flavonoid library was subjected to virtual screening using molecular docking techniques. Top-ranked flavonoids were further assessed based on binding affinity, dissociation constants, and key protein-ligand interactions. Pharmacokinetic profiling, molecular dynamics simulations, MM/PBSA energy calculations, and principal component analysis were performed to validate the most promising candidate.

Results: The top ten scoring flavonoids demonstrated strong binding affinities and stable interactions with key catalytic residues of the NS3/4A protease. CID 100943380 emerged as the most promising candidate, exhibiting favorable pharmacokinetic properties and sustained stability throughout molecular dynamics simulations. MM/PBSA and PCA analyses further confirmed its robust binding and conformational stability.

Discussion: The findings highlight flavonoids as promising inhibitors of NS3/4A protease, supporting their potential for further antiviral development.

Conclusion: This investigation identifies 10 flavonoids with high potential as NS3/4A protease inhibitors, providing a basis for future biological validation and safer drug development.

As the body's main metabolic organ, the liver performs many crucial functions. Liver diseases such as hepatitis and liver cancer are chronic diseases that can seriously damage health. Currently, effective therapeutic strategies remain limited. In recent years, ferroptosis has become an emerging therapeutic target in the diagnosis and treatment of human diseases. Initially identified in tumor cells linked to neurological disorders, it has recently been acknowledged as a crucial element in the advancement of hepatic ailments. Acyl-CoA synthetase long-chain family member 4 (ACSL4) could be a target for ferroptosis driven by unsaturated fatty acid (FA). More specifically, overexpression of ACSL4 causes reactive oxygen species (ROS) and lipid peroxidation (LPO) products to accumulate, therefore aggravating the course of liver cell ferroptosis. Given that ACSL4 has a complex involvement in liver pathophysiology, its targeted control may represent a novel therapeutic approach for liver illnesses. Even so, more research is required to better understand the molecular mechanisms of ACSL4 and its clinical implications. This article will focus on elucidating the key regulatory molecular mechanisms of ACSL4 in ferroptosis and liver disease progression, aiming to highlight ACSL4 as a potential therapeutic target and provide deep insights into the molecular basis of liver pathology.

Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Schizophrenia (Sch) present significant challenges for healthcare systems, both in terms of prevalence and the complexity of pharmacological treatment. While current therapies offer symptomatic relief, there is a high rate of failure in addressing the full spectrum of clinical symptoms and patient adherence issues, especially in long-term care. Since ancient times, various civilizations, including the Chinese, Egyptians, and indigenous South African cultures, have investigated and utilized the transdermal route for therapeutic and medicinal applications. Recent advances in transdermal drug delivery systems (TDS) offer a promising alternative to traditional routes of administration, enhancing drug absorption and minimizing side effects, such as gastrointestinal distress. This review explores the potential of TDS for improving the pharmacotherapy of AD, PD, and Sch. We also highlight the ongoing challenges in optimizing TDS formulations, such as drug absorption through the skin, skin irritation, and maintaining therapeutic efficacy. Furthermore, the review discusses the progress in prodrug design strategies aimed at enhancing skin permeation and bioavailability, particularly in the context of CNS-targeted drugs. The need for continued research into TDS technology is emphasized, as it holds promise for improving treatment adherence, patient quality of life, and caregiver burden, thereby advancing therapeutic options for CNS disorders.