Search Results (1,704)

Background: The optimal duration of neoadjuvant therapy for high-risk colorectal liver metastases (CRLM) remains debated. While prolonged chemotherapy may enhance response, it also increases toxicity and risks delaying potentially curative resection. These considerations have raised the question whether a short-course neoadjuvant strategy might achieve sufficient oncologic selection and response while minimizing treatment-related morbidity. Methods: Patients with synchronous or metachronous CRLM who received two cycles of neoadjuvant CAPOX plus bevacizumab followed by curative-intent liver resection treated between 2014 and 2024 at Health Network Vienna, Austria, were included. Clinicopathologic characteristics, treatment tolerability, response assessments (biochemical, radiologic, and pathologic), and survival outcomes were collected and analyzed. Results: A total of 57 patients were included (65% synchronous, 35% metachronous), with the rectum being the most frequent primary tumor site (45.6%). Most liver lesions were <5 cm (84.2%), and 47% had bilobar disease. Minor hepatectomy was performed in 65% of cases, predominantly via open surgery (72%). Grade ≥3 treatment-related adverse events occurred in 6 patients (10.6%), mainly neutropenia and diarrhea. Biochemically, 53.7% achieved >50% tumor marker reduction. Radiologic assessment showed partial response in 31.6% and complete response in 1.7%. Pathologic evaluation revealed TRG 3 as the most common finding (57.1%), followed by TRG 2 in 22.5%. Subgroup analyses demonstrated significantly improved OS and RFS in patients receiving adjuvant therapy and in those with tumors < 5 cm. Conclusion: A two-cycle, short-course regimen of CAPOX plus bevacizumab proved both effective and safe in high-risk CRLM, achieving meaningful biochemical, radiologic, and pathologic responses with acceptable toxicity. This abbreviated approach allowed delivery of neoadjuvant therapy while limiting cumulative treatment-related toxicity, supporting its feasibility as a neoadjuvant strategy in selected high-risk CRLM patients. Full article

Chronic kidney disease (CKD) has emerged as a pervasive global health concern, for which there are no known curative treatments. Consequently, there is an imperative for the implementation of preventive and kidney-protective strategies. The renal kallikrein–kinin system (KKS) is a vasodilator, anti-inflammatory, and antifibrotic pathway located in the distal nephron, whose decline contributes to hypertension and CKD progression. In this narrative, non-systematic review, a thorough evaluation of both experimental and clinical data was undertaken to ascertain the interactions between dietary potassium, renal KKS activity, and kidney protection. A particular emphasis was placed on animal models of proteinuria, tubulointerstitial damage, and salt-sensitive hypertension, in conjunction with human studies on potassium intake and renal outcomes. A body of experimental evidence suggests a relationship between potassium-rich diets and renal kallikrein synthesis, urinary kallikrein activity, and up-regulated kinin B2 receptor expression. Collectively, these factors have been shown to result in reduced blood pressure, oxidative stress, apoptosis, inflammation, and fibrosis, and these effects are counteracted by B2 receptor blockade. In humans, higher potassium intake has been shown to enhance kallikrein excretion and lower cardiovascular and renal risk, independently of aldosterone. Conversely, low potassium intake has the potential to exacerbate CKD progression. Notwithstanding the concerns that have been raised regarding the potential necessity of increasing potassium intake in cases of advanced CKD, extant evidence would appear to indicate that potassium excretion persists until late disease stages. The activation and preservation of the renal KKS through a potassium-rich diet is a rational, cost-effective strategy for renoprotection. When combined with sodium reduction and nutritional education, this approach has the potential to halt the progression of CKD and enhance cardiovascular health on a population scale. Full article

The development of next-generation HIV-1 therapeutics, including ultralong-acting antivirals, novel mechanistic classes, and curative immunotherapies, promises to overcome the limitations of lifelong, daily antiretroviral therapy (ART). However, the real-world efficacy of these treatments depends on the complex epidemiological landscapes in which they are used. In South America, HIV-1 epidemics intersect hyperendemic arboviruses, including dengue, Zika, chikungunya, and yellow fever, and regionally isolated pathogens, such as mammarenaviruses. These co-infections cause profound episodic immune activation and organ dysfunction that alter drug pharmacokinetics, disrupting healthcare access and adherence. These factors can compromise ART efficacy, promote resistance, and influence latent reservoir dynamics. This review synthesizes clinical and translational evidence of this intersection. We evaluate how emergent agents, such as capsid inhibitors (lenacapavir), long-acting injectables (cabotegravir/rilpivirine), maturation inhibitors (GSK3640254), and broadly neutralizing antibodies (bNAbs), perform in the context of co-endemic viral challenges. Specifically, we argue that therapeutic development must become “co-infection-aware” to progress toward a cure and achieve durable HIV-1 control. We provide a translational roadmap that explicitly incorporates co-infection endpoints into clinical trials, develops preclinical models that better reflect real-world viral exposures, and prioritizes implementation strategies that remain effective in the case of recurrent outbreaks. Integrating regional viral ecology into HIV-1 therapeutic research is therefore a necessary step toward developing interventions that are durable and effective on a global scale. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative condition with a multifactorial etiology, characterized by dopaminergic neurons being selectively absent in the midbrain. Clinically, PD manifests primarily with core motor symptoms of resting tremor, bradykinesia, and muscle rigidity, and is often accompanied by non-motor symptoms including depression, cognitive impairment, and gastrointestinal dysfunction. Among the extensive relevant research, few have explored the precise pathogenic mechanisms underlying PD, and no curative treatment is available. Current pharmacological therapies mainly provide symptomatic relief by enhancing central dopaminergic function or modulating cholinergic activity; however, their long-term efficacy is frequently constrained by waning therapeutic response, drug tolerance, and adverse reactions. Accumulating evidence suggests that several naturally derived neuroactive compounds—such as gastrodin, uncarin, and paeoniflorin—demonstrate significant potential in combating PD. In this systematic review, we examined original research articles published from 2010 to 2025, retrieved from PubMed, Web of Science, and CNKI databases, using predefined keywords of Parkinson’s disease, neuroprotective herbal compounds, traditional medicine, multi-target mechanisms, natural product, autophagy, neuroinflammation, and oxidative stress. Studies were included if they specifically investigated the mechanistic actions of natural compounds in PD models. Conference abstracts, review articles, publications not in English or Chinese, and studies lacking clearly defined mechanisms were excluded. Analysis of the available literature reveals that natural neuroactive compounds may exert anti-PD effects through multiple mechanisms, e.g., inhibiting pathological α-synuclein aggregation, attenuating neuronal apoptosis, suppressing neuroinflammation, mitigating oxidative stress, and restoring mitochondrial dysfunction. This review provides insights that may inform the clinical application of natural bioactive compounds and guide their further development as potential therapeutic candidates against PD. Full article

Coagulation is a physiological process necessary to achieve homeostasis. Many pathologies lead to spontaneous activation of the coagulation pathways and increase the risk of venous thrombosis (e.g., atrial fibrillation, orthopaedic surgery, cancer). Therefore, a lot of patients need anticoagulant drugs as preventive or curative treatment. In general, older molecules (unfractionated heparin, low-molecular-weight heparins, vitamin K antagonists) have good efficacy. Still, their adverse reactions, increased risk of bleeding, or difficult administration led to low adherence to treatment and had even limited their use. Recently, new molecules were authorised to improve patient adherence to treatment, mainly formulated for oral administration (e.g., dabigatran, rivaroxaban, apixaban, etc.). This therapeutic approach has a low risk of bleeding and does not require special monitoring by laboratory tests. Also, new anticoagulants for patients with heparin-induced thrombocytopenia (e.g., argatroban, lepirudin, bivalirudin, etc.) were obtained. Moreover, reversal agents for the new anticoagulant molecules used in overdoses or in situations where immediate cessation of the anticoagulant effect is required (e.g., emergency surgery) were studied, some of them being authorised on the pharmaceutical market. This narrative review aims to provide a pharmacological and therapeutic overview of anticoagulant drugs, underlining their implementation and limitations. Full article

Flavonoids are a diverse group of natural polyphenolic compounds, recognized for their ability to modulate cellular pathways and mitigate the pathological processes of many neurodegenerative diseases. This study investigates the neurotrophic potential of a polyphenolic-rich lemon peel extract (Lpe) in a Zebrafish larvae spinal cord injury (SCI) model. To evaluate its potential effects, embryos were divided into six experimental groups: a baseline control group in which larvae were neither subjected to spinal cord injury nor treated (Ctrl Group); a group with larvae subjected to spinal cord injury at 3 dpf without treatment (SCI Group); a group treated continuously with Lpe (25 µg/mL) from 0 to 5 dpf without injury (Continuous Group); a group treated continuously with Lpe and injured at 3 dpf (Continuous SCI Group); a group treated with Lpe starting at 3 dpf without injury (Curative Group); and finally, a group injured at 3 dpf and treated simultaneously with Lpe (Curative SCI Group). Lpe treatment significantly downregulated proinflammatory cytokines (tnfa, il1b, and xcl8), and modulated the neuroregenerative pathways Wnt/β catenin, and neurotrophic factor Bdnf. Immunohistochemical analysis further revealed Sox2-positive cells localized around the central canal, consistent with activation of ependymal progenitor populations involved in injury-induced repair processes. These findings support the exploration of Lpe for mitigating SCI-induced damage. Full article

Doxorubicin (DOX), a widely used chemotherapeutic, is constrained by its nephrotoxicity, characterized by endothelial injury, inflammation, and oxidative stress. Vascular endothelial growth factor (VEGF) signaling in the kidney serves a dual function. Under normal conditions, it supports the survival of glomerular endothelial cells and maintains vascular stability, but when excessively activated, it disrupts angiogenesis and contributes to kidney injury. In this context, we hypothesize that Nanocurcumin (CUR-NP), a nano-formulated curcumin derivative with enhanced bioavailability, can modulate the VEGF pathway and restore regular renal activity. Thus, this study aims to explore the potential protective effect of CUR-NP on DOX-induced renal injury in male rats. Thirty-two Wistar albino rats were used and distributed into four groups. CUR-NP (80 mg/kg dissolved in 1% CMC) was administered by oral gavage for two weeks. A single dose of DOX (15 mg/kg) (i.p.) was injected on day seven of the study. Results showed that DOX increased the circulating creatinine, urea, and urea-nitrogen levels, while pretreatment with CUR-NP markedly alleviated kidney function. In addition, CUR-NP treatment significantly normalized oxidative stress markers in renal tissues, such as NO, GSH, and SOD, and improved renal pro-inflammatory mediators, TNF-α, IL-6, and NF-κB-p65. DOX caused degeneration of glomeruli and tubules with degenerated epithelial lining and casts in their lumens. Conversely, CUR-NP maintained standard tubular and glomerular structure. Immunohistochemistry showed that DOX strongly upregulated VEGF and AhR, while CUR-NP markedly reduced their expression, countering VEGF/AhR pathway disruption and helping restore physiological signaling. Full article

Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, an important molecule in energy recycling. GAMT loss of function leads to GAMT deficiency (GAMT-D), an autosomal recessive disorder resulting in low creatine levels and the accumulation of a toxic intermediate, guanidinoacetate (GAA). GAMT-D patients present with intellectual disability and epilepsy, emphasizing the detrimental consequences of disturbed creatine metabolisms in the central nervous system (CNS). Current treatments are not curative and may not restore creatine metabolism in the brain. Here, we present a proof-of concept study testing the first CNS-directed, Adeno-associated virus serotype 9 (AAV9)-based gene therapy for the treatment of GAMT-D. the delivery of GAMT construct to cellular models of GAMT-D effectively restored protein and mRNA expression of GAMT while increasing intracellular creatine content and decreasing GAA accumulation. In murine models of GAMT-D, treatment with scAAV9.hGAMT, delivered intrathecally, resulted in increased creatine content as well as significant decreases in GAA accumulation in the CNS and peripheral organs. Overall, we found that scAAV9.hGAMT represents a promising gene therapy for treating GAMT-D, warranting further investigation in animal models to determine an appropriate therapeutic window for both efficacy and safety that allows for translation into human patients in the future. Full article

Background: Nanotechnology provides innovative strategies to enhance drug delivery and therapeutic efficacy through advanced nanocarrier systems. Objectives: This study aimed to develop and optimize a nanostructured lipid carrier (NLC) co-encapsulating curcumin (CUR) and resveratrol (RESV) using a fractional factorial design to develop a topical formulation with antioxidant and anti-inflammatory properties. Methods: NLCs were produced via hot emulsification followed by high-pressure homogenization, and their physicochemical characteristics, drug content, stability, release profile, antioxidant activity, skin delivery, and cellular compatibility were evaluated. Results: The optimized formulation exhibited an average particle size of approximately 300 nm, a polydispersity index below 0.3, and high drug loading for both compounds. Stability studies over 90 days revealed no significant changes in physicochemical parameters, confirming the formulation’s robustness. In vitro release assays demonstrated sustained release of both actives, with 58.6 ± 2.9% of CUR and 97 ± 3% of RESV released after 72 h. Antioxidant activity, assessed by the DPPH and ABTS assays, showed concentration-dependent radical-scavenging effects, indicating antioxidant potential. Skin permeation/retention experiments using porcine skin showed enhanced retention of CUR and RESV within the tissue, with no detectable permeation, indicating suitability for topical delivery. In addition, in vitro cell assays using human keratinocytes showed concentration-dependent responses and acceptable cellular compatibility. Conclusions: Overall, this study demonstrates the successful application of nanotechnology and experimental design to develop stable and efficient lipid-based nanocarriers containing natural polyphenol for topical therapy targeting oxidative and inflammatory skin disorders. Full article

Background: Triple-negative breast cancer (TNBC) remains primarily treated with chemotherapy due to the lack of effective therapeutic targets, but this approach carries significant systemic toxicity and a high risk of drug resistance. Curcumin (Cur), despite its multifaceted antitumor activity, faces limitations in clinical application due to poor water solubility and weak targeting properties. This study aims to develop a folate/mitochondria dual-targeted curcumin–copper chelate liposome (Cu-Cur DTLPs) formulation that enables copper accumulation within tumor cells and induces copper-mediated cell death, thereby providing an effective and relatively low-toxicity therapeutic strategy for triple-negative breast cancer. Methods: Curcumin–copper chelates (Cu-Cur) were first synthesized and characterized using mass spectrometry, NMR, and infrared spectroscopy. Subsequently, dual-targeted liposomes (Cu-Cur DTLPs) were prepared via the thin-film dispersion method, with systematic evaluation of particle size, zeta potential, encapsulation efficiency, and in vitro release profiles. In vitro cytotoxicity was assessed against 4T-1 and MDA-MB-231 cells using the MTT assay. In a 4T-1 tumor-bearing BALB/c mouse model, comprehensive evaluation of targeting efficiency, antitumor efficacy, and mechanisms of action was conducted via in vivo imaging, tumor volume monitoring, immunohistochemistry (detecting FDX1 and DLAT proteins), and TUNEL staining. Results: Cu-Cur DTLPs with a uniform particle size of approximately 104.4 nm were successfully synthesized. In vitro and in vivo studies demonstrated that compared to free curcumin and conventional liposomes, Cu-Cur DTLPs significantly enhanced drug accumulation in tumor tissues and exhibited effective tumor growth inhibition. Mechanistic studies confirmed that this formulation specifically accumulates copper ions within tumor cells, upregulates FDX1, promotes DLAT oligomerization, and induces mitochondrial dysfunction, thereby driving copper death. TUNEL staining ruled out apoptosis as the primary mechanism. Safety evaluation revealed no significant toxicity in major organs. Conclusions: The Cu-Cur DTLPs developed in this study effectively induce copper-mediated death in TNBC through a dual-targeted delivery system, significantly enhancing antitumor activity with favorable safety profiles. This establishes a highly promising novel nanotherapeutic strategy for TNBC treatment. Full article

Cutaneous melanoma is a highly aggressive skin cancer prone to relapse and metastasis. Surgery is often curative when combined with early screening and prevention. However, in recurrent or advanced disease, the development of new targeted and immune therapies has demonstrated promising clinical outcomes, although the acquisition of resistance limits their effectiveness. Thus, new therapeutic approaches are needed. Emerging data indicate that the Hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly reactivated in melanoma and may represent a promising therapeutic target. Here, we demonstrate its chronic up-modulation in a panel of patient-derived cell lines and, by investigating the underlying molecular mechanisms, we excluded mutations in the principal components of the pathway. We observed reduced PTCH1 and SUFU repressors expression and GLI2 upregulation as common melanoma features. At the same time, copious SHH release, the principal PTCH1 ligand, evidenced autocrine Hh signaling activation. Consistently, a tendency of greater level of this factor resulted higher in the blood of patients compared to controls, confirming the relevance of ligand-dependent trigger in melanoma. The therapeutic potential of inhibiting the Hh pathway is highlighted by the reduced proliferation and migration observed in the presence of clinically approved pharmacological Hh antagonists. Profiling inflammatory mediators revealed significant modulation upon treatment with SMO inhibitors, possibly affecting chemotactic and immune functions. Collectively, these findings provide deeper insight into the role of the Hh pathway in melanoma and support the potential repurposing of Hh inhibitors as therapeutic agents for melanoma. Full article

Gastric cancer (GC) is the fifth most common type of cancer and a leading cause of cancer-related deaths worldwide. Surgery remains the most effective treatment, but new therapeutic strategies are urgently needed. The use of natural polyphenolic compounds such as curcumin (CUR) and resveratrol (RSV) has played a significant role in this effort. This review provides a comprehensive overview of the current applications and molecular mechanisms of curcumin and resveratrol in gastric cancer, highlighting their therapeutic potential and translational relevance. Analytically, CUR induces apoptosis, endoplasmic stress and cell cycle arrest. On the other hand, resveratrol enhances apoptosis and reduces inflammation. Both compounds increase cancer cell sensitivity to chemotherapy and help prevent chemoresistance, highlighting their potential as molecular enhancers in anticancer therapy. Combined with standard therapeutic drugs, they represent an innovative strategy for GC treatment. By presenting these innovative approaches, this review offers a global perspective on how their administration could shape future treatment strategies. Full article

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools—including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors—and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as PCSK9, ANGPTL3, CETP, APOC3, ASGR1, LPA, and IDOL, supported by findings from human genetics, preclinical models, and recent first-in-human trials. Emerging delivery vehicles (AAVs, LNPs, lentivirus, virus-like particles) and their translational implications are discussed. The review highlights ongoing clinical trials employing liver-targeted in vivo editing modalities (LivGETx-CVD) and provides insights into challenges in delivery, off-target effects, genotoxicity, and immunogenicity. Collectively, this review captures the rapid progress of LivGETx-CVD from conceptual innovation to clinical application, and positions gene editing as a transformative, single-dose strategy with the potential to redefine prevention and long-term management of dyslipidemia and atherosclerotic cardiovascular disease. Full article

This study developed an efficient interfacial stabilization strategy, using metal ions (Cu²⁺) and octyl gallate (OG) to protect curcumin (Cur) via interfacial coordination. Macroscopic observation, droplet size, and Turbiscan stability index analysis demonstrated that the addition of Cu²⁺ to the OG/Cur emulsion significantly influenced its emulsification efficiency and physical stability, which depended on both the OG concentration and the amount of Cu²⁺ added. Interfacial rheological analysis showed that Cu²⁺ addition significantly enhanced droplet interfacial strength, with distinct effects from different metal ions. FT-IR confirmed the coordination bonds of Cu²⁺ with both Cur (keto/enol) and OG (phenolic hydroxyl). Under appropriate concentrations of OG and Cu²⁺, the retention rate of curcumin in the emulsion was significantly improved under various processing conditions. After 100 min of UV exposure, the OG/Cur/Cu²⁺ system increased curcumin retention by 49.64% compared to Cu²⁺-free systems. The study presents a metal-phenolic coordination-based strategy for constructing stable functional emulsions with high curcumin protection. Full article

Background: Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality. Transarterial radioembolization (TARE) has emerged as a locoregional therapy to downstage tumors and expand surgical eligibility. Methods: This retrospective study included patients with HCC who underwent TARE as a bridging treatment. The primary outcomes assessed were the efficacy of TARE in facilitating curative surgery and long-term oncological outcomes, specifically overall survival (OS) and disease-free survival (DFS). Results: This study included 25 patients. 17 patients subsequently underwent surgical resection and eight underwent living-donor liver transplantation (LDLT). At a median follow-up of 33.4 months, the median disease-free survival (DFS) was 11.2 months. Patients with recurrence had a median DFS of 3.65 months, and those without recurrence had a median DFS of 27.1 months. The median overall survival (OS) for the cohort was 33.4 months. At the last follow-up, 76% of patients were alive and disease-free. Kaplan–Meier analysis demonstrated sustained OS in the LDLT group, while resection patients gradually declined within the first two years. Conclusions: TARE is an effective bridging strategy that enables curative-intent surgery in selected patients with HCC and supports favorable long-term oncological outcomes. Careful patient selection and multidisciplinary management remain essential to optimize survival benefits. Full article