Biomolecules & Therapeutics最新文献

6-gingerol, a bioactive compound from ginger, has demonstrated promising anticancer properties across various cancer models by inducing apoptosis and inhibiting cell proliferation and invasion. In this study, we explore its mechanisms against glioblastoma multiforme (GBM), a notably aggressive and treatment-resistant brain tumor. We found that 6-gingerol crosses the blood-brain barrier more effectively than curcumin, enhancing its potential as a therapeutic agent for brain tumors. Our experiments show that 6-gingerol reduces cell proliferation and triggers apoptosis in GBM cell lines by disrupting cellular energy homeostasis. This process involves an increase in mitochondrial reactive oxygen species (mtROS) and a decrease in mitochondrial membrane potential, primarily due to the downregulation of manganese superoxide dismutase (MnSOD). Additionally, 6-gingerol reduces ERK phosphorylation by inhibiting EGFR and RAF, leading to G1 phase cell cycle arrest. These findings indicate that 6-gingerol promotes cell death in GBM cells by modulating MnSOD and ROS levels and arresting the cell cycle through the ERFR-RAF-1/MEK/ERK signaling pathway, highlighting its potential as a therapeutic agent for GBM and setting the stage for future clinical research.

Obesity requires treatment as it is associated with health problems such as type 2 diabetes, hypertension, dyslipidemia, cardiovascular diseases, and some cancers, which increase mortality rates. Achieving sufficient weight loss to reduce obesity-related diseases requires a variety of interventions, including comprehensive lifestyle modification of diet and exercise, change in behavior, anti-obesity medications, and surgery. To date, anti-obesity agents with various mechanisms of action have been developed, and mostly reduce energy intake, resulting in weight loss of about 5% to 10% compared to baseline. Recently developed drugs and those currently under development have been shown to reduce body weight by more than 10% and are expected to reduce obesity-related complications. This article summarizes existing and emerging anti-obesity medications, with a particular focus on those evaluated in clinical trials.

We identified drugs or mechanisms targeting ABCB1 (or P-glycoprotein; P-gp)-overexpressing drug-resistant cancer populations, given that these cells play a key role in tumor recurrence. Specifically, we searched for Akt inhibitors that could increase cytotoxicity in P-gp-overexpressing drug-resistant cancer cells. We performed cytotoxicity assays using five cell lines: 1. MCF-7/ADR, 2. KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3. MCF-7, 4. normal HaCaT cells (non-P-gp-overexpressing, VIC-sensitive, and GSK690693-sensitive), and 5. MDA-MB-231 cancer cells (non-P-gp overexpression, relatively VIC-resistance, and GSK690693-sensitive). Herein, we found that low-dose perifosine markedly and selectively sensitizes both MCF-7/ADR and KBV20C drug-resistant cancer cells exhibiting P-gp overexpression. Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells. Conversely, Akt inhibitors (other than perifosine) could enhance sensitization effects in drugsensitive MCF-7 and HaCaT cells. Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206). However, we found that these inhibitors were non-specific, suggesting that the specificity of perifosine in P-gp-overexpressing resistant cancer cells is unrelated to phospholipid localizing membranes or allosteric inhibition. Furthermore, we examined the molecular mechanism of low-dose perifosine in drug-resistant MCF-7/ADR cancer cells. MCF-7/ADR cells exhibited increased apoptosis via G2 arrest and autophagy induction. However, no increase in P-gp-inhibitory activity was observed in drug-resistant MCF-7/ADR cancer cells. Single low-dose perifosine treatment exerted a sensitization effect similar to co-treatment with VIC in P-gp-overexpressing drug-resistant MCF-7/ADR cancer cells, suggesting that single treatment with low-dose perifosine is a more powerful tool against P-gp-overexpressing drug-resistant cancer cells. These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations. Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells.

With the increasing use of plastics worldwide, the amount of plastic waste being discarded has also risen. This plastic waste undergoes physical and chemical processes, breaking down into smaller particles known as microplastics (MPs) or nanoplastics (NPs). Advances in technology have enhanced our ability to detect these smaller particles, and it has been confirmed that plastics can be found in marine organisms as well as within the human body. However, research on the effects of MPs or NPs on living organisms has only recently been started, and our understanding remains limited. Studies on the immunological impacts are still ongoing, revealing that MPs and NPs can differentially affect various immune cells based on the material, size, and shape of the plastic particles. In this review, we aim to provide a comprehensive understanding of the effects of MPs and NPs on the immune system. We will also explore the methods for plastic removal through physicochemical, microbial, or biological means.

A previously reported study highlighted the neuroprotective potential of the novel benzylideneacetophenone derivative, JC3, in mice. In pursuit of compounds with even more robust neuroprotective and anti-inflammatory properties compared to JC3, we synthesized substituted 1,3-diphenyl-2-propen-1-ones based on chalcones. Molecular modeling studies aimed at discerning the chemical structural features conducive to heightened biological activity revealed that JCII-8,10,11 exhibited the widest HOMOLUMO gap within this category, indicating facile electron and radical transfer between HOMO and LUMO in model assessments. From the pool of synthesized compounds, JCII-8,10,11 were selected for the present investigation. The biological assays involving JCII-8,10,11 demonstrated their concentration-dependent suppression of iNOS and COX-2 protein levels, alongside various cytokine mRNA expressions in LPS-induced murine microglial BV2 cells. Furthermore, western blot analyses were conducted to investigate the MAPK pathways and NF-κB/p65 nuclear translocation. These evaluations conclusively confirmed the inflammatory inhibition effects in both in vitro and in vivo inflammation models. These findings establish JCII-8,10,11 as potent anti-inflammatory agents, hindering inflammatory mediators and impeding NF-κB/p65 nuclear translocation via JNK and ERK MAPK phosphorylation in BV2 cells. The study positions them as potential therapeutics for inflammation-related conditions. Additionally, JCII-11 exhibited greater activity compared to other tested JCII compounds.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks hormone receptor and Her2 (ERBB2) expression, leaving chemotherapy as the only treatment option. The urgent need for targeted therapy for TNBC patients has led to the investigation of small interfering RNAs (siRNAs), which can target genes in a sequence-specific manner, unlike other drugs. However, the clinical translation of siRNAs has been hindered by the lack of an effective delivery system, except in the case of liver diseases. The MYC oncogene is commonly overexpressed in TNBC compared to other breast cancer subtypes. In this study, we used siRNA to target MYC in MDA-MB-231, MDA-MB-157, MDA-MB-436 and Hs-578T cells. We designed various symmetric and asymmetric (asiRNAs), screened them for in vitro efficacy, modified them for enhanced nuclease resistance and reduced off-target effects, and conjugated them with cholesterol (ChoL) and docosanoic acid (DCA) as a delivery system. DCA was conjugated to the 3' end of asiRNA by a cleavable phosphodiester linker for in vivo delivery. Our findings demonstrated that asiRNA-VP and Mod_asiRNA10-6 efficiently downregulated MYC and its downstream targets, including RRM2, RAD51 and PARP1. Moreover, in a tumor xenograft model, asiRNA-VP-DCA effectively knocked down MYC mRNA and protein expression. Remarkably, durable knockdown persisted for at least 46 days postdosing in mouse tumor xenografts, with no visible signs of toxicity, underscoring the safety of DCA-conjugated asiRNAs. In conclusion, this study developed novel asiRNAs, design platforms, validated modification patterns, and in vivo delivery systems specifically targeting MYC in TNBC.

Diabetic kidney disease (DKD) poses a major global health challenge, affecting millions of individuals and contributing to substantial morbidity and mortality. Traditional treatments have focused primarily on managing symptoms and slowing disease progression rather than reversing or halting kidney damage. However, recent advancements in natural compound research have unveiled promising new avenues for therapeutic development. Extensive research has been conducted to showcase the antioxidant advantages for kidney health, supporting the potential effectiveness of natural and synthetic products in clinical and experimental research. Bioactive substances found in large quantities in food, such as polyphenols, have emerged as adjuvants. This review manuscript aims to provide a comprehensive overview of natural compounds and their potential efficacy, mechanisms of action, and clinical applications in the prevention and treatment of various kidney diseases. This review emphasizes the connection between oxidative stress and inflammation in diabetic nephropathy (DN), which leads to harmful effects on kidney cells due to pathological damage. A lower incidence of DM2-related problems and a slower progression of end-stage renal disease have been associated with the consumption of these compounds.

AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.

Translationally controlled tumor protein (TCTP) is a regulatory protein that plays pivotal roles in cellular processes including the cell cycle, apoptosis, microtubule stabilization, embryo development, stress responses, and cancer. However, the molecular mechanism by which it promotes tumor angiogenesis is still unclear. In this study, we explored the mechanisms underlying stimulation of angiogenesis by a novel TCTP. Recombinant TCTP enhanced vascular endothelial growth factor (VEGF)-induced endothelial cell migration, capillary-like tubular structure formation, and cell proliferation by interacting with VEGF receptor 2 (VEGFR-2) in vitro. In contrast, we showed that TCTP knockdown (using short interfering [si]TCTP) led to a decrease in ovarian tumor cells. We also examined the expression of VEGF and hypoxia inducible factor 1 (HIF-1α), an important angiogenic factor. The expression of VEGF as well as HIF-1α was dramatically decreased by siTCTP. Mechanistically, siTCTP inhibited VEGFR-2 tyrosine phosphorylation and phosphorylation of its downstream targets PI3K, Akt, and mTOR. Collectively, these findings indicate that TCTP can promote proliferation and angiogenesis via the VEGFR-2/PI3K and mTOR signaling pathways in ovarian tumor cells, providing new insight into the mechanism behind the involvement of TCTP in tumor angiogenesis.