Biomolecules & Therapeutics最新文献

This study was done to evaluate the inhibitory effects of benzylideneacetophenone derivatives (JCII) on rheumatoid arthritis (RA). This was done by using carrageenan/kaolin-induced arthritis in rats and human RA fibroblast-like synoviocytes (FLS). In FLS cells and Jurkat T cells, JCII compounds at 5, 10, and 20 μM were used to treat the cells followed by stimulation with IL-1β (10 ng/mL) for FLS cells and PMA/A23187 for Jurkat T cells. Inflammatory mediators and cytokines related to activated T cell functions were then analyzed using RT-PCR and ELISA. In rats, JCII compounds at 1, 5, and 10 mg/kg were given intraperitoneally daily for 6 days. Thereafter, arthritis evaluation was conducted by measuring squeaking scores, knee thickness, and WDR as well as histological assessments of the knee joints. Inflammatory mediators were also measured in the serum of the rats. JCII compounds given at 10 mg/kg significantly alleviated arthritis symptoms especially on day 5 or day 6 following arthritis in rats. The histological results were found to be consistent with the behavioral evaluation that were measured. In stimulated FLS cells, the same pattern was seen wherein JCII compounds also decreased the levels of different inflammatory mediators and MMPs. Also, the phosphorylation of JNK and p38 MAPK pathways were inhibited by JCII compounds. In addition, the level of TNF-α from activated T cells were downregulated by JCII treatment. These show that JCII compounds show a potential anti-arthritic effect at least via anti-inflammation and can be used potentially for the treatment in arthritis and the accompanying inflammatory disease.

Despite its relatively low adenosine triphosphate (ATP) production efficiency, cancer cells reprogram their metabolism to utilize aerobic glycolysis for rapid proliferation. This "Warburg effect" not only provides biosynthetic precursors but also creates a tumor-favorable microenvironment. Key oncogenic regulators such as protein kinase B (AKT), nuclear factor kappa B (NF-κB), and cellular myelocytomatosis oncogene (c-Myc) enhance glycolytic activity by inducing the expression of enzymes including glucose transporters (GLUTs), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and monocarboxylate transporters (MCTs). Moreover, telomerase reverse transcriptase (TERT), beyond its canonical role in telomere maintenance, also promotes glycolysis via the NF-κB and c-Myc pathways. From a therapeutic perspective, aerobic glycolysis contributes to glucose-mediated chemoresistance, limiting the efficacy of irinotecan in colorectal cancer (CRC). In this study, we investigated the role of Toxoplasma gondii-derived dense granule protein 16 (GRA16) in modulating glycolysis and irinotecan sensitivity. In HCT116 CRC cells stably expressing GRA16, AKT and NF-κB signaling were suppressed, leading to the downregulation of c-Myc and TERT. This resulted in decreased expression of GLUTs, HK2, LDHA, and MCTs, ultimately reducing glucose uptake and lactate production. Functional assays revealed that GRA16 induced G2/M cell cycle arrest, increased apoptosis, and suppressed proliferation. Notably, GRA16-expressing cells treated with irinotecan exhibited increased Sub-G1 accumulation and late-apoptotic and necrotic populations. Furthermore, siRNA-mediated silencing of c-Myc confirmed its key role in regulating TERT and glycolytic enzymes. These findings indicate that GRA16 suppresses aerobic glycolysis via the c-Myc/TERT axis and enhances irinotecan sensitivity, offering a promising strategy to overcome chemoresistance in CRC.

Diabetic nephropathy (DN) remains a leading cause of end-stage renal disease (ESRD), driven by chronic inflammation, oxidative stress, and apoptosis. Current therapies targeting glycemic and blood pressure control fail to address the underlying molecular mechanisms of DN. This study investigates the therapeutic potential of andrographolide (AD), a diterpenoid lactone from Andrographis paniculata, in mitigating DN by modulating key molecular pathways. Through integrative network pharmacology, molecular docking, and in vivo/in vitro experiments, 107 overlapping DN-related targets were identified, with STAT3, PI3K, and AKT1 emerging as core nodes. Molecular docking revealed high binding affinities between AD and these targets, supporting its modulatory potential. In vivo, AD significantly improved renal function in streptozotocin-induced DN rats, reducing proteinuria, glomerular hypertrophy, and renal fibrosis. AD also attenuated oxidative stress, decreased pro-inflammatory cytokine levels, and enhanced antioxidant enzyme activities, demonstrating systemic anti-inflammatory and antioxidative effects. In vitro studies further confirmed that AD alleviates podocyte oxidative stress and apoptosis under high glucose conditions by suppressing the RAGE-NF-κB and STAT3/PI3K/Akt pathways. Histological analyses revealed substantial improvements in renal architecture, including reductions in fibrosis and mesangial expansion. These results underscore AD's multi-target mechanism, directly addressing DN's core pathological drivers, including inflammation, oxidative stress, and apoptosis. As a natural compound with notable safety and efficacy, AD holds promise as an adjunct or standalone therapeutic agent for DN. This study establishes a robust preclinical foundation for AD, warranting further exploration in clinical trials and its potential application in other diabetic complications.

Tofacitinib, which is used to treat rheumatoid arthritis (RA), is primarily metabolized by the hepatic cytochrome P450 (CYP) enzymes, CYP3A1/2 and CYP2C11. Acetaminophen (APAP), which is frequently used for pain relief in patients with RA, can induce acute liver injury (ALI) when taken in excess, profoundly affecting drug metabolism. Resveratrol (RVT) is a polyphenolic compound with hepatoprotective properties. This study investigated the protective effects of RVT against APAP-induced ALI in rats, and explored its influence on the pharmacokinetics of tofacitinib. In ALI rats, both intravenous and oral administration of tofacitinib resulted in a significant (207% and 181%) increase in the area under the plasma concentration-time curve (AUC), primarily driven by a substantial reduction (66.1%) in non-renal clearance (CL_NR) compared to that in control (CON) rats. Notably, RVT administration in ALI rats provided effective liver protection, partially restoring liver function, as evidenced by normalized glutamate oxaloacetate transaminase levels and the pharmacokinetic parameters, AUC and CL_NR, closer to those observed in untreated CON rats (117% and 81.9%, respectively). These findings highlight the importance of considering the potential interactions between RVT or polyphenol-rich natural products and medications in patients with ALI in clinical practice.

This study aimed to evaluate the potential of hederacoside C, an active compound isolated from Hedera helix, which has been used for managing inflammatory respiratory diseases, in attenuating epidermal growth factor (EGF)-induced airway MUC5AC mucin gene expression. Human pulmonary mucoepidermoid NCI-H292 cells were pretreated with hederacoside C for 30 min and subsequently stimulated with EGF for 24 h. The study also examined the effect of hederacoside C on the EGF-induced mitogen-activated protein kinase (MAPK) signaling pathway. The results showed that hederacoside C inhibited MUC5AC mucin mRNA expression and the production of mucous glycoproteins by suppressing the phosphorylation of the EGF receptor (EGFR), as well as the phosphorylation of MAPK/extracellular signal-regulated kinase (ERK) 1/2 (MEK1/2), p38 MAPK, ERK 1/2 (p44/42), and the nuclear expression of specificity protein-1 (Sp1). These findings suggest that hederacoside C has the potential to reduce EGF-induced mucin gene expression by inhibiting the EGFR-MAPK-Sp1 signaling pathway in NCI-H292 cells.

Microplastics (MP) are pervasive environmental pollutants with potential adverse effects on human health, particularly concerning neurotoxicity. This study investigates the accumulation and neurotoxic effects of MP in cerebral organoids and mouse brains. Utilizing in vitro cerebral organoids and in vivo mouse models, we examined the penetration of MP, revealing that smaller MP (50 nm) infiltrated deeper into the organoids compared to larger ones (100 nm). Exposure to 50 nm MP resulted in a significant reduction in organoid viability. Furthermore, total RNA sequencing indicated substantial alterations in neurotoxicity-related gene expression. In vivo, MP-treated mice exhibited notable DNA fragmentation in the hippocampus and cortex, alongside elevated levels of inflammatory markers and neurotoxic metabolites, such as kynurenine (KYN) and 3-hydroxykynurenine (3-HK). Our findings suggest that MP may promote neurotoxicity through the kynurenine pathway, leading to heightened levels of neurotoxic compounds like quinolinic acid. This research highlights the potential for MP to induce neuroinflammatory responses and disrupt normal brain function, underscoring the need for further investigation into the long-term effects of MP exposure on neurological health.

Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have shown that necroptosis is involved in the development of inflammatory and neurodegenerative diseases. Receptor-interacting protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) play key roles in necroptosis, with MLKL being the final executor of necroptosis. Necrosulfonamide (NSA) is a specific inhibitor of MLKL, and its therapeutic effects in various inflammatory and neurological disorders have been previously reported. However, its role in PD has not yet been clearly demonstrated. In this study, we examined the effects of NSA in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. NSA reduced dopaminergic cell death and restored the expression of neurotrophic factors, such as BDNF, GDNF, and PGC-1α, in the SN region of MPTP mice. In addition, NSA inhibited microglial/astrocyte activation and the expression of proinflammatory markers, such as iNOS, TNF-α, IL-1β, and IL-6. NSA also reduced oxidative stress markers, such as 8-OHdG and 4-HNE, while enhancing Nrf2-driven antioxidant enzymes, including HO-1, catalase, MnSOD, GCLC, and GCLM. We found that NSA inhibited MLKL phosphorylation in dopaminergic neurons and microglia, which may have reduced neuronal cell death and inflammation. Therefore, NSA-mediated suppression of dopaminergic neuronal cell death, inflammation, and oxidative stress may have therapeutic potential in PD.

Oxidative stress due to hyperglycemia damages the functions of retinal pigment epithelial (RPE) cells and is a major risk factor for diabetic retinopathy (DR). Paeoniflorin is a monoterpenoid glycoside found in the roots of Paeonia lactiflora Pall and has been reported to have a variety of health benefits. However, the mechanisms underlying its therapeutic effects on high glucose (HG)-induced oxidative damage in RPE cells are not fully understood. In this study, we investigated the protective effect of paeoniflorin against HG-induced oxidative damage in cultured human RPE ARPE-19 cells, an in vitro model of hyperglycemia. Pretreatment with paeoniflorin markedly reduced HG-induced cytotoxicity and DNA damage. Paeoniflorin inhibited HG-induced apoptosis by suppressing activation of the caspase cascade, and this suppression was associated with the blockade of cytochrome c release to cytoplasm by maintaining mitochondrial membrane stability. In addition, paeoniflorin suppressed the HG-induced production of reactive oxygen species (ROS), increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox regulator, and the expression of its downstream factor heme oxygenase-1 (HO-1). On the other hand, zinc protoporphyrin (ZnPP), an inhibitor of HO-1, abolished the protective effect of paeoniflorin against ROS production in HG-treated cells. Furthermore, ZnPP reversed the protective effects of paeoniflorin against HG-induced cellular damage and induced mitochondrial damage, DNA injury, and apoptosis in paeoniflorin-treated cells. These results suggest that paeoniflorin protects RPE cells from HG-mediated oxidative stress-induced cytotoxicity by activating Nrf2/HO-1 signaling and highlight the potential therapeutic use of paeoniflorin to improve the symptoms of DR.

To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

A histone deacetylase SIRT6 regulates the transcription of various genes involved in lipid metabolism. Fatty acid (FA) oxidation plays a pivotal role in maintaining hepatic lipid homeostasis, and its dysregulation significantly contributes to lipotoxicity and inflammation, driving the progression of steatotic liver disease. While SIRT6 is known to activate peroxisome proliferator-activated receptor-alpha (PPARα), a central regulator of FA oxidation, the development of SIRT6 activators capable of enhancing FA oxidation and mitigating steatotic liver disease has yet to be achieved. This study evaluated the effect of MDL-800, a selective SIRT6 activator, on the expression of PPARα and genes related to FA oxidation. In AML12 mouse hepatocytes, MDL-800 treatment activated SIRT6 but unexpectedly decreased the expression of PPARα and its FA oxidation-associated target genes. Furthermore, OSS128167, a selective SIRT6 inhibitor, did not reverse the suppressive effects of MDL-800 on PPARα, suggesting that MDL-800 downregulates PPARα and FA oxidation-related genes through a mechanism independent of SIRT6 activation. Mechanistic investigations revealed that MDL-800 increased the production of reactive oxygen species and activated stress kinases. The inhibition of PPARα by MDL-800 was reversed by co-treatment with the antioxidant N-acetylcysteine or the JNK inhibitor SP600125. In summary, MDL-800 suppresses PPARα and FA oxidation-related genes primarily through the induction of oxidative stress in hepatocytes, independent of its role as a SIRT6 activator.