Search Results (5,393)

Phthalocyanines (Pcs) are well-established photosensitizers in photodynamic therapy, valued for their strong light absorption, high singlet oxygen generation, and photostability. Recent advances have focused on covalently conjugating Pcs, particularly zinc phthalocyanines (ZnPcs), with a wide range of small bioactive molecules to improve selectivity, efficacy, and multifunctionality. These conjugates combine light-activated reactive oxygen species (ROS) production with targeted delivery and controlled release, offering enhanced treatment precision and reduced off-target toxicity. Chemotherapeutic agent conjugates, including those with erlotinib, doxorubicin, tamoxifen, and camptothecin, demonstrate receptor-mediated uptake, pH-responsive release, and synergistic anticancer effects, even overcoming multidrug resistance. Beyond oncology, ZnPc conjugates with antibiotics, anti-inflammatory drugs, antiparasitics, and antidepressants extend photodynamic therapy’s scope to antimicrobial and site-specific therapies. Targeting moieties such as folic acid, biotin, arginylglycylaspartic acid (RGD) and epidermal growth factor (EGF) peptides, carbohydrates, and amino acids have been employed to exploit overexpressed receptors in tumors, enhancing cellular uptake and tumor accumulation. Fluorescent dye and porphyrinoid conjugates further enrich these systems by enabling imaging-guided therapy, efficient energy transfer, and dual-mode activation through pH or enzyme-sensitive linkers. Despite these promising strategies, key challenges remain, including aggregation-induced quenching, poor aqueous solubility, synthetic complexity, and interference with ROS generation. In this review, the examples of Pc-based conjugates were described with particular interest on the synthetic procedures and optical properties of targeted compounds. Full article

Background and Objectives: The cytokine IL-6, methyltransferase NSD2, pro-protein convertase Furin, and growth factor receptor IGF-1R are essential factors in the proliferation of cancer cells. These proteins are involved in the tumor process by generating several cell-signaling pathways. However, the interactions of these oncogenic biomarkers, Furin, IL-6, and NSD2, and their links with the inhibitor SERPINA-1 remain largely unknown. Materials and Methods: Cell proliferation is measured by colorimetric and enzymatic methods. The genetic expressions of SERPINA-1, Furin, IL-6, and NSD2 are measured by qRT-PCR, while the expression of IGF-1R on the cell surface is measured by flow cytometry. Results: The proliferation of cells overexpressing SERPINA-1 (JP7pSer+) is decreased by more than 90% compared to control cells (JP7pSer-). The kinetics of the gene expression ratios of Furin, IL-6, and NSD2 show an increase for 48 h, followed by a decrease after 72 h for the three biomarkers in JP7pSer+ cells compared to JP7pSer- cells. The expression of IGF-1R on the cell surface in both cell lines is low, with JP7pSer- cells expressing 1.33 times more IGF-1R than JP7pSer+ cells. Conclusions: These results suggest gene correlations of SERPINA-1 overexpression with decreased cell proliferation and modulation of gene expression of Furin, IL-6, and NSD2. This study should be complemented by molecular transcriptomic and proteomic experiments to better understand the interaction of SERPINA-1 with IL-6, Furin, and NSD2, and their effect on tumor progression. Full article

Background/Objective: Sepsis-associated acute kidney injury (SA-AKI) is a substantial contributor to mortality in critically ill patients. This study aimed to investigate the impact of gum acacia (GA) and dexamethasone (DEX) combination on lipopolysaccharide (LPS)-induced SA-AKI in rats. Methods: Thirty-six male Sprague Dawley rats were separated into six groups, including the control, GA group, LPS-induced AKI group, DEX + LPS group, GA + LPS group, and GA + DEX + LPS group. AKI was induced in rats using LPS (10 mg/kg, i.p.). GA was administered orally (7.5 g/kg) for 14 days before LPS injection, and DEX was injected (1 mg/kg, i.p.) 2 h after LPS injection. Results: LPS injection significantly (p < 0.05, vs. control group) impaired renal function, as evidenced through increased levels of kidney function biomarkers, decreased creatinine clearance, and histopathological alterations in the kidneys. LPS also significantly (p < 0.05, vs. control group) elevated levels of oxidative stress markers, while it reduced levels of antioxidant enzymes. Furthermore, LPS triggered an inflammatory response, manifested by significant (p < 0.05, vs. control group) upregulation of Toll-like receptor 4, myeloid differentiation primary response 88, interleukin-1β, tumor necrosis factor-α, and nuclear factor-κB, along with increased expression of high-mobility group box 1. Administration of GA significantly ameliorated LPS-induced renal impairment by enhancing antioxidant defenses and suppressing inflammatory pathways (p < 0.05, vs. LPS group). Furthermore, GA-DEX-treated rats showed improved kidney function, reduced oxidative stress, and attenuated inflammatory markers (p < 0.05, vs. LPS group). Conclusions: The GA-DEX combination exhibited potent renoprotective effects against LPS-induced SA-AKI, possibly due to their antioxidant and anti-inflammatory properties. These results suggest that the GA-DEX combination could be a promising and effective therapeutic agent for managing SA-AKI. Full article

Microglia-mediated chronic neuroinflammation is a common pathological feature of Parkinson’s disease (PD). Strong evidence suggests that activated microglia can lesion neurons by releasing exosomes. However, the mechanisms of exosome release from activated microglia remain unclear. We recently revealed a key role of complement receptor 3 (CR3) in regulating microglial activation in the process of progressive neurodegeneration. This study aimed to investigate whether CR3 can regulate exosome release from activated microglia, as well as the underlying mechanisms. We found that LPS, an inducer of microglial M1 activation, induced exosome release from activated microglia. Inhibition of exosome synthesis suppressed LPS-induced microglial activation, gene expression of proinflammatory factors, and related neurotoxicity. Silencing or knocking out CR3 attenuated LPS-induced exosome release in microglia. NADPH oxidase (NOX2) was further identified as a downstream signal of CR3, mediating microglial exosome release and related neurotoxicity. CR3 silencing blocked LPS-induced NOX2 activation and superoxide production through inhibition of p47^phox phosphorylation and membrane translocation. Moreover, NOX2 activation elicited by PMA or supplementation of H₂O₂ recovered exosome release from CR3-silenced microglia. Subsequently, we demonstrated that the CR3-NOX2 axis regulates syntenin-1 to control microglial exosome release. Finally, we observed that the expression of CR3 was increased in the brain of LPS-treated mice, and genetic ablation of CR3 significantly reduced LPS-induced NOX2 activation, microglial M1 polarization, and exosome production in mice. Overall, our findings revealed a critical role of the CR3-NOX2 axis in controlling microglial exosome release and related neurotoxicity through syntenin-1, providing a novel target for the development of a therapeutic strategy for neuroinflammation-mediated neurodegeneration. Full article

It has long been accepted that breathing gases that are physiologically inert include helium (He), neon (Ne), nitrogen (N₂), argon (Ar), krypton (Kr), xenon (Xe), and hydrogen (H₂). The term “inert gas” has been used to describe them due to their unusually high chemical stability. However, as investigations have advanced, many have shown that inert gas can have specific biological impacts when exposed to high pressure or atmospheric pressure. Additionally, different inert gases have different effects on intracellular signal transduction, ion channels, and cell membrane receptors, which are linked to their anesthetic and cell protection effects in normal or pathological processes. Through a selective analysis of the representative literature, this study offers a concise overview of the state of research on the biological impacts of inert gas and their molecular mechanisms. Full article

Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to target cancer cells, offers promising solutions. Gamma delta (γδ) T cells are noteworthy due to their potent ability to kill various cancer cells without needing conventional antigen presentation. Recent studies have focused on the role of γδ T cells in α-galactosylceramide (α-GalCer)-mediated immunity, opening new possibilities for cancer immunotherapy. We engineered humanized T cell receptor (HuTCR)-T1 γδ mice by replacing mouse sequences with human counterparts. This study investigates the cytotoxic activity of humanized γδ T cells against several human cancer cell lines (A431, HT-29, K562, and Daudi) in vitro, aiming to elucidate mechanisms underlying their anticancer efficacy. Human cancer cells were co-cultured with humanized γδ T cells, with and without α-GalCer, for 24 h. The humanized γδ T cells showed enhanced cytotoxicity across all tested cancer cell lines compared to wild-type γδ T cells. Additionally, γδ T cells from HuTCR-T1 mice exhibited higher levels of anticancer cytokines (IFN-γ, TNF-α, and IL-17) and Granzyme B, indicating their potential as potent mediators of anticancer immune responses. Blocking γδ T cells’ cytotoxicity confirmed their γδ-mediated function. These findings represent a significant step in preclinical development of γδ T cell-based cancer immunotherapies, providing insights into their mechanisms of action, optimization of therapeutic strategies, and identification of predictive biomarkers for clinical application. Full article

Cardiovascular disease (CVD) is the leading cause of death worldwide, with pathophysiological mechanisms often involving platelet activation and chronic inflammation. While antiplatelet agents targeting adenosine diphosphate (ADP)-mediated pathways are well established in CVD management, less is known about drug interactions with the platelet-activating factor (PAF) pathway, a key mediator of inflammation. This study aimed to evaluate the effects of several commonly used cardiovascular and anti-inflammatory drug classes—including clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin II receptor blockers (ARBs), β-blockers, and analgesics—on platelet function via both the ADP and PAF pathways. Using human platelet-rich plasma (hPRP) from healthy donors, we assessed platelet aggregation in response to these two agonists in the absence and presence of graded concentrations of each of these drugs or of their usually prescribed combinations. The study identified differential drug effects on platelet aggregation, with some agents showing pathway-specific activity. Clopidogrel and NSAIDs demonstrated expected antiplatelet effects, while some (not all) antihypertensives exhibited additional anti-inflammatory potential. These findings highlight the relevance of evaluating pharmacological activity beyond traditional targets, particularly in relation to PAF-mediated inflammation and thrombosis. This dual-pathway analysis may contribute to a broader understanding of drug mechanisms and inform the development of more comprehensive therapeutic strategies for the prevention and treatment of cardiovascular, hypertension, and inflammation-driven diseases. Full article

Nuclear receptors are involved in multiple biological processes, among which RORγ can regulate the expression of inflammation-related genes and is thus frequently used as a therapeutic target for cancer. Canine mammary cancer is one of the most common tumor diseases in dogs, with a relative incidence rate of 46.71% for CMT in China over the past five years, severely threatening the life and health of dogs. Therefore, the search for novel drugs targeting canine mammary cancer is of great significance. This study aims to investigate how the RORγ inhibitors W6134 and XY018 affect the expression of inflammatory genes through histone modifications in CMT-N7 cells. These results show that W6134 and XY018 can upregulate signaling pathways related to inflammation and apoptosis and influence the expression of associated genes. The close link between RORγ and inflammation-related genes further confirms that RORγ may serve as a therapeutic target for canine cancer. Additionally, ChIP-qPCR was used to detect the enrichment of histone markers such as P300, H3K27ac, H3K4me1, H3K9la, and H3K9bhb at the target loci of CXCL10 and MECOM genes. Collectively, our findings provide molecular evidence for the protective role of RORγ in canine mammary cancer, potentially by regulating inflammatory pathways via histone modifications, offering new insights for improving the cure rate and survival of affected dogs. Full article

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the onset of pruritus and elevated serum transaminases and bile acids (BA). The key enzyme in BA synthesis is CYP7A1, and its functions are regulated by various nuclear receptors. The goal of this study is to evaluate the association between CYP7A1, NR1H1, RXRA, and PPARA gene variants and risk of ICP. Five single nucleotide variants (SNVs), rs3808607 (CYP7A1), rs56163822 (NR1H4), rs1800206 (PPARA), rs749759, and rs11381416 (NR2B1), were genotyped in a group of 96 ICP and 211 controls. The T allele of the CYP7A1 (rs3808607) variant may be a protective factor against ICP risk (OR = 0.697, 95% CI: 0.495–0.981, p = 0.038). Genetic model analysis showed that rs3808607 was associated with decreased risk of ICP under dominant (OR = 0.55, 95% CI: 0.32–3.16, p = 0.032, AIC = 380.9) and log-additive models (OR = 0.71, 95% CI: 0.51–1.00, p = 0.046, AIC = 381.4). The A insertion in the rs11381416 NR2B1 variant was associated with the degree of elevation in the liver function tests TBA (34.3 vs. 18.8 μmol/L, p = 0.002), ALT (397.0 vs. 213.0 IU/L, p = 0.017), and AST (186.0 vs. 114.4 IU/L, p = 0.032) in ICP women. Results indicate an association between the CYP7A1 rs3808607 and the risk of ICP and the association of the rs11381416 of the NR2B1 receptor with higher values of liver function tests in women with ICP. A better understanding of the cooperation of proteins involved in BA metabolism may have important therapeutic implications in ICP and other hepatobiliary diseases. Full article

Leishmaniasis is an infectious disease common in tropical and subtropical regions worldwide. This study aimed to develop a topical meglumine antimoniate gel (MA-gel) for the treatment of cutaneous leishmaniasis. The MA-gel was characterized in terms of morphology, pH, swelling, porosity, rheology, and thermal properties by differential scanning calorimetry (DSC). Biopharmaceutical evaluation included in vitro drug release and ex vivo skin permeation. Safety was evaluated through biomechanical skin property measurements and cytotoxicity in HaCaT and RAW 267 cells. Leishmanicidal activity was tested against promastigotes and amastigotes of Leishmania infantum, and in silico studies were conducted to explore possible mechanisms of action. The composition of the MA-gel included 30% MA, 20% Pluronic^® F127 (P407), and 50% water. Scanning electron microscopy revealed a sponge-like and porous internal structure of the MA-gel. This formula exhibited a pH of 5.45, swelling at approximately 12 min, and a porosity of 85.07%. The DSC showed that there was no incompatibility between MA and P407. Drug release followed a first-order kinetic profile, with 22.11 µg/g/cm² of the drug retained in the skin and no permeation into the receptor compartment. The MA-gel showed no microbial growth, no cytotoxicity in keratinocytes, and no skin damage. The IC₅₀ for promastigotes and amastigotes of L. infantum were 3.56 and 23.11 µg/mL, respectively. In silico studies suggested that MA could act on three potential therapeutic targets according to its binding mode. The MA-gel demonstrated promising physicochemical, safety, and antiparasitic properties, supporting its potential as a topical treatment for cutaneous leishmaniasis. Full article

Resveratrol (RSV), a polyphenol found in a variety of berries and wines, is known for its anti-inflammatory, anticancer, and antioxidant properties. It has been suggested that RSV may play a role in the regulation of metabolic disorders, including diabetes and insulin resistance. However, in recent years, it has been reported to completely inhibit Akt kinase function in liver cells. Akt is a central protein involved in the metabolic function of insulin and is regulated by the phosphatidylinositol-3-kinase (PI3K) pathway. In this study, we examined the effect of RSV on insulin-induced insulin receptor (IR) phosphorylation and proteins involved in the PI3K/Akt pathway in a hepatic cell model, clone 9 (C9), and in hepatoma cells, Hepa 1-6 (H1-6). In both cell lines, RSV inhibited tyrosine phosphorylation of IR and insulin-induced activation of Akt. We also evaluated the effect of RSV on the activation of protein tyrosine phosphatase 1B (PTP1B), which is associated with IR dephosphorylation, and found that RSV increased PTP1B-Tyr¹⁵² phosphorylation in a time- and concentration-dependent manner. Furthermore, we found that the protein kinase C (PKC) inhibitors BIM and Gö6976 prevented the inhibition of Akt phosphorylation by RSV and increased the phosphorylation of Ser/Thr residues in IR, suggesting that PKC is involved in the inhibition of the insulin pathway by RSV. Thus, classical PKC isoforms impair the PI3K/Akt pathway at the IR and GSK3 and GS downstream levels; however, IRS-Tyr⁶³² phosphorylation remains unaffected. These results suggest that RSV can lead to insulin resistance by activating PTP1B and PKC, consequently affecting glucose homeostasis in hepatic cells. Full article

Background: We recently reported sex-dependent impairment in cognitive functions in male and female mice exposed for 24 h, 48 h or 15 days to 2G hypergravity (HG). Methods: In the present study, we investigated brain functional correlates by analyzing synaptic activity and plasticity in the CA1 area of the hippocampus in both genders of mice previously exposed to 2G for the same duration. This was assessed by electrophysiological extracellular recordings in ex vivo slice preparations. Results: Basal synaptic transmission and glutamate release were unchanged regardless of HG duration. However, plasticity was altered in a sex- and time-specific manner. In males, long-term potentiation (LTP) induced by strong high-frequency stimulation and NMDA receptor (NMDAr) activation was reduced by 26% after 24 h of exposure but recovered at later timepoints. This deficit was reversed by D-serine or glycine, suggesting decreased activation at the NMDAr co-agonist site. In females, LTP deficits (23%) were found only after 15 days following mild theta burst stimulation and were not reversed by D-serine. Long-term depression (LTD) was unaffected in both sexes. Conclusions: This study highlights, for the first time, sex-dependent divergence in the CA1 hippocampal plasticity timeline following 2G exposure. The synaptic changes depend on exposure duration and the stimulation protocol and could underlie the previously observed cognitive deficits. Full article

Background/Objectives: Gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer and might be used as a theranostics target. The expression of GRPR strongly correlates with estrogen receptor (ER) expression. Visualization of GRPR-expressing breast tumors might help to select the optimal treatment. Developing GRPR-specific probes for SPECT would permit imaging-guided therapy in regions with restricted access to PET facilities. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the [^99mTc]Tc-DB8 GRPR-antagonistic peptide. We also addressed the important issue of finding the optimal injected peptide mass. Methods: Fifteen female patients with ER-positive primary breast cancer were enrolled and divided into three cohorts receiving [^99mTc]Tc-DB8 (corresponding to three distinct doses of 40, 80, or 120 µg DB8) comprising five patients each. Additionally, four patients with ER-negative primary tumors were injected with 80 µg [^99mTc]Tc-DB8. The injected activity was 360 ± 70 MBq. Planar scintigraphy was performed after 2, 4, 6, and 24 h, and SPECT/CT scans followed planar imaging 2, 4, and 6 h after injection. Results: No adverse events were associated with [^99mTc]Tc-DB8 injections. The effective dose was 0.009–0.014 mSv/MBq. Primary tumors and all known lymph node metastases were visualized irrespective of injected peptide mass. The highest uptake in the ER-positive tumors was 2 h after injection of [^99mTc]Tc-DB8 at a 80 µg DB8 dose (SUV_max 5.3 ± 1.2). Injection of [^99mTc]Tc-DB8 with 80 µg DB8 provided significantly (p < 0.01) higher uptake in primary ER-positive breast cancer lesions than injection with 40 µg DB8 (SUV_max 2.0 ± 0.3) or 120 µg (SUV_max 3.2 ± 1.4). Tumor-to-contralateral breast ratio after injection of 80 μg was also significantly (p < 0.01, ANOVA test) higher than ratios after injection of other peptide masses. The uptake in ER-negative lesions was significantly lower (SUV_max 2.0 ± 0.3) than in ER-positive tumors. Conclusions: Imaging using [^99mTc]Tc-DB8 is safe, tolerable, and associated with low absorbed doses. The tumor uptake is dependent on the injected peptide mass. The injection of an optimal mass (80 µg) provides the highest uptake in ER-positive tumors. At optimal dosing, the uptake was significantly higher in ER-positive than in ER-negative lesions. Full article

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems. Full article

The β-glucosidase CEL1B has been linked to regulating cellulase expression in Trichoderma reesei, yet its inducer-specific functions and broader regulatory roles remain poorly characterized. In this study, CRISPR-Cas9-mediated gene knockout was applied in the industrial high-producing T. reesei Rut C30 to investigate CEL1B function without the confounding effects of KU70 deletion. Unlike previous studies focused solely on cellulose or lactose induction, transcriptomic analysis of the CEL1B knockout strain revealed its regulatory roles under both lactose- and sophorose-rich conditions, with sophorose representing the most potent natural inducer of cellulase expression. Under lactose induction, CEL1B deletion resulted in a 52.4% increase in cellulase activity (p < 0.05), accompanied by transcriptome-wide upregulation of β-glucosidase genes (CEL3A: 729%, CEL3D: 666.8%, CEL3C: 110.9%), cellulose-sensing receptors (CRT1: 203.0%, CRT2: 105.8%), and key transcription factors (XYR1: 2.7-fold, ACE3: 2.8-fold, VIB1: 2.1-fold). Expression of ER proteostasis genes was significantly upregulated (BIP1: 3.3-fold, HSP70: 6.2-fold), contributing to enhanced enzyme secretion. Conversely, under sophorose induction, CEL1B deletion reduced cellulase activity by 25.7% (p < 0.05), which was associated with transcriptome profiling showing significant downregulation of β-glucosidase CEL3H (66.6%) and cellodextrin transporters (TrireC30_91594: 79.3%, TrireC30_127980: 76.3%), leading to reduced cellobiohydrolase expression (CEL7A: 57.8%, CEL6A: 67.8%). This first transcriptomic characterization of the CEL1B knockout strain reveals its dual opposing roles in modulating cellulase expression in response to lactose versus sophorose, providing new strategies for optimizing inducer-specific enzyme production in T. reesei. Full article