Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Urinary tract infections are among the most frequently occurring forms of infection, and inflammation and tissue damage contribute significantly to symptoms, e.g., dysuria and urge. Canephron N is an orally bioavailable herbal medicine with anti-inflammatory, spasmolytic, anti-adhesive, and anti-nociceptive therapeutic effects that is approved for the treatment of uncomplicated urinary tract infections. Here, we used renal tubular epithelial HK-2 cells to study the anti-inflammatory and cytoprotective effects and molecular mechanisms of its active component, BNO 2103. BNO 2103 suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation by lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) and prevented inhibitory κB kinase (IKK)-dependent phosphorylation and degradation of inhibitor of nuclear factor kappa B alpha (IκBα). BNO 2103 also suppressed the inflammation-specific S536 phosphorylation of the NF-κB subunit p65 and the production of a specific set of inflammatory cytokines. Unlike other NF-κB inhibitors, BNO 2103 demonstrated cytoprotection against TNFα-induced cytotoxicity. Our data suggest that BNO 2103 acts primarily through the mitogen-activated protein kinase p38 (p38 MAPK)-MAPK-activated protein kinase 2 (MK2) axis by promoting receptor-interacting serine/threonine protein kinase 1 (RIPK1) phosphorylation at S320. Simultaneously, it suppresses S166 autophosphorylation and subsequent activation of RIPK1, which is required for apoptotic and necroptotic responses to TNFα. This study confirms Canephron N as an effective alternative to traditional anti-inflammatory drugs and provides initial evidence of its ability to inhibit apoptosis and necroptosis in the urogenital system. It also presents a detailed pathway investigation that identifies the specific targets of Canephron N within the NF-κB signaling cascade.

ABCB1/MDR-1/P-glycoprotein (Pgp) is an ABC transporter responsible for cancer cell multi-drug resistance. It is expressed in cytotoxic T lymphocytes (CTL). Eliminating sensitive cancer cells during high-dose chemotherapy can also damage immune cells. Our study aimed to assess which maturing human CD8 + CTL memory subsets may be affected based on their Pgp protein expression. In an in vitro CTL differentiation model system, we tracked the maturation of naive, effector, and memory cells and the expression of Pgp. This system involves co-culturing blood lymphocytes with proliferation-inhibited JY antigen-presenting B-lymphoblastoid cells expressing HLA-I A2. These JY-primed maturing CTLs were TCR-activated using beads, and the effect of the maturation-modifying JAK1/2 inhibitor ruxolitinib was examined. Multidimensional analysis identified six major CTL subsets: naive, young memory (Tym), stem cell memory (Tscm), central memory (Tcm), effector memory (Tem), and effectors (Te). These subsets were further divided into thirteen specific subsets: TymCD127 + , TymCD127-, Tscm, TcmCD95 + , TcmCD73 +CD95 + , TcmCD95+CD127 + , TcmPD1 + , TemCD95 + , TemraCD127 + , TemraCD127-, TeCD95 + , and TeCD73 +CD95 + . Pgp expression was detectable in naïve cells and dynamically changed across the thirteen identified subsets. Increased Pgp was detected in young memory T cells and in Tscm, TcmCD95 + , and TcmPD1 + human CTL subsets. Unlike other transiently appearing memory cells, the number of cells in these core Pgp-expressing memory subsets stabilized by the end of the contraction phase. Ruxolitinib treatment downregulated effector T-cell polarization while upregulating small memory subsets expressing Pgp. In conclusion, activation increased Pgp expression, whereas ruxolitinib treatment preserved small early and late memory subset core that primarily expressed Pgp.

Aims: The term ovarian carcinoma (OC) refers to a heterogeneous collection of five distinct diseases known as histotypes. While histotype-specific treatment is still a clinical challenge in OC, well-characterized models are required for testing new therapeutic strategies. We employed OncoTherad® (MRB-CFI-1), an interferon (IFN-γ)-stimulating nano-immunotherapy mediated by Toll-like receptors (TLR) 2/4, in association or not with Erythropoietin (EPO) in a chemically-induced ovarian cancer model. Besides characterization of the therapies effects, we also assessed whether the animal model was representative of human OC by providing histotype classification.

Main methods: Thirty-five Fischer rats were distributed into five groups: Control (Sham surgery); Cancer (7,12-dimethylbenzoanthracene - DMBA injection in the ovarian bursa, 1.25 mg/kg); OncoTherad® (20 mg/kg intraperitoneal); EPO (8.4 µg/kg intraperitoneal); and OncoTherad+EPO (same doses). Ovaries were formalin-fixed into paraffin-embedded blocks. TLR pathway and the inflammatory response profile were evaluated by immunohistochemistry (IHC). After DNA extraction and tissue microarray construction, we assessed typical gene mutations directly (Sanger sequencing) or indirectly (IHC surrogates) and examined biomarkers of different OC histotypes.

Key findings: OC induction decreased TLR2, TLR4, and proinflammatory cytokines. OncoTherad® alone or associated with EPO modulated the OC microenvironment to a cytotoxic immune profile through stimulation of the TLR4-mediated non-canonical pathway. EPO stimulated TLR2-mediated canonical pathway and notably increased Tregs.

Significance: The features analyzed favored interpretation of our DMBA-induced tumor model as predominantly low-grade, serous carcinoma-like, in which treatments with OncoTherad® and EPO showed immunomodulatory properties related to the reduction of ovarian lesions.

Ketogenic diet has a wide range of beneficial effects but presents practical limitations due to its low compliance, hence dietary supplements have been developed to induce ketosis without nutrient deprivation. The alcohol 1,3-butanediol (BD) is a promising molecule for its ability to induce ketosis, but its effects on brain have been investigated so far only in disease models, but never in physiological conditions. To support BD use to preserve brain health, the analysis of its activity is mandatory. Therefore, we investigated, in healthy rats, the effect of a fourteen-days BD-administration on the hippocampus, an area particularly vulnerable to oxidative and inflammatory damage. Since BD treatment has been reported to reduce energy intake, results were compared with those obtained from rats undergoing a restricted dietary regimen, isoenergetic with BD group (pair fed, PF). Reduced pro-inflammatory signaling pathways and glial activation were revealed in hippocampus of BD treated rats in comparison to control (C) and PF groups. ROS content and the extent of protein oxidative damage were lower in BD and PF groups than in C. Interestingly, higher amounts of nuclear factor erythroid 2-related factor 2 (Nrf2), decreased level of lipid hydroperoxides, lower susceptibility to oxidative insult, higher amounts of superoxide dismutase-2, glutathione reductase and glutathione peroxidase (GPx), and increased GPx activity were observed in BD animals. BD administration, but not dietary restriction, attenuated endoplasmic reticulum stress, reduced autophagic response activation, and was associated with an increase of both the neurotrophin BDNF and pre-synaptic proteins synaptophysin and synaptotagmin. Our results highlight that BD plays a neuroprotective role in healthy conditions, thus emerging as an effective strategy to support brain function without the need of implementing ketogenic nutritional interventions.

Cancer is a devastating disease worldwide with high mortality rates and is a foremost concern for society. Immunotherapy has emerged as a promising strategy for treating cancer, harnessing the power of immune system to recognize and kill tumor cells. Bacterial ghosts (BGs), a novel platform in cancer vaccination, are suitable for personalized and effective immunotherapeutic interventions. BG are empty bacterial cell envelopes generated through a controlled lysis process, leaving behind empty but structurally intact cell membranes. BGs have been used as vaccine adjuvants and vaccine delivery vehicles worldwide. They possess inherent immunogenicity, enabling them to be used for controlled release and targeted drug delivery. Recently, the potential of BGs has been explored for tumor inhibition, making them suitable carrier vehicles. This review highlights cancer immunotherapy, methods of BG preparation, characterization of BGs, the interaction of BGs with the immune system, and research progress on BG-based cancer vaccines with future insights.

Patients suffering from psoriatic arthritis (PsA) often experience depression due to chronic joint pain, which significantly hinders their recovery process. However, the relationship between these two conditions is not well understood. Through a review of existing studies, we revealed that certain neuroendocrine hormones and neurotransmitters are involved in the neuroimmune interactions related to both PsA and depression. These include adrenocorticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), cortisol, monoamine neurotransmitters, and brain-derived neurotrophic factor (BDNF). Notably, the signalling pathway involving CRH, MCs, and Th17 cells plays a crucial role in linking PsA with depression; thus, this pathway may help clarify their connection. In this review, we outline the inflammatory immune changes associated with PsA and depression. Additionally, we explore how neuroendocrine hormones and neurotransmitters influence inflammatory responses in these two conditions. Finally, our focus will be on potential treatment strategies for patients with PsA and depression through the targeting of the CRH-MC-Th17 pathway. This review aims to provide a theoretical framework as well as new therapeutic targets for managing PsA alongside depression.

Exosomes, minute vesicles originating from diverse cell types, exhibit considerable potential as carriers for drug delivery in glioma therapy. These naturally occurring nanocarriers facilitate the transfer of proteins, RNAs, and lipids between cells, offering advantages such as biocompatibility, efficient cellular absorption, and the capability to traverse the blood-brain barrier (BBB). In the realm of cancer, particularly gliomas, exosomes play pivotal roles in modulating tumor growth, regulating immunity, and combating drug resistance. Moreover, exosomes serve as valuable biomarkers for diagnosing diseases and assessing prognosis. This review aims to elucidate the therapeutic and diagnostic promise of exosomes in glioma treatment, highlighting the innovative advances in exosome engineering that enable precise drug loading and targeting. By circumventing challenges associated with current glioma treatments, exosome-mediated drug delivery strategies can enhance the efficacy of chemotherapy drugs like temozolomide and overcome drug resistance mechanisms. This review underscores the multifaceted roles of exosomes in glioma pathogenesis and therapy, underscoring their potential as natural nanocarriers for targeted therapy and heralding a new era of hope for glioma treatment.

The uncontrolled overproduction of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) is linked to chronic inflammation, although they are also essential signaling molecules for the immune system against infectious agents. Bioactive compounds hold promise as functional bioactive nutrients, contributing to the immunomodulatory response. This study investigates the potential of chickpea protein hydrolysate to modulate ROS/RNS stress and inflammatory responses in a cellular low-grade chronic inflammatory model. This study was focused on their effects on endogenous antioxidant enzyme activities and key pro-inflammatory markers. ROS and nitric oxide (NO) production and molecular biology techniques were used to evaluate cell metabolism. Hydrolysate exposure notably increased ROS and NO release in a dose-dependent manner, while also exhibiting significant anti-inflammatory effects by inhibiting NF-κB and NLRP3 inflammasome components in treated cells. Therefore, chickpea protein hydrolysates hold promise as functional bioactive compounds for use in therapeutic applications, promoting human health and well-being.

This study sheds light on the ameliorative influence of combined sericin and hydroxychloroquine (HQ) on mitigating diethylnitrosamine (DEN)-induced lung oxidative impairment and inflammation, thereby precluding early carcinogenic episodes in mice. Besides, the pivotal role of sericin and HQ in controlling the PI3K/Akt/Nrf2/NF-κB signaling pathway was probed. Therefore, male Swiss albino mice were assigned to different groups and treated with different drugs. Oxidative stress and inflammatory biomarkers, in addition to the expression of PI3K and Akt genes were evaluated in lung tissues. Treatment with DEN disturbed the redox homeostasis associated with inflammation in the lungs. Conversely, sericin combined with HQ remarkably upregulated Nrf2 expression in the lungs associated with significant ameliorations of antioxidant factors, including SOD, GST, GSH, and MDA. Furthermore, sericin and HQ abated inflammation instigated by DEN through downregulating NF-κB and inflammatory biomarkers, including TNF-α and IL-6, with an increase in IL-10. Importantly, sericin and HQ treatment significantly downregulated PI3K and Akt expression. Immunohistochemical investigations demonstrated marked diminutions in Ki-67 and p53 expressions in animals cotreated with sericin and HQ compared to the DEN-treated group, inhibiting lung cancer progression. Histopathological and ultrastructural anomalies were detected in lung tissues from the DEN group, while significant enhancements were perceived in lung tissues treated with sericin and HQ. Our findings emphasized that the combinatorial therapy of sericin and HQ could orchestrate the PI3K/Akt/Nrf2/NF-κB signaling pathway in the lungs, counteracting oxidative stress, inflammation, and uncontrolled cellular proliferation and sustaining lung structures. Furthermore, they could serve as anticancer agents, hindering lung cancer progression.