Chuanxiong Renshen Decoction Inhibits Alzheimer's Disease Neuroinflammation by Regulating PPARγ/NF-κB Pathway.

Background and Aim: Previous studies of our research group have shown that Chuanxiong Renshen Decoction (CRD) has the effect of treating AD, but the exact mechanism of its effect is still not clarified. The aim of this study was to investigate the effect and mechanism of CRD on AD neuroinflammation. Materials and Methods: Morris Water Maze (MWM) tests were employed to assess the memory and learning capacity of AD mice. HE and Nissl staining were used to observe the neural cells of mice. The expression of Iba-1 and CD86 were detected by immunohistochemical staining. Utilize UHPLC-MS/MS metabolomics techniques and the KEGG to analyze the metabolic pathways of CRD against AD. Lipopolysaccharide (LPS) induced BV2 microglia cells to construct a neuroinflammatory model. The expression of Iba-1 and CD86 were detected by immunofluorescence and flow cytometry. The contents of TNF-α and IL-1ß were detected by ELISA. Western blot assay was used to detect the expression of PPARγ, p-NF-κB p65, NF-κB p65 proteins and inflammatory cytokines iNOS and COX-2 in PPARγ/NF-κB pathway with and without PPARγ inhibitor GW9662. Results: CRD ameliorated the learning and memory ability of 3×Tg-AD mice, repaired the damaged nerve cells in the hippocampus, reduced the area of Iba-1 and CD86 positive areas in both the hippocampus and cortex regions, as well as attenuated serum levels of IL-1ß and TNF-α in mice. CRD-containing serum significantly decreased the expression level of Iba-1, significantly reduced the levels of TNF-α and IL-1ß, significantly increased the protein expression of PPARγ, and significantly decreased the proteins expression of iNOS, COX-2 and p-NF-κB p65 in BV2 microglia cells. After addition of PPARγ inhibitor GW9662, the inhibitory effect of CRD-containing serum on NF-κB activation was significantly weakened. Conclusion: CRD can activate PPARγ, regulating PPARγ/NF-κB signaling pathway, inhibiting microglia over-activation and reducing AD neuroinflammation.

Targeted nanoparticles triggered by plaque microenvironment for atherosclerosis treatment through cascade effects of reactive oxygen species scavenging and anti-inflammation.

Inflammatory factors and reactive oxygen species (ROS) are risk factors for atherosclerosis. Many existing therapies use ROS-sensitive delivery systems to alleviate atherosclerosis, which achieved certain efficacy, but cannot eliminate excessive ROS. Moreover, the potential biological safety concerns of carrier materials through chemical synthesis cannot be ignored. Herein, an amphiphilic low molecular weight heparin- lipoic acid conjugate (LMWH-LA) was used as a ROS-sensitive carrier material, which consisted of injectable drug molecules used clinically, avoiding unknown side effects. LMWH-LA and curcumin (Cur) self-assembled to form LLC nanoparticles (LLC NPs) with LMWH as shell and LA/Cur as core, in which LMWH could target P-selectin on plaque endothelial cells and competitively block the migration of monocytes to endothelial cells to inhibit the origin of ROS and inflammatory factors, and LA could be oxidized to trigger hydrophilic-hydrophobic transformation and accelerate the release of Cur. Cur released within plaques further exerted anti-inflammatory and antioxidant effects, thereby suppressing ROS and inflammatory factors. We used ultrasound imaging, pathology and serum analysis to evaluate the therapeutic effect of nanoparticles on atherosclerotic plaques in apoe-/- mice, and the results showed that LLC showed significant anti-atherosclerotic effects. Our finding provided a promising therapeutic nanomedicine for the treatment of atherosclerosis.

Enzyme/ROS dual-sensitive nanoplatform with on-demand Celastrol release capacity for enhanced ulcerative colitis therapy by ROS scavenging, microbiota rebalancing, inflammation alleviating.

BACKGROUND: The oral administration of drugs for treating ulcerative colitis (UC) is hindered by several factors, including inadequate gastrointestinal stability, insufficient accumulation in colonic lesions, and uncontrolled drug release. METHODS: A multiple sensitive nano-delivery system comprising ß-cyclodextrin (CD) and 4-(hydroxymethyl)phenylboronic acid (PAPE) with enzyme/reactive oxygen species (ROS) sensitivity was developed to load celastrol (Cel) as a comprehensive treatment for UC. RESULTS: Owing to the positive charge in the site of inflamed colonic mucosa, the negatively charged nanomedicine (Cel/NPs) could efficiently accumulate. Expectedly, Cel/NPs showed excellent localization ability to colon in vitro and in vivo tests. The elevated concentration of ROS and intestinal enzymes in the colon microenvironment quickly break the CD, resulting in Cel release partially to rebalance microbiota and recover the intestinal barrier. The accompanying cellular internalization of residual Cel/NPs, along with the high concentration of cellular ROS to trigger Cel burst release, could decrease the expression of inflammatory cytokines, inhibit colonic cell apoptosis, promote the macrophage polarization, scavenge ROS, and regulate the TLR4/NF-κB signaling pathway, which certified that Cel/NPs possessed a notably anti-UC therapy outcome. CONCLUSIONS: We provide a promising strategy for addressing UC symptoms via an enzyme/ROS-sensitive oral platform capable of releasing drugs on demand.

VALD-2 mitigates cisplatin-induced acute kidney injury: Mechanistic insights into oxidative stress modulation and inflammation suppression.

This study explores the compelling antitumor properties of VALD-2, a synthetic Schiff base ligand known for its low toxicity. The focus is on investigating VALD-2's protective role against cisplatin-induced acute kidney injury (AKI) in mice, with a specific emphasis on mitigating oxidative stress and inflammation. The study involves daily intraperitoneal injections of amifostine or VALD-2 over 7 days to establish an AKI model. Subsequently, mice were assigned to normal control, cisplatin group, cisplatin + amifostine group, and cisplatin + VALD-2 10 mg/kg group, cisplatin + VALD-2 20 mg/kg, and cisplatin + VALD-2 40 mg/kg. Kidney injury is assessed through serum blood urea nitrogen (BUN) and creatinine (Cr) activity assays. Levels of inflammatory factors, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in kidney tissue of mice were assessed through enzyme-linked immunosorbent assay (ELISA). The protective effect of VALD-2 is further examined through HE staining to observe pathological changes in kidney injury. The ultrastructural changes of renal cells and tubular epithelial cells were observed by electron microscopy under experimental conditions, indicating the effect of VALD-2 on reversing cisplatin-induced renal injury. The study delves into VALD-2's protective mechanisms against cisplatin-induced kidney injury by using western blot analysis to assess the expression levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) in kidney tissues. VALD-2 demonstrates significant improvement in cisplatin-induced AKI, as evidenced by increased BUN and Cr levels. It effectively protects kidney tissue from oxidative damage, enhancing SOD and GSH-Px activities while reducing MDA levels. The study also reveals a decrease in TNF-α and IL-6 levels, supported by ELISA results, and histological findings confirm anti-nephrotoxic effects. Western blot analysis shows an upregulation of antioxidant enzymes (SOD, GSH-Px) and a reduction in MDA production. VALD-2 emerges as a promising mitigator of cisplatin-induced AKI, showcasing its ability to enhance oxidative stress-related protein expression. The findings suggest VALD-2 as a potential therapeutic agent for protecting against cisplatin-induced kidney injury.

Oxycodone attenuates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1 signalling pathway.

Myocardial injury and cardiovascular dysfunction are the most common complications of sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in myocardial injury of lipopolysaccharide-induced sepsis and its related signalling pathways. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout mice, as well as H9c2 cardiomyocytes cultures treated with lipopolysaccharide (LPS) were used as models of septic myocardial injury. H9c2 cardiomyocytes culture showed that oxycodone protected cells from pyroptosis induced by LPS. Mice model confirmed that oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function demonstrated by increased ejection fraction (EF) and fractional shortening (FS), as well as decreased cardiac troponin I (cTnI) and creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including: Nod-like receptor protein 3 (NLRP3), Caspase 1, Apoptosis-associated speck-like protein contain a CARD (ASC), and Gasdermin D (GSDMD). These changes were mediated by Nrf2 and heme oxygenase-1 (HO-1) because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings yielded that oxycodone therapy reduces LPS-induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signalling pathway in vivo and in vitro.

Can Vitamin D Reduce Inflammation? The Influence of Supplementation on Selected Immunological Markers.

There is increasing evidence that vitamin D (VitD) supplementation may reduce inflammation in individuals with multiple sclerosis (MS). The aim of this study was to evaluate the effect of different doses of VitD on selected markers of inflammation in patients with relapsing-remitting MS (RRMS). Participants were divided depending on the supplemented dose of VitD into a high-dose (2000 IU/d; HD) group and a low-dose (15,960 IU/month; LD) group (n = 23 and n = 29, respectively). The concentration of 25(OH)D and the levels of CXCL16, PTX3, ALCAM, IL-1RA, and OPG were measured initially and after six months of VitD supplementation in blood serum. A significant increase in the concentrations of CXCL16, PTX3, and OPG was observed during the study (p = 0.02, p = 0.01, and p < 0.01, respectively). Furthermore, a higher increase in PTX3 and OPG in the LD group was observed (p = 0.04 and p = 0.03, respectively). A significant positive correlation was observed between the 25(OH)D serum concentration and PTX3 (R = 0.28, p < 0.05) and OPG (R = 0.28, p < 0.05) only at the beginning of the study. In patients with RRMS, such doses of VitD might be too low to induce obvious beneficial effects on the pro-inflammatory and inflammatory balance.

Potential for Drug Repositioning of Midazolam as an Inhibitor of Inflammatory Bone Resorption.

Drug repositioning is a method for exploring new effects of existing drugs, the safety and pharmacokinetics of which have been confirmed in humans. Here, we demonstrate the potential drug repositioning of midazolam (MDZ), which is used for intravenous sedation, as an inhibitor of inflammatory bone resorption. We cultured a mouse macrophage-like cell line with or without MDZ and evaluated its effects on the induction of differentiation of these cells into osteoclasts. For in vivo investigations, we administered lipopolysaccharide (LPS) together with MDZ (LPS+MDZ) to the parietal region of mice and evaluated the results based on the percentage of bone resorption and calvaria volume. Furthermore, we examined the effects of MDZ on the production of reactive oxygen species (ROS) in cells and on its signaling pathway. MDZ inhibited osteoclast differentiation and bone resorption activity. In animal studies, the LPS+MDZ group showed a decreasing trend associated with the rate of bone resorption. In addition, the bone matrix volume in the LPS+MDZ group was slightly higher than in the LPS only group. MDZ inhibited osteoclast differentiation by decreasing ROS production and thereby negatively regulating the p38 mitogen-activated protein kinase pathway. Thus, we propose that MDZ could potentially be used for treating inflammatory bone resorption, for example, in periodontal disease.

Effects of Bosentan on Hypoxia, Inflammation and Oxidative Stress in Experimental Blunt Thoracic Trauma Model.

Background and Objectives: In this study, we aimed to investigate the effects of bosentan, an endothelin receptor antagonist, on endothelin-1 (ET-1), hypoxia-inducible factor-1 (HIF-1), nuclear factor-kappa B (NF-κB), and tumor necrosis factor (TNF)-α as inflammation markers, pro-oxidant antioxidant balance (PAB), and total antioxidant capacity (TAC) levels as oxidative stress parameters in lung tissues of rats in an experimental model of pulmonary contusion (PC) induced by blunt thoracic trauma. Materials and Methods: Thirty-seven male Sprague-Dawley rats were divided into five groups. C: The control group (n = 6) consisted of unprocessed and untreated rats. PC3 (n = 8) underwent 3 days of PC. PC-B3 (n = 8) received 100 mg/kg bosentan and was given orally once a day for 3 days. The PC7 group (n = 7) underwent 7 days of PC, and PC-B7 (n = 8) received 100 mg/kg bosentan and was given orally once a day for 7 days. Results: ET-1, NF-κB, TNF-α, HIF-1α, and PAB levels were higher, while TAC activity was lower in all groups compared with the control (p < 0.05). There was no significant difference in ET-1 and TNF-α levels between the PC-B3 and PC-B7 groups and the control group (p < 0.05), while NF-κB, HIF-1α, and PAB levels were still higher in both the PC-B3 and PC-B7 groups than in the control group. Bosentan decreased ET-1, NF-κB, TNF-α, HIF-1α, and PAB and increased TAC levels in comparison to the nontreated groups (p < 0.05). Conclusions: Bosentan decreased the severity of oxidative stress in the lungs and reduced the inflammatory reaction in rats with PC induced by blunt thoracic trauma. This suggests that bosentan may have protective effects on lung injury mechanisms by reducing hypoxia, inflammation, and oxidative stress. If supported by similar studies, bosentan can be used in both pulmonary and emergency clinics to reduce ischemic complications, inflammation, and oxidative stress in some diseases that may be accompanied by ischemia.

Ageratum conyzoides Extract Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia via Inhibiting Proliferation, Inflammation of Prostates, and Induction of Apoptosis in Rats.

Ageratum conyzoides, an annual herbaceous plant that inhabits tropical and subtropical regions, has been traditionally used in Asia, Africa, and South America for phytotherapy to treat infectious and inflammatory conditions. However, the pharmacological effects of standardized ethanolic extract of Ageratum conyzoides (ACE) on benign prostatic hyperplasia (BPH) remain unexplored. The objective of this research is to examine the potential physiological impacts of ACE, a traditionally utilized remedy for inflammatory ailments, in a rat model with BPH induced by testosterone propionate (TP). Rats were subcutaneously administered TP (3 mg/kg) to induce BPH and concurrently orally administered ACE (20, 50, and 100 mg/kg) daily for 42 days. ACE markedly improved BPH characteristics, including prostate weight, prostate index, and epithelial thickness, while also suppressing androgens and related hormones. The findings were supported by a decrease in androgen receptor and downstream signals associated with BPH in the prostate tissues of the ACE groups. Furthermore, increased apoptotic signals were observed in the prostate tissue of the ACE groups, along with heightened detection of the apoptotic nucleus compared to the BPH alone group. These changes seen in the group that received finasteride were similar to those observed in this group. These findings suggest that ACE shows promise as an alternative phytotherapeutic agent for treating BPH.

Quinoa Polyphenol Extract Alleviates Non-Alcoholic Fatty Liver Disease via Inhibiting Lipid Accumulation, Inflammation and Oxidative Stress.

Recently, the incidence of NAFLD has exploded globally, but there are currently no officially approved medications for treating the condition. The regulation of NAFLD through plant-derived active substances has become a new area of interest. Quinoa (Chenopodium quinoa Willd.) has been discovered to contain a large quantity of bioactive compounds. In this study, we established a free fatty acid (FFA)-induced steatosis model and explored the effects of quinoa polyphenol extract (QPE) on the major hallmarks of NAFLD. The results indicated that QPE significantly reduced intracellular triglyceride (TG) and total cholesterol (TC) levels. Additionally, QPE remarkably elevated the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) and lowered levels of malondialdehyde (MDA). Further examination revealed that QPE attenuated intracellular inflammation, which was verified by the reduced levels of pro-inflammatory cytokines. Mechanistically, QPE inhibited fatty acid biosynthesis mainly by targeting de novo lipogenesis (DNL) via the AMPK/SREBP-1c signaling pathway. Moreover, network pharmacology was used to analyze key targets for NAFLD mitigation by ferulic acid (FA), a major component of QPE. Taken together, this study suggests that QPE could ameliorate NAFLD by modulating hepatic lipid metabolism and alleviating oxidative stress and inflammation.

The Impact of the CB2 Cannabinoid Receptor in Inflammatory Diseases: An Update.

The emergence of inflammatory diseases is a heavy burden on modern societies. Cannabis has been used for several millennia to treat inflammatory disorders such as rheumatism or gout. Since the characterization of cannabinoid receptors, CB1 and CB2, the potential of cannabinoid pharmacotherapy in inflammatory conditions has received great interest. Several studies have identified the importance of these receptors in immune cell migration and in the production of inflammatory mediators. As the presence of the CB2 receptor was documented to be more predominant in immune cells, several pharmacological agonists and antagonists have been designed to treat inflammation. To better define the potential of the CB2 receptor, three online databases, PubMed, Google Scholar and clinicaltrial.gov, were searched without language restriction. The full texts of articles presenting data on the endocannabinoid system, the CB2 receptor and its role in modulating inflammation in vitro, in animal models and in the context of clinical trials were reviewed. Finally, we discuss the clinical potential of the latest cannabinoid-based therapies in inflammatory diseases.

Flaxseed Oil Alleviates Trimethyltin-Induced Cell Injury and Inhibits the Pro-Inflammatory Activation of Astrocytes in the Hippocampus of Female Rats.

Exposure to the neurotoxin trimethyltin (TMT) selectively induces hippocampal neuronal injury and astrocyte activation accompanied with resultant neuroinflammation, which causes severe behavioral, cognitive, and memory impairment. A large body of evidence suggests that flaxseed oil (FSO), as one of the richest sources of essential omega-3 fatty acids, i.e., α-linolenic acids (ALA), displays neuroprotective properties. Here, we report the preventive effects of dietary FSO treatment in a rat model of TMT intoxication. The administration of FSO (1 mL/kg, orally) before and over the course of TMT intoxication (a single dose, 8 mg/kg, i.p.) reduced hippocampal cell death, prevented the activation of astrocytes, and inhibited their polarization toward a pro-inflammatory/neurotoxic phenotype. The underlying protective mechanism was delineated through the selective upregulation of BDNF and PI3K/Akt and the suppression of ERK activation in the hippocampus. Pretreatment with FSO reduced cell death and efficiently suppressed the expression of inflammatory molecules. These beneficial effects were accompanied by an increased intrahippocampal content of n-3 fatty acids. In vitro, ALA pretreatment prevented the TMT-induced polarization of cultured astrocytes towards the pro-inflammatory spectrum. Together, these findings support the beneficial neuroprotective properties of FSO/ALA against TMT-induced neurodegeneration and accompanied inflammation and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction.

Vitamin 25(OH)D3, E, and C Supplementation Impact the Inflammatory and Antioxidant Responses in Piglets Fed a Deoxynivalenol-Contaminated Diet and Challenged with Lipopolysaccharides.

Using alternative ingredients or low-quality grain grades to reduce feeding costs for pig diets can introduce mycotoxins such as deoxynivalenol (DON) into feed, which is known to induce anorexia, inflammation, and oxidative stress. Adding vitamin 25(OH)D3 or vitamins E and C to the feed could increase piglets' immune system to alleviate the effects of DON. This study used 54 pigs (7.8 ± 0.14 kg) in 27 pens (2 pigs/pen) with a vitamin 25(OH)D3 or vitamin E-C supplementation, or their combination, in DON-contaminated (5.1 mg/kg) feed ingredients over 21 days followed by a lipopolysaccharide (LPS) challenge (20 µg/kg BW) 3 h prior to euthanasia for 1 piglet per pen. DON contamination induced anorexia, which reduced piglet growth. DON also induced immunomodulation, oxidative stress, and downregulated vitamin D status. The vitamin E and C supplementation and the combination of vitamins E, C, and 25(OH)D3 provided protection against DON contamination by not only decreasing blood and liver oxidative stress markers, but also by increasing antioxidant enzymes and tocopherol levels in blood, indicating improved antioxidant defense mechanisms. The combination of vitamins also restored the vitamin D status. After LPS challenge, DON contamination decreased intestinal and liver antioxidant statuses and increased inflammation markers. The addition of vitamins E and C to DON-contaminated feed reduced markers of inflammation and improved the antioxidant status after the LPS immune stimulation. The combination of all these vitamins also reduced the oxidative stress markers and the inflammation in the intestine and mesenteric lymph nodes, suggesting an anti-inflammatory effect.

Multifunctional curcumin-based polymer coating: A promising platform against bacteria, inflammation and coagulation.

The extensive use of polymers in the medical field has facilitated the development of various devices and implants, contributing to the restoration of organ function. However, despite their advantages such as biocompatibility and robustness, these materials often face challenges like bacterial contamination and subsequent inflammation, leading to implant-associated infections (IAI). Integrating implants effectively is crucial to prevent bacterial colonization and reduce inflammatory responses. To overcome these major issues, surface chemical modifications have been extensively explored. Indeed, click chemistry, and particularly, copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has emerged as a promising approach for surface functionalization without affecting material bulk properties. Curcumin, known for its diverse biological activities, suffers from low solubility and stability. To enhance its bioavailability, bioconjugation strategy has garnered attention in recent years. This study represents pioneering work in immobilizing curcumin derivative onto polyethylene terephthalate (PET) surfaces, aiming to combat bacterial adhesion, inflammation and coagulation. Before curcumin derivative bioconjugation, a fluorophore, dansyl derivative, was employed in order to monitor and determine the efficiency of the proposed methodology. Previous surface chemical modifications were required for the immobilization of both dansyl and curcumin derivatives. Ultraviolet-Visible (UV-Vis) demonstrated the amidation functionalization of PET surface. Other surface characterization techniques including X-ray Photoelectron Spectroscopy (XPS), Attenuated Total Reflectance Fourier Transformed Infrared (ATR-FTIR), Scanning Electron Microscopy (SEM) and contact angle, among others, confirmed also the conjugation of both dansyl and curcumin derivatives. On the other hand, different biological assays corroborated that curcumin derivative immobilized PET surfaces do not exhibit cytotoxicity effect. Additionally, corresponding inflammation test were performed, indicating that these polymeric surfaces do not produce inflammation and, when curcumin derivative is immobilized, they decrease the inflammation marker level (IL-6). Moreover, the bacterial growth of both Gram positive and Gram negative bacteria were measured, demonstrating that the immobilization of curcumin derivative on PET provided antibacterial properties to the material. Finally, hemolysis rate analysis and whole blood clotting assay demonstrated the antithrombogenic effect of PET-Cur surfaces as well as no hemolysis concern in the fabricated functional surfaces.

T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including hepatocyte growth factor.

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. We show in two mouse T-ALL cell models that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils using anti-Ly6G treatment or resident monocytes by clodronate liposomes treatment does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA, an agonist of adenosine receptors, diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. Altogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF/cMET pathway as important to target for limiting T-ALL progression.

Lymphoid organ-targeted nanomaterials for immunomodulation of cancer, inflammation, and beyond.

Nanomaterials exhibit significant potential for stimulating immune responses, offering both local and systemic modulation across a variety of diseases. The lymphoid organs, such as the spleen and lymph nodes, are home to various immune cells, including monocytes and dendritic cells, which contribute to both the progression and prevention/treatment of diseases. Consequently, many nanomaterial formulations are being rationally designed to target these organs and engage with specific cell types, thereby inducing therapeutic and protective effects. In this review, we explore crucial cellular interactions and processes involved in immune regulation and highlight innovative nano-based immunomodulatory approaches. We outline essential considerations in nanomaterial design with an emphasis on their impact on biological interactions, targeting capabilities, and treatment efficacy. Through selected examples, we illustrate the strategic targeting of therapeutically active nanomaterials to lymphoid organs and the subsequent immunomodulation for infection resistance, inflammation suppression, self-antigen tolerance, and cancer immunotherapy. Additionally, we address current challenges, discuss emerging topics, and share our outlook on future developments in the field.

Baicalin attenuated oxidative stress and inflammation in ethylene glycol-induced urolithiasis in adult male SD rats.

AIMS: Baicalin is a flavonoid derived from the root of the medicinal plant Scutellaria baicalensis Georgi (S. baicalensis) and is known for its various pharmacological properties. This study aimed to investigate the impact of baicalin (BAI) on the occurrence of kidney calcium oxalate crystal formation induced by ethylene glycol in male SD rats. MAIN METHODS: A rat model of renal stones was created and various concentrations of baicalin were used for intervention. Samples of urine, blood, and kidney tissue were taken from the rats, and they were euthanized for biochemical and histopathological examinations. KEY FINDINGS: Our results show that baicalin treatment improved the weight loss induced by ethylene glycol (EG) and ammonium chloride (AC) in rats. Baicalin also reduced the formation of calcium oxalate crystals and protected kidney function in rats with urolithiasis. Furthermore, it lowered the level of malondialdehyde (MDA) and elevated the activity of antioxidant enzymes compared to the stone control group. Additionally, baicalin notably alleviated renal inflammation in rats with urolithiasis. SIGNIFICANCE: The present study attributed clinical evidence first time that claiming the significant antiurolithic effect of baicalin and could be a cost-effective candidate for the prevention and treatment of urolithiasis.

Yeast ß-glucan-based nanoparticles loading methotrexate promotes osteogenesis of hDPSCs and periodontal bone regeneration under the inflammatory microenvironment.

The regeneration of absorbed alveolar bone and reconstruction of periodontal support tissue are huge challenges in the clinical treatment of periodontitis due to the limited regenerative capacity of alveolar bone. It is essential to regulate inflammatory reaction and periodontal cell differentiation. Based on the anti-inflammatory effect of baker's yeast ß-glucan (BYG) with biosafety by targeting macrophages, the BYG-based nanoparticles loading methotrexate (cBPM) were fabricated from polyethylene glycol-grafted BYG through chemical crosslinking for treatment of periodontitis. In our findings, cBPM promoted osteogenesis of human dental pulp stem cells (hDPSCs) under inflammatory microenvironment, characterized by the enhanced expression of osteogenesis-related Runx2 and activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/Erk) pathway in vitro. Animal experiments further demonstrate that cBPM effectively promoted periodontal bone regeneration and achieved in a better effect of recovery indicated by 19.2 % increase in tissue volume, 7.1 % decrease in trabecular separation, and a significant increase in percent bone volume and trabecular thickness, compared with the model group. Additionally, cBPM inhibited inflammation and repaired alveolar bone by transforming macrophage phenotype from inflammatory M1 to anti-inflammatory M2. This work provides an alternative strategy for the clinical treatment of periodontitis through BYG-based delivery nanoplatform of anti-inflammatory drugs.

Diminazene aceturate inhibits the SARS-CoV-2 spike protein-induced inflammation involving leukocyte migration and DNA extracellular traps formation.

AIMS: To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE). MATERIALS AND METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction. KEY FINDINGS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as ß2 integrin, PI3K, and PAD2 due to its intermolecular coupling. SIGNIFICANCE: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.

2-(Piperidin-3-yl)phthalimides reduce classical markers of cellular inflammation in LPS-challenged RAW 264.7 cells and also demonstrate potentially relevant sigma and serotonin receptor affinity in membrane preparations.

Herein, we report the synthesis of new 4-amino-2-(piperidin-3-yl)isoindoline-1,3-diones and their biological evaluation in a series of in vitro experiments. The synthetic production of these materials was initiated upon the condensation of appropriate nitrophthalic acid derivatives with various 3-aminopiperidines; subsequent reduction provided the final products in moderate to good yields. Readily available chiral pool reagents facilitated entry into optically enriched samples, while the piperidine scaffold furnished a variety of amide and alkylated entries. In total, 16 candidates were produced, and their ensuing treatment in LPS-challenged RAW cells effected slight reductions in secreted TNF-α but provided more robust and dose-dependent declines in nitrite and IL-6 levels relative to basal amounts, all concurrent with maintenance of cellular viability across the concentration ranges screened. The secondary amine cohort including rac-6, (R)-7, and (S)-8 rendered the most pronounced dose-dependent reductions in nitrite and IL-6. When dosed at 30 µM, (R)-7 demonstrated the most compelling effects, with decreases of 32 % and 40 % for nitrite and IL-6, respectively. Notable reductions in the inflammatory markers were also observed for 19 which effected declines in TNF-α (14 %), nitrite (19 %), and IL-6 (11 %) when treated at 30 µM. Additionally, four representative compounds were further evaluated against numerous CNS receptors, channels, and transporters, with 6, 9, and 19 demonstrating varying degrees of nanomolar-to-low-micromolar binding to the σ-1 and σ-2 receptors and also to serotonin receptors 5HT2A, 5HT2B and 5HT3. In this regard, 6 displayed perhaps the most noteworthy affinities, with binding at σ-2 (Ki = 2.2uM), 5HT2B (Ki = 561 nM) and 5HT3 (Ki = 536 nM). Furthermore, no pronounced or dose-dependent Cereblon/DDB1 binding was observed for the screened representative compounds 6, 9, 18 and 19.