Prominent Anti-inflammatory Effects Research Articles

Comparison of the anti-inflammatory effects of carotenoids-rich product from microalgal mass-cultured between natural seawater and magma seawater

Microalgae can be mass-produced in a short period of time and are rich in high value-added product such as carotenoids, thereby it is widely used in a variety industrial field. However, the production cost expensed a lot due to high price of culture ingredient, vitamins. Additionally, >80% of synthetic carotenoids are used in industrial field, and their cost is also highly expensed. Therefore, in this study, a microalga, Tetraselmis sp. was mass-cultured using natural seawater (NS) and magma seawater (MS) as vitamins. As a result of comparing the general composition between the extracts cultured in two culture media, crude carbohydrate and crude lipid contents were 2.68% and 4.38% higher, respectively, while crude protein content was 4.1% lower in the MS culture media. The extraction yield was 8.6% higher in the MS than the NS culture media. Also, lutein and zeaxanthin were predominantly presented in the species and detected in the microalgal extract cultured in MS was 2- and 8-folds higher, respectively, than in NS. Consequently, the carotenoids-rich extracts cultured with two seawaters were exhibited prominent anti-inflammatory effects by suppressing nitric oxide (NO) overproduction and pro-inflammatory mediator such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 expression through MAPKSs and NF-κB pathway. Interestingly, extract of microalgal cultured in MS showed a more efficient anti-inflammatory effect. These results suggest that the value of MS in increasing the carotenoids contents with beneficial effects in mass cultivation of microalgae.

Massa Medicata Fermentata, a Functional Food for Improving the Metabolic Profile via Prominent Anti-Oxidative and Anti-Inflammatory Effects.

Massa Medicata Fermentata (MMF) is a naturally fermented product used to treat indigestion and increase stomach activity in traditional medicine. This study examined the ability of the hydrothermal extract of MMF to scavenge free radicals corresponding to biological oxidative stresses, further protecting essential biomolecules. The anti-inflammatory effects of MMF were evaluated in LPS-induced RAW264.7 macrophages and zebrafish. In addition, the effects of MMF on the body mass index (BMI) and cholesterol accumulation in adult zebrafish fed a high-cholesterol diet (HCD) for three weeks were examined. MMF prevented the DNA and lipid damage caused by oxidative stress, inhibited LDL oxidation, and reduced the expression of cytokines and related proteins (MAPK and NFκB), with prominent anti-oxidative pathway (NRF2-HO-1) activation properties. LPS-induced NO production was reduced, and the increase in BMI and TC caused by the HCD diet was suppressed by MMF in zebrafish embryos or adult zebrafish. The bioactive aglycone of quercetin may be contributing to the mechanisms of systemic effects. MMF has excellent antioxidant properties and is useful for improving inflammation status and metabolic profile, thus highlighting its potential as a healthy, functional food.

2D MXene Nanosheets with ROS Scavenging Ability Effectively Delay Osteoarthritis Progression.

MXenes nanosheets with high conductivity, hydrophilicity, and excellent reactive oxygen species (ROS) scavenging ability have shown promise in treating various degenerative diseases correlated with abnormal ROS accumulation. Herein, the therapeutic potential of Ti3C2Tx nanosheets, which is the most widely investigated MXene material, in delaying osteoarthritis (OA) progression is demonstrated. In vitro experiments indicate the strong ROS scavenging capacity of Ti3C2Tx nanosheets and their acceptable biocompatibility. Ti3C2Tx nanosheets effectively protect chondrocytes from cell death induced by oxidative stress. In addition, Ti3C2Tx nanosheets demonstrate a prominent anti-inflammatory effect and the ability to restore homeostasis between anabolic activities and catabolic activities in chondrocytes. Furthermore, RNA sequencing reveals the potential mechanism underlying the Ti3C2Tx nanosheet-mediated therapeutic effect. Finally, the in vivo curative effect of Ti3C2Tx nanosheets is verified using a rat OA model. Histological staining and immunohistochemical analyses indicate that Ti3C2Tx nanosheets effectively ameliorate OA progression. Conclusively, the in vitro and in vivo experiments suggest that Ti3C2Tx nanosheets could be a promising and effective option for OA treatment.

Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress.

The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib. hydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A in vitro. JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol®934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. In vivo, we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS. Deu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. In vivo, Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis. Deu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.

Zn-Shik-PEG nanoparticles alleviate inflammation and multi-organ damage in sepsis

Sepsis is defined as a life-threatening organ dysfunction caused by excessive formation of reactive oxygen species (ROS) and dysregulated inflammatory response. Previous studies have reported that shikonin (Shik) possess prominent anti-inflammatory and antioxidant effects and holds promise as a potential therapeutic drug for sepsis. However, the poor water solubility and the relatively high toxicity of shikonin hamper its clinical application. To address this challenge, we constructed Zn2+-shikonin nanoparticles, hereafter Zn-Shik-PEG NPs, based on an organic-inorganic hybridization strategy of metal-polyphenol coordination to improve the aqueous solubility and biosafety of shikonin. Mechanistic studies suggest that Zn-Shik-PEG NPs could effectively clear intracellular ROS via regulating the Nrf2/HO-1 pathway, meanwhile Zn-Shik-PEG NPs could inhibit NLRP3 inflammasome-mediated activation of inflammation and apoptosis by regulating the AMPK/SIRT1 pathway. As a result, the Zn-Shik-PEG NPs demonstrated excellent therapeutic efficacies in lipopolysaccharide (LPS) as well as cecal ligation puncture (CLP) induced sepsis model. These findings suggest that Zn-Shik-PEG NPs may have therapeutic potential for the treatment of other ROS-associated and inflammatory diseases.

The Microtubule-Targeting Agent Pretubulysin Impairs the Inflammatory Response in Endothelial Cells by a JNK-Dependent Deregulation of the Histone Acetyltransferase Brd4.

The anti-inflammatory effects of depolymerizing microtubule-targeting agents on leukocytes are known for a long time, but the potential involvement of the vascular endothelium and the underlying mechanistic basis is still largely unclear. Using the recently synthesized depolymerizing microtubule-targeting agent pretubulysin, we investigated the anti-inflammatory potential of pretubulysin and other microtubule-targeting agents with respect to the TNF-induced leukocyte adhesion cascade in endothelial cells, to improve our understanding of the underlying biomolecular background. We found that treatment with pretubulysin reduces inflammation in vivo and in vitro via inhibition of the TNF-induced adhesion of leukocytes to the vascular endothelium by down-regulation of the pro-inflammatory cell adhesion molecules ICAM-1 and VCAM-1 in a JNK-dependent manner. The underlying mechanism includes JNK-induced deregulation and degradation of the histone acetyltransferase Bromodomain-containing protein 4. This study shows that depolymerizing microtubule-targeting agents, in addition to their established effects on leukocytes, also significantly decrease the inflammatory activation of vascular endothelial cells. These effects are not based on altered pro-inflammatory signaling cascades, but require deregulation of the capability of cells to enter constructive transcription for some genes, setting a baseline for further research on the prominent anti-inflammatory effects of depolymerizing microtubule-targeting agents.

Anti-inflammatory probiotic Lactiplantibacillus plantarum HF05 screening from Qula: Genomic analysis and alleviating effect on intestinal inflammation

The use of probiotics for their anti-inflammatory potential is an area with limited research, and there is currently limited understanding of the connection between the genotype and phenotype of the majority of probiotics. In this study, Lactiplantibacillus plantarum HF05 with prominent anti-inflammatory effects and excellent probiotic characteristics was screened from Qula by combining RAW264.7 inflammatory cell model screening with in vitro comparison of probiotic properties. Through whole genome analysis, we found that the HF05 genome encoded a large number of environmental adaptation, adhesion, colonization, anti-inflammatory and antioxidant-related genes. The in vitro experiments demonstrated that HF05 inhibited pro-inflammatory cytokine release in RAW264.7 inflammatory cells. Furthermore, we found that prophylactic intake of HF05 alleviated intestinal inflammation and oxidative damage in mice with acute colitis and inhibited the value-added of enteropathogenic bacteria (Escherichia coli, Enterococcus faecalis, Staphylococcus xylosus) and reversed the depletion of Lactobacillus (Lactobacillus johnsonii, Lactobacillus intestinalis). Collectively, we demonstrated that HF05 can serve as a new probiotic for the relief of intestinal inflammation.

Prevention of atrial fibrillation after open chest surgery with extracellular vesicle therapy.

Almost half of patients recovering from open chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that post-operative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent post-operative AF. Middle-aged female and male rats were randomized to undergo sham operation or induction of sterile pericarditis followed by trans-epicardial injection of human EVs or vehicle into the atrial tissue. Pericarditis increased the probability of inducing AF while EV treatment abrogated this effect in a sex independent manner. EV treatment reduced infiltration of inflammatory cells and production of pro-inflammatory cytokines. Atrial fibrosis and hypertrophy seen after pericarditis was markedly attenuated by EV pre-treatment; an effect attributable to suppression of fibroblast proliferation by EVs. Our study demonstrates that injection of extracellular vesicles at the time of open-chest surgery shows prominent anti-inflammatory effects and prevents AF due to sterile pericarditis. Translation of this finding to patients might provide an effective new strategy to prevent post-operative AF by reducing atrial inflammation and fibrosis.

Flavonols in Action: Targeting Oxidative Stress and Neuroinflammation in Major Depressive Disorder.

Major depressive disorder is one of the most common mental illnesses that highly impairs quality of life. Pharmacological interventions are mainly focused on altered monoamine neurotransmission, which is considered the primary event underlying the disease's etiology. However, many other neuropathological mechanisms that contribute to the disease's progression and clinical symptoms have been identified. These include oxidative stress, neuroinflammation, hippocampal atrophy, reduced synaptic plasticity and neurogenesis, the depletion of neurotrophic factors, and the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Current therapeutic options are often unsatisfactory and associated with adverse effects. This review highlights the most relevant findings concerning the role of flavonols, a ubiquitous class of flavonoids in the human diet, as potential antidepressant agents. In general, flavonols are considered to be both an effective and safe therapeutic option in the management of depression, which is largely based on their prominent antioxidative and anti-inflammatory effects. Moreover, preclinical studies have provided evidence that they are capable of restoring the neuroendocrine control of the HPA axis, promoting neurogenesis, and alleviating depressive-like behavior. Although these findings are promising, they are still far from being implemented in clinical practice. Hence, further studies are needed to more comprehensively evaluate the potential of flavonols with respect to the improvement of clinical signs of depression.

Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance

Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD's effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases.

Neobaicalein Inhibits Th17 Cell Differentiation Resulting in Recovery of Th17/Treg Ratio through Blocking STAT3 Signaling Activation

Huangqin is the dried root of Scutellaria baicalensis Georgi, which has been widely utilized for heat-clearing (Qingre) and dewetting (Zaoshi), heat-killed (Xiehuo) and detoxifying (Jiedu) in the concept of Traditional Chinese Medicine and is used for treating inflammation and cancer in clinical formulas. Neobaicalein (NEO) is of flavonoid isolated from Huangqin and has been reported to possess prominent anti-inflammatory effects in published work. Th17/Treg balance shift to Th17 cells is an essential reason for autoimmune inflammatory diseases. However, the role NEO plays in Th17 and Treg and the underlying mechanism has not been elucidated yet. Network pharmacology-based study revealed that NEO predominantly regulated IL-17 signaling pathway. Moreover, our result shown that NEO (3-30 μmol/L) down-regulated Th17 differentiation and cellular supernatant and intracellular IL-17A level and tumor necrosis factor α production in a concentration-dependent manner. The further mechanism research revealed that NEO also specifically inhibited phosphorylation of STAT3(Tyr725) and STAT4 (Y693) without influence on activation of STAT5 and STAT6 in splenocytes. Immunofluorescence results illuminated that NEO effectively blocked STAT3 translocated into nucleus. Interestingly, NEO at appreciated dose could only inhibit Th17 cell differentiation and have no effect on Treg differentiation. The present study revealed that NEO effectively inhibited Th17 cell differentiation through specifically blocking the activation of STAT3 signaling without inactivation of STAT5 and STAT6. Additional inhibitory effect on activation of STAT4 by NEO also suggested the potential for antagonism against Th1 differentiation. All work suggested that NEO may be a potential candidate for immunoregulation and treating autoimmune inflammatory diseases through inhibiting immune cell viability and T cell differentiation.

The therapeutic effects of Lagopsis supina (Steph. ex Willd.) Ikonn.-Gal. fractions in trauma-induced blood stasis model rats

BackgroundLagopsis supina (Steph. ex Willd.) Ikonn.-Gal. has been a traditional Chinese medicine (TCM) for the treatment of blood stasis, inflammation, and diuresis. Moreover, Huo Xue Li Shui theory was an important TCM theory that used to treat many ailments. Nevertheless, the scientific connotation of this theory has not been clearly elucidated so far. Aim of the studyThe aim of this study was to explore the scientific connotation of Huo Xue Li Shui with promoting blood circulation and removing blood stasis (PBCRBS), anti-inflammatory and diuretic effects in trauma-induced blood stasis model (TBSM) rats, taking microporous adsorption resin with water (LSB) and 30% ethanol (LSC) elution fractions from L. supina as a classical demonstration. Materials and methods48 rats were randomly assigned into six groups (n = 8/group): the control group, the model group, and model groups treatment with LSB or LSC. The biochemical parameters and protein expression were measured using kit method and Western blot assay, respectively. ResultsBoth LSB and LSC were effective in elevating body weight, food consumption, and water intake in model rats. In PBCRBS efficacy evaluation, LSB and LSC remarkably improved histopathological tissues. On the other hand, LSB and LSC prominently decreased the contents of plasma viscosity, platelet aggregation rate, thrombin time, prothrombin time, activated partial thromboplastin time (APTT), fibrinogen, thromboxane B2, thromboxane B2/6-keto-prostaglandin F1α, urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor-1(PAI-1), PAI-1/tissue-type plasminogen activator (t-PA), and PAI-1/u-PA, while significantly enhanced the contents of antithrombin III, 6-keto-prostaglandin F1α, and t-PA. In parallel, LSB and LSC obviously down-regulated the levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8, and remarkably up-regulated the level of IL-10. In determining diuretic activities, LSB and LSC prominently elevated urinary excretion volume and the level of atriopeptin, and remarkably reduced the levels of angiotensin II, anti-diuretic hormone, aldosterone, aquaporin 1 (AQP1), AQP2, and AQP3. In addition, LSB and LSC clearly suppressed protein expressions of AQP1, AQP2, and AQP3. Finally, LSB and LSC did not caused urinary pH, Na+, and Cl− electrolytes and had minor effects on K+ and Ca2+ concentrations. ConclusionsLSB and LSC exhibited prominent PBCRBS, anti-inflammatory, and diuretic effects in TBSM rats, thereby supported the traditional folk use of L. supina. This study successfully provided an experimental basis for the scientific connotation of Huo Xue Li Shui.

Chemical Composition, Total Phenolic Content, and Anti-Ulcerative Colitis Effects of Extract and Essential Oil of Cupressus arizonica Greene Fruits


 Ulcerative colitis (UC) is a chronic inflammatory bowel disease, which has a global prevalence. Also, the plants of the Cupressaceae family have prominent anti-inflammatory and wound healing effects, so they can be considered as promising candidates for the treatment of UC. In this study, the therapeutic effects of extract and essential oil of Cupressus arizonica Greene (C. arizonica) fruits in the animal model of UC were investigated. Total of 35 Wistar male rats were treated with essential oil and hydroalcoholic extract for one week after induction of colitis by acetic acid. The colonic segment cut for macroscopic and histological analysis. The total amount of extract phenol and flavonoid content was assayed by Folin–Ciocalteu and aluminum chloride colorimetric method, respectively. The essential oil was analyzed by gas chromatography/mass spectrometer (GC/MS). The extract at doses of 100 mg/kg and 250 mg/kg and essential oil at doses of 0.5 mg/kg showed significant effects on UC (P < 0.05). The total phenolic content of hydroalcoholic extract in terms of mg of gallic acid/ g of extract was 191.625 ± 7.04 and the amount of total flavonoids in terms of mg of rutin/g of extract was 66.52 ± 6.51. Also, according to the results of GC/MS analysis, α-pinene was the major constituent of essential oil. Our results revealed that the extract and essential oil of C. arizonica fruits had therapeutic effects on UC, and this effect may be related to the presence of polyphenolic and terpene compounds.

"Theranekron: A Novel Anti-inflammatory Candidate for Acetic Acid-Induced Colonic Inflammation in Rats".

Inflammatory bowel disease (IBD) is characterized with chronic inflammation of gastrointestinal track. In the pathogenesis of IBD, inflammation is the main mechanism. Induction of inflammation triggers the oxidative stress that subsequently leading to apoptosis. Considering the all pathological mechanisms, many therapeutic agents have been used for IBD but because of serious side effects there is still a need for new therapeutic drugs. In this study, we aim to evaluate the possible protective effects of Theranekron (TH) on acetic acid (AA)- induced colonic damage and to describe the probable effect mechanisms of TH. Fourty female adult Wistar albino rats were divided into 5 groups. Following 24h fasting, colitis was induced by rectal instillation of AA. In TH group, a single dose of subcutaneous 0.2 ml TH was used. In treatment groups, 0.2 ml TH single dose or 100mg/kg sulfasalazine (SS) for 7 days were used after colitis induction. Normal salin was used for all applications in control group. Histopathologically hemorrhage, edema and inflammatory reactions were seen in AA group. TH and SS decreased the severity of lesions. Nuclear factor kappa B, Serum amyloid A, C-reactive protein, Growth-related oncogene, and Osteopontin expressions were markedly increased in AA group and TH markedly reduced these expressions. In Western analysis, decreased NF-kB and caspase-3 levels were observed with TH. Oxidative markers did not changed significantly. TH has a prominent anti-inflammatory effect on AA-induced colonic inflammation via NF-kB signaling whereas antiapoptic effects seem to be independent from this pathway.

Hepatoprotective effect of phillygenin on carbon tetrachloride-induced liver fibrosis and its effects on short chain fatty acid and bile acid metabolism

Ethnopharmacological relevanceForsythiae fructus, the dried fruit of Oleaceae plant Forsythia suspensa (Thunb.) Vahl, is a traditional Chinese medicine widely used in clinical practice and has a variety of pharmacological activities, such as anti-inflammation, antioxidation, and hepatoprotection. Aim of the studyPhillygenin (PHI), an important fingerprint lignan component of Forsythiae fructus, has prominent hepatoprotective, anti-inflammatory and antioxidant effects. Previously, it was shown that PHI could exert anti-fibrotic effects by modulating inflammation and gut microbiota. Therefore, given the important roles of SCFAs and BAs in the development of liver fibrosis, as well as their close links with gut microbiota, we aimed to determine the protective effects of PHI on carbon tetrachloride (CCl4)-induced liver fibrosis and its effects on the metabolism of SCFAs and BAs based on metabolomics. Materials and methodsIn C57BL/6J mice, liver fibrosis model was established by intraperitoneal injection of olive oil containing 10% CCl4 for 4 weeks. Firstly, the mouse liver tissues were subjected to histological analysis and biochemical index assay to evaluate the protective effect of PHI on CCl4-induced liver fibrosis. Subsequently, the effects of PHI on the metabolism of SCFAs and BAs in CCl4-induced liver fibrosis mice were determined using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) for metabolomics analysis. Finally, the levels of the closely related proteins and genes were detected by immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) to explore the underlying mechanisms of the protective effect of PHI on CCl4-induced liver fibrosis. ResultsThe histological analysis and the determination of relevant biochemical indexes of liver tissues showed that PHI could attenuate CCl4-induced liver fibrosis. The metabolomic analysis on SCFAs showed that PHI could promote SCFA production in the gut of mice with CCl4-induced liver fibrosis, especially acetic acid, propionic acid and butyric acid. It has been reported that the increased production of SCFAs was possibly beneficial to health. The metabolomic analysis on BAs found that PHI could restore the disturbance of BA metabolism in mice with CCl4-induced liver fibrosis. The immunohistochemistry and RT-qPCR results confirmed that PHI could ameliorate intestinal epithelial barrier disruption, and reverse the expression of BA metabolism-related genes in mice with CCl4-induced liver fibrosis. ConclusionsPromoting the production of SCFAs in the gut and restoring the disturbance of BA metabolism may be the potential mechanisms by which PHI alleviated CCl4-induced liver fibrosis.

Upregulation of neuronal progranulin mediates the antinociceptive effect of trimetazidine in paclitaxel-induced peripheral neuropathy: Role of ERK1/2 signaling

Neuronal progranulin (PGRN) overexpression is an endogenous adaptive pain defense following nerve injury. It allows the survival of injured neurons to block enhanced nociceptive responses. Trimetazidine (TMZ) is widely used by cardiac patients as an anti-anginal drug, reflecting its anti-ischemic property. TMZ promotes axonal regeneration of sciatic nerves after crush injury. This study explored the interplay between PGRN and extracellular signal-regulated kinases (ERK1/2) to address mechanisms underlying neuropathic pain alleviation following paclitaxel (PTX) administration. Rats were given four injections of PTX (2 mg/kg, i.p.) every other day. Two days after the last dose, rats received TMZ (25 mg/kg) with or without the ERK inhibitor, PD98059, daily for 21 days. TMZ preserved the integrity of myelinated nerve fibers, as evidenced by an obvious reduction in axonal damage biomarkers. Accordingly, it alleviated PTX-evoked thermal, cold, and mechanical hyperalgesia/allodynia. TMZ also promoted ERK1/2 phosphorylation with a profound upsurge in PGRN content. These effects were associated with a substantial increase in Notch1 receptor gene expression and a prominent anti-inflammatory effect with a marked increase in mRNA expression of secretory leukocyte protease inhibitor. Further, TMZ decreased oxidative stress and caspase-3 activity in the sciatic nerve. Conversely, co-administration of PD98059 completely abolished these beneficial effects. Thus, the robust antinociceptive effect of TMZ is largely attributed to upregulating PGRN and Notch1 receptors via ERK1/2 activation.

Oral Delivery of Pterostilbene by L-Arginine-Mediated "Nano-Bomb" Carrier for the Treatment of Ulcerative Colitis.

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of unknown aetiology affecting the colon and rectum. Pterostilbene (PS) has been reported as an effective antioxidant and anti-inflammatory agent in preclinical IBD models. However, the therapeutic outcomes of PS are limited by potential side effects associated with the systemic exposure and the modest bioavailability afforded by its oral administration. These issues can be improved with the use of intelligent responsive nanoparticles with the ability of lysosome escape, given their high drug delivery capacity and reducing the side effects.Materials and MethodsHerein, the hyaluronic acid (HA)-modified L-arginine CO2 nanoparticles (HA-L-Arg-CO2@NPs) loaded with PS (HA-PS@NPs) are constructed. Under lysosomal pH conditions, HA-PS@NPs liberate CO2 and generate a pH-activated nano-bomb effect to augment the cytosolic delivery of PS.ResultsHA-L-Arg-CO2@NPs show great biocompatibility and the excellent ability to target the colon. Using lipopolysaccharide-induced inflammation in vitro, the prominent anti-inflammatory effect of HA-L-Arg-CO2@NPs and HA-PS@NPs is observed. Further, orally administered HA-L-Arg-CO2@NPs and HA-PS@NPs via the colon-targeted chitosan/alginate (CA) hydrogel downregulate pro-inflammatory cytokines and reduce intestinal permeability, yielding significant outcomes in alleviating the symptoms of UC.ConclusionThis pH-activated “nano-bomb” carrier with therapeutic effect can be exploited as efficient oral drug carriers for UC treatment.

Forsythosides as Essential Components of Forsythia-based Traditional Chinese Medicines Used to Treat Inflammatory Diseases and COVID-19

The dried fruits of the plant Forsythia suspensa (Forsythia Fructus: Lianqiao in Chinese) are used in many herbal preparations to treat various diseases or the associated symptoms. Forsythia extracts contain phenylethanoid glycosides (PhGs) such as the forsythosides (Fst A-to-P). The leading products, Fst-A,-B and-F (arenarioside), can be found also in >90 other plants inventoried here. The pharmacological properties of Fst are reviewed, with emphasis on their anticancer, antiviral, and antibacterial activities, which essentially derive from their anti-inflammatory and antioxidant effects. Fst-B functions as a potential binder of the repressor protein Kelch-like ECH-association protein 1 (Keap 1), thus promoting the nuclear translocation of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) implicated in the subsequent activation of the production of antioxidant enzymes and repression of the oxidative stress. The regulation of the Nrf2/Heme oxygenase-1 pathway is the central piece of the multifaceted mechanism of action of Fst-A/B. Their prominent antioxidant and anti-inflammatory effects support the use of these compounds in different inflammation-related diseases and conditions, from sepsis to neuroprotection and many other pathologies discussed here. In addition, these properties contribute to the antiviral action of the compounds. Fst-A/B displays activities against the influenza A virus and different Fst-containing traditional Chinese medicinal (TCMs) have revealed beneficial effects to combat the current COVID-19 pandemic. The mechanisms whereby Fst-A/B could inhibit viral multiplication are discussed. PhGs likely contribute to the anti-COVID-19 activities reported with several TCM such as Shuang-Huang-Lian oral liquid, Lianhua-Qingwen capsules, and others. This review highlights the pharmacological profile of Fst and illustrates health benefits associated with the use of Forsythia Fructus.

Protective effects of lotus plumule ethanol extracts on bleomycin-induced pulmonary fibrosis in mice

Pulmonary fibrosis (PF) is a progressive fibrosing disease, characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture, which finally result in respiratory failure. Currently, there is no satisfactory treatment for PF， therefore, the development of effective agents is urgently needed. Lotus plumule, the green embryo of Nelumbo nucifera Gaertn., a plant of the Nymphaeaceae family, is a traditional Chinese food with exceptional nutritional value and its extracts exert prominent anti-inflammatory and anti-fibrotic effects. The aim of the present study was to investigate the inhibitory effects of lotus plumule extracts (LPEs) on bleomycin (BLM)-induced PF in mice. Therefore, enzyme-linked immunosorbent assay, RT-PCR, and western blot analysis were performed. The histopathological examination demonstrated that LPEs could obviously decrease the degree of alveolitis, deposition of ECM and the production of collagen I (Col-I) in the pulmonary interstitium. In addition, the results showed that LPEs markedly alleviated the expression of interleukin (IL)-6, IL-17, transforming growth factor (TGF)-β, and α-smooth muscle actin (α-SMA). Additionally, the content of Col-I and hydroxyproline (HYP) was also attenuated. In conclusion, LPEs could ameliorate the BLM-induced lung fibrosis, thus suggesting that LPEs could serve as a potential therapeutic approach for PF.

Panaxadiol inhibits IL-1β secretion by suppressing zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages

Ethnopharmacological relevanceThe use of Panax ginseng C.A.Mey. in traditional Chinese medicine dates back to about 5000 years ago thanks to its several beneficial and healing properties. Panaxadiol is a triterpenoid sapogenin monomer found in the roots of Panax ginseng C.A.Mey. and has been proven to have various bio-activities such as anti-inflammatory, anti-tumour and neuroprotective effects. Aim of the studyThe present study focuses on investigating the inflammation inhibitory effect and mechanism of panaxadiol by regulating zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages. Materials and methodsIn vitro, the underlying mechanisms by which panaxadiol inhibits ZFP91-regulated IL-1β expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence, and immunoprecipitation assays. In vivo, colitis was induced by oral administration of DSS in drinking water, and peritonitis was induced by an intraperitoneal injection of alum. Recombinant adeno-associated virus (AAV serotype 9) vector was used to establish ZFP91 knockdown mouse. ResultsWe confirmed that panaxadiol inhibited IL-1β secretion by suppressing ZFP91 in macrophages. Further analysis revealed that panaxadiol inhibited IL-1β secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome. Meanwhile, panaxadiol inhibited IL-1β secretion by suppressing ZFP91-regulated activation of MAPKs. In vivo, prominent anti-inflammatory effects of panaxadiol were demonstrated in a DSS induced acute colitis mouse model and in an alum-induced peritonitis model by suppressing ZFP91-regulated secretion of inflammatory mediators, consistent with the results of the AAV-ZFP91 knockdown in mice. ConclusionsWe report for the first time that panaxadiol inhibited IL-1β secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs, providing evidence for anti-inflammation mechanism of panaxadiol treatment for inflammatory diseases.