Chemopreventive and immunomodulatory effects of phenolic-rich extract of Commiphora leptophloeos against inflammatory bowel disease: Preclinical evidence.

ETHNOPHARMACOLOGY RELEVANCE: Commiphora leptophloeos (Mart.) J.B. Gillet (Burseraceae) is a medicinal plant native to Brazil, popularly known as "imburana". Homemade leaf decoction and maceration were used to treat general inflammatory problems in the Brazilian Northeast population. Our previous research confirmed the anti-inflammatory activity of the C. leptophloeos hydroalcoholic leaf extract. AIM OF THE STUDY: Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut with no ideal treatment to maintain the remissive status. This work aimed to characterize the phytochemical composition and physicochemical properties of the C. leptophloeos hydroalcoholic leaf extract and its efficacy in chemopreventive and immunomodulatory responses in inflammatory bowel disease in non-clinical models. MATERIALS AND METHODS: Mass spectrometry and physicochemical tests determined the phytochemical profile and physicochemical characteristics of the Commiphora leptophloeos (CL) extract. The chemopreventive and immunomodulatory effects of CL extract (50 and 125 µg/mL) were evaluated in vitro in the RAW 264.7 lipopolysaccharide (LPS) induced cell assay and in vivo in the model of intestinal inflammation induced by 2,4-Dinitrobenzenesulfonic acid (DNBS) in mice when they were treated with CL extract by intragastric gavage (i.g.) at doses of 300, 400 and 500 mg/kg. RESULTS: Phytochemical annotation of CL extract showed a complex phenolic composition, characterized as phenolic acids and flavonoids, and satisfactory physicochemical characteristics. In addition, CL extract maintained the viability of RAW macrophages, reduced ROS and NO production, and negatively regulated COX-2, iNOS, TNF-α, IL-1ß, IL-6, and IL-17 (p < 0.05). In the intestinal inflammation model, CL extract was able to downregulate NF-κB p65/COX-2, mTOR, iNOS, IL-17, decrease levels of malondialdehyde and myeloperoxidase and cytokines TNF-α, IL-1ß and IL-6 (p < 0.05). CONCLUSION: Based on these findings, CL extract reduced inflammatory responses by down-regulating pro-inflammatory markers in macrophages induced by LPS and DNBS-induced colitis in mice through NF-κB p65/COX-2 signaling. CL leaf extract requires further investigation as a candidate for treating inflammatory bowel disease.

Ameliorative effects of Atriplex crassifolia (C.A.Mey) on pain and inflammation through modulation of inflammatory biomarkers and GC-MS-based metabolite profiling.

Atriplex crassifolia (A. crassifolia) is a locally occurring member of Chenopodiaceae family that has been used in folk medicine for the treatment of joint pain and inflammation. The present study was focused to determine the analgesic and anti-inflammatory potential of the plant. n-hexane (ACNH) and methanol (ACM) extracts of A. crassifolia were evaluated for in vitro anti-inflammatory potential using protein denaturation inhibition assay. In vivo anti-inflammatory potential was determined by oral administration of 250, 500, and 1000 mg/kg/day of extracts against carrageenan and formalin-induced paw edema models. Inflammatory mediators such as TNF-α, IL-10, IL-1ß, NF-kB, IL-4, and IL-6 were estimated in blood samples of animals subjected to formalin model of inflammation. Analgesic activity was determined using acetic acid-induced writhing and tail flick assay model. Phytochemical profiling was done by GC-mass spectrophotometer. The results of in vitro anti-inflammatory activity revealed that both ACNH and ACM displayed eminent inhibition of protein denaturation in concentration-dependent manner. In acute in vivo carrageenan-induced paw edema model, both extracts reduced inflammation at 5th and 6th hour of study (p < 0.05). A. crassifolia extracts exhibited significant inhibition against formalin-induced inflammation with maximum effect at 1000 mg/kg. ACNH and ACM significantly augmented the inflammatory mediators (p < 0.05). Levels of TNF-α, IL-6, IL-1ß, and NF-kB were reduced, while those of IL-4 and IL-10 were upregulated. ACNH displayed maximum analgesic effect at 1000 mg/kg, while ACM showed potent activity at 500 and 1000 mg/kg. The extracts restored the CBC, TLC and CRP toward normal. GC-MS analysis revealed the presence of compounds like n-hexadecanoic acid, Phytol, (9E,11E)-octadecadienoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester, 1-hexacosene, vitamin E, campesterol, stigmasterol, gamma sitosterol in both extracts. These compounds have been reported to suppress inflammation by inhibiting inflammatory cytokines. The current study concludes that A. crassifolia possesses significant anti-nociceptive and anti-inflammatory potential owing to the presence of phytochemicals.

Novel drug therapy of acute hepatic failure induced in rats by a combination of tadalafil and Lepidium sativum.

BACKGROUND: Hepatocyte death and a systemic inflammatory response are the outcome of a complex chain of events mediated by numerous inflammatory cells and chemical mediators. The point of this study was to find out if tadalafil and/or Lepidium sativum (L. sativum) could help people who have been exposed to carbon tetrachloride (CCL4) and are experiencing acute moderate liver failure. This was especially true when the two were used together. METHOD AND MATERIALS: To cause mild liver failure 24 h before sacrifice, a single oral dosage of CCL4 (2.5 mL/kg b.w.) (50% in olive oil) was utilized. Furthermore, immunohistochemical expression of nuclear factor kappa B (NF-κB) as well as histological abnormalities were performed on liver tissue. RESULTS: The results showed that tadalafil and/or L. sativum, especially in combination, performed well to cure acute mild liver failure caused by CCL4. This was demonstrated by a decrease in NF-κB expression in the liver tissue and an improvement in organ damage markers observed in the blood and liver tissues. Furthermore, such therapy reduced interleukin1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels in the liver tissue. It's worth noting that the tested combination resulted in greater liver improvement. CONCLUSIONS: According to the findings, tadalafil and L. sativum, particularly in combination, have the ability to protect the liver from the negative effects of CCL4 exposure. Because of its capacity to improve liver function, restore redox equilibrium, and decrease inflammatory mediators, it is a prospective option for mitigating the negative effects of common environmental pollutants such as CCL4.

Antiarthritic activity of Physalis peruviana fruit extract via inhibition of inflammatory mediators: Integrated in vitro, in vivo and in silico study.

ETHNOPHARMACOLOGICAL RELEVANCE: P. peruviana fruit, native to Andean region, is cultivated worldwide for its adaptability to various soil natures and climatic conditions. It is increasingly consumed for its high nutritional profile and history of ethnomedical uses including treatment of arthritis. Little pharmacological evidences support this folk use except for previous in vitro study that reported significant inhibition of protein denaturation. AIM OF THE STUDY: The study aims at providing new in vivo evidence on antiarthritic activity of P. peruviana fruits in vivo that justifies its traditional use through mechanism-based experiment. MATERIAL AND METHODS: Inhibition of inflammatory mediators is considered one of the key treatments to alleviate painful symptoms of rheumatoid arthritis (RA). Anti-inflammatory activity was assessed against COX-1 and COX-2 activity in vitro. Serum TNFα, IL-1ß and IL-6 were traced using in vivo model of adjuvant-induced arthritis. Gross/inflammatory changes in rat paw, relative mass indices of spleen and liver were further investigated together with joint tissue histoarchitecture. Seven metabolites from different phytochemical classes, that were previously reported in P. peruviana fruit, were evaluated in silico against TNF-α target protein (PDB ID: 2AZ5) to assess their inhibitory effect. This was followed by assessment of their drug-likeness based on Lipinski's rule according to their physicochemical and pharmacokinetic properties. RESULTS: High dose of extract (E-1000 mg) improved adjuvant-induced cachexia and attenuated immune-inflammatory responses in paw and serum parameters, with equipotent effect to MTX, in addition to minimal side effect profile on spleen and liver. Histopathological study of knee joint tissues confirmed dose-dependent improvement in arthritic groups treated with P. peruviana fruit extracts. The insilico study recommended steroidal lactones withaperuvin E/C and hydroxywithanolide E as promising lead compounds for inhibiting TNF enzyme as evidenced by docking scores of 6.301, 5.488 and 5.763 kcal/mol, respectively, fitting as well the Lipinski's rule of drug likeness. CONCLUSION: The study provided novel approach that rationalize folk use of P. peruviana fruit in treatment of arthritis.

Therapeutic potential of natural products in inflammation: underlying molecular mechanisms, clinical outcomes, technological advances, and future perspectives.

Chronic inflammation is a common underlying factor in many major diseases, including heart disease, diabetes, cancer, and autoimmune disorders, and is responsible for up to 60% of all deaths worldwide. Metformin, statins, and corticosteroids, and NSAIDs (non-steroidal anti-inflammatory drugs) are often given as anti-inflammatory pharmaceuticals, however, often have even more debilitating side effects than the illness itself. The natural product-based therapy of inflammation-related diseases has no adverse effects and good beneficial results compared to substitute conventional anti-inflammatory medications. In this review article, we provide a concise overview of present pharmacological treatments, the pathophysiology of inflammation, and the signaling pathways that underlie it. In addition, we focus on the most promising natural products identified as potential anti-inflammatory therapeutic agents. Moreover, preclinical studies and clinical trials evaluating the efficacy of natural products as anti-inflammatory therapeutic agents and their pragmatic applications with promising outcomes are reviewed. In addition, the safety, side effects and technical barriers of natural products are discussed. Furthermore, we also summarized the latest technological advances in the discovery and scientific development of natural products-based medicine.

In Vitro Assessment of Anti-Adipogenic and Anti-Inflammatory Properties of Black Cumin (Nigella sativa L.) Seeds Extract on 3T3-L1 Adipocytes and Raw264.7 Macrophages.

Background and Objectives: This study evaluated the in vitro anti-adipogenic and anti-inflammatory properties of black cumin (Nigella sativa L.) seed extract (BCS extract) as a potential candidate for developing herbal formulations targeting metabolic disorders. Materials and Methods: We evaluated the BCS extract by assessing its 2,2-diphenyl-1-picrohydrazyl (DPPH) radical scavenging activity, levels of prostaglandin E2 (PGE2) and nitric oxide (NO), and mRNA expression levels of key pro-inflammatory mediators. We also quantified the phosphorylation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPK) signaling molecules. To assess anti-adipogenic effects, we used differentiated 3T3-L1 cells and BCS extract in doses from 10 to 100 µg/mL. We also determined mRNA levels of key adipogenic genes, including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/BEPα), adipocyte protein 2 (aP2), lipoprotein lipase (LPL), fatty acid synthase (FAS), and sterol-regulated element-binding protein 1c (SREBP-1c) using real-time quantitative polymerase chain reaction (qPCR). Results: This study showed a concentration-dependent DPPH radical scavenging activity and no toxicity at concentrations up to 30 µg/mL in Raw264.7 cells. BCS extract showed an IC50 of 328.77 ± 20.52 µg/mL. Notably, pre-treatment with BCS extract (30 µg/mL) significantly enhanced cell viability in lipopolysaccharide (LPS)-treated Raw264.7 cells. BCS extract treatment effectively inhibited LPS-induced production of PGE2 and NO, as well as the expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), interleukin (IL)-1ß and IL-6, possibly by limiting the phosphorylation of p38, p65, inhibitory κBα (I-κBα), and c-Jun N-terminal kinase (JNK). It also significantly attenuated lipid accumulation and key adipogenic genes in 3T3-L1 cells. Conclusions: This study highlights the in vitro anti-adipogenic and anti-inflammatory potential of BCS extract, underscoring its potential as a promising candidate for managing metabolic disorders.

Exploring the potential use of Chinese herbs in regulating the inflammatory microenvironment of tumours based on the concept of 'state-target identification and treatment': a scooping review.

Tumours do not exist in isolation from the organism; their growth, proliferation, motility, and immunosuppressive response are intricately connected to the tumour's microenvironment. As tumour cells and the microenvironment coevolve, an inflammatory microenvironment ensues, propelling the phenomenon of inflammation-cancer transformation-an idea proposed by modern medicine. This review aims to encapsulate the array of representative factors within the tumour's inflammatory microenvironment, such as interleukins (IL-6, IL-10, IL-17, IL-1ß), transforming growth factor-beta (TGF-ß), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Moreover, drawing upon research in traditional Chinese medicine (TCM) and pharmacology, we explore the delicate interplay between these factors and tumour-associated inflammatory cells: tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (TANs) and dendritic cells (DCs). By analyzing the tumour-promoting effects of these entities, we delve into the connotations of Academician Tong Xiao-lin's novel model of "state-target differentiation" and its application in the diagnosis and treatment of tumours. Our aim is to enhance the precision and targeting of tumour treatment in clinical practice. Delving deeper into our understanding of tumour pathogenesis through the lens of modern medicine, we discern the key etiology and pathogenesis throughout the entire developmental stage of tumours, unveiling the evolutionary patterns of Chinese Medicine (CM) states: heat state → phlegm state → stagnation state → deficiency state. Building upon this foundation, we devised a state-regulating formula. Simultaneously, drawing on pharmacological research in traditional Chinese medicine (TCM), we meticulously identified a range of targeted drugs that effectively modulate the aforementioned tumour-related mediators. This comprehensive strategy-a harmonious integration of state identification, target recognition, and simultaneous regulation-aims to elevate clinical efficacy. The fusion of TCM with Western medicine in tumour treatment introduces novel dimensions to the precise and refined application of TCM in clinical practice.

A new approach for the treatment of bleomycin-induced rat pulmonary injury by combined protein fraction of major royal jelly protein 2 and its isoform X1.

Nowadays, royal jelly (RJ) has gained great interest as a functional food due to its valuable pharmacological effects. We investigated the therapeutic potency of combined protein fraction (PF50) of major RJ protein 2 and its isoform X1 on bleomycin (Bleo)-induced pulmonary injury in rats. Our study examined the impact of PF50 on pulmonary oxidative and inflammatory stress as well as smooth muscle alpha-actin (α-SMA). In addition, the predicted impacts of this PF on the activity of matrix metalloproteinase (MMP)- 8 and 15-prostaglandin dehydrogenase (15-PGDH) and the E-type prostanoid 2 (EP2) and IL-13 α2 subunit (IL13α2R) receptors, were evaluated using molecular docking. The results showed that PF50 reduced pulmonary inflammatory cells and their secreted pro-inflammatory mediators, including NF-κB, IKK, IL-4, IL-6, and NO. Additionally, the levels of IgE and mucin were diminished after treatment with PF50. Moreover, PF50 treatment improved pulmonary oxidative stress indices such as lipid peroxidation, GSH, SOD, and GPX. The histopathological findings, chest conventional X-ray, and immunohistochemistry of α-SMA confirmed the ameliorating effect of PF50. The docking outcomes reported the probable competitive inhibitory influence of PF50 on MMP-8 and a postulated blocking effect on EP2 and IL13α2R. Thus, PF50 could be a novel approach for treating pulmonary injuries.

Emerging Paradigms in Inflammatory Disease Management: Exploring Bioactive Compounds and the Gut Microbiota.

The human gut microbiota is a complex ecosystem of mutualistic microorganisms that play a critical role in maintaining human health through their individual interactions and with the host. The normal gastrointestinal microbiota plays a specific physiological function in host immunomodulation, nutrient metabolism, vitamin synthesis, xenobiotic and drug metabolism, maintenance of structural and functional integrity of the gut mucosal barrier, and protection against various pathogens. Inflammation is the innate immune response of living tissues to injury and damage caused by infections, physical and chemical trauma, immunological factors, and genetic derangements. Most diseases are associated with an underlying inflammatory process, with inflammation mediated through the contribution of active immune cells. Current strategies to control inflammatory pathways include pharmaceutical drugs, lifestyle, and dietary changes. However, this remains insufficient. Bioactive compounds (BCs) are nutritional constituents found in small quantities in food and plant extracts that provide numerous health benefits beyond their nutritional value. BCs are known for their antioxidant, antimicrobial, anticarcinogenic, anti-metabolic syndrome, and anti-inflammatory properties. Bioactive compounds have been shown to reduce the destructive effect of inflammation on tissues by inhibiting or modulating the effects of inflammatory mediators, offering hope for patients suffering from chronic inflammatory disorders like atherosclerosis, arthritis, inflammatory bowel diseases, and neurodegenerative diseases. The aim of the present review is to summarise the role of natural bioactive compounds in modulating inflammation and protecting human health, for their safety to preserve gut microbiota and improve their physiology and behaviour.

An outlook on the target-based molecular mechanism of phytoconstituents as immunomodulators.

The immune system is one of the essential defense mechanisms. Immune system inadequacy increases the risk of infections and cancer diseases, whereas over-activation of the immune system causes allergies or autoimmune disorders. Immunomodulators have been used in the treatment of immune-related diseases. There is growing interest in using herbal medicines as multicomponent agents to modulate the complex immune system in immune-related diseases. Many therapeutic phytochemicals showed immunomodulatory effects by various mechanisms. This mechanism includes stimulation of lymphoid cell, phagocytosis, macrophage, and cellular immune function enhancement. In addition increased antigen-specific immunoglobulin production, total white cell count, and inhibition of TNF-α, IFN-γ, NF-kB, IL-2, IL-6, IL-1ß, and other cytokines that influenced the immune system. This review aims to overview, widely investigated plant-derived phytoconstituents by targeting cells to modulate cellular and humoral immunity in in vivo and in vitro. However, further high-quality research is needed to confirm the clinical efficacy of plant-based immunomodulators.

Cocktail of three isoquinoline alkaloids derived from Glaucium grandiflorum Boiss. & A. Huet subsp. refractum (Nábelek) Mory inhibits the production of LPS-induced ROS, pro-inflammatory cytokines, and mediators through the down-regulation of p38 MAPK in BV-2 cells.

Glaucium grandiflorum extracts have traditionally been used to treat brain-related disorders. G. grandiflorum extracts also exhibited inhibitory effects on cholinesterase enzymes, as well as antigenotoxic activity. However, no research has been done on the effect of G. grandiflorum alkaloid extracts on the anti-oxidative and anti-inflammatory mechanisms. In this study we aimed to evaluate the anti-oxidative and anti-inflammatory activities of the alkaloid extract obtained from G. grandiflorum as well as the mechanisms responsible for their neuroprotective effects in neuronal damage caused by LPS in BV2 cells. We used LC-MS/MS and 1H, 13C NMR analysis to determine the presence of major alkaloids (allocryptopine, tetrahydropalmatine, and tetrahydroberberine N-oxide (trans-cannadine-N-oxide) in the alkaloid extracts. We used flow cytometry to study the alkaloid extracts' effects on ROS production; we also employed qRT-PCR and Western Blot to analyze the effects of oxidative stress and inflammation-related genes and proteins. ROS production within the cell was inhibited by chloroform alkaloid extract (CAE). There occurred marked CAE-induced reductions in IL-1ß, Cox-2, and iNOS mRNA expressions. We also observed marked reductions in IL-6 and TNF-α mRNA expressions with methanol alkaloid extract (MAE). CAE effectively suppressed IL-1ß and iNOS protein levels, especially as in qRT-PCR studies, while MAE effectively reduced IL-6 and TNF-α protein levels. Additionally, MAE was found to be prominent in suppressing the levels of Cox-2 protein, unlike qRT-PCR studies. According to our study findings, oxidative stress brought about by inflammation was suppressed by alkaloid extracts from G. grandiflorum which can be attributed to their suppressor effects on the pro-inflammatory cytokines-mediators, and p38 MAPK. As a result, a drug active substance that suppresses oxidative stress and inflammation has been brought to the neuropharmacological field.

Nutritional therapy for persistent cognitive impairment after resolution of overt hepatic encephalopathy in patients with cirrhosis: A double-blind randomized controlled trial.

BACKGROUND AND AIM: Minimal hepatic encephalopathy (MHE) reflects cognitive impairment in patients with liver cirrhosis and is associated with poor prognosis. We assessed the effects of nutritional therapy on cognitive functions, health-related quality of life (HRQOL), anthropometry, endotoxins, and inflammatory markers in cirrhotic patients with MHE. METHODS: In a double-blind randomized controlled trial, cirrhotic patients with MHE were randomized to nutritional therapy (group I: 30-35 kcal/kg/day and 1.0-1.5 g of protein/kg/day) and no nutritional therapy (group II: diet as patients were taking before) for 6 months. MHE was diagnosed based on psychometric hepatic encephalopathy score (PHES). Anthropometry, ammonia, endotoxins, inflammatory markers, myostatin, and HRQOL were assessed at baseline and after 6 months. Primary endpoints were improvement or worsening in MHE and HRQOL. RESULTS: A total of 150 patients were randomized to group I (n = 75, age 46.3 ± 12.5 years, 58 men) and group II (n = 75, age 45.2 ± 9.3 years, 56 men). Baseline PHES (-8.16 ± 1.42 vs -8.24 ± 1.43; P = 0.54) was comparable in both groups. Reversal of MHE was higher in group I (73.2% vs 21.4%; P = 0.001) than group II. Improvement in PHES (Δ PHES 4.0 ± 0.60 vs -4.18 ± 0.40; P = 0.001), HRQOL (Δ Sickness Impact Profile 3.24 ± 3.63 vs 0.54 ± 3.58; P = 0.001), anthropometry, ammonia, endotoxins, cytokines, and myostatin levels was also significantly higher in group I than group II. Overt hepatic encephalopathy developed in 6 patients in group I and 13 in group II (P = 0.04). CONCLUSIONS: Nutritional therapy is effective in treatment of MHE and associated with improvement in nutritional status, HRQOL, ammonia, endotoxins, inflammatory markers, and myostatin levels.

Immunometabolism Modulation by Extracts from Pistachio Stalks Formulated in Phospholipid Vesicles.

Several studies have demonstrated the effectiveness of plant extracts against various diseases, especially skin disorders; namely, they exhibit overall protective effects. The Pistachio (Pistacia vera L.) is known for having bioactive compounds that can effectively contribute to a person's healthy status. However, these benefits may be limited by the toxicity and low bioavailability often inherent in bioactive compounds. To overcome these problems, delivery systems, such as phospholipid vesicles, can be employed. In this study, an essential oil and a hydrolate were produced from P. vera stalks, which are usually discarded as waste. The extracts were characterized by liquid and gas chromatography coupled with mass spectrometry and formulated in phospholipid vesicles intended for skin application. Liposomes and transfersomes showed small size (<100 nm), negative charge (approximately -15 mV), and a longer storage stability for the latter. The entrapment efficiency was determined via the quantification of the major compounds identified in the extracts and was >80%. The immune-modulating activity of the extracts was assayed in macrophage cell cultures. Most interestingly, the formulation in transfersomes abolished the cytotoxicity of the essential oil while increasing its ability to inhibit inflammatory mediators via the immunometabolic citrate pathway.

Effect of Thymbra capitata (L.) Cav. on Inflammation, Senescence and Cell Migration.

Aromatic plants are reported to display pharmacological properties, including anti-aging. This work aims to disclose the anti-aging effect of the essential oil (EO) of Thymbra capitata (L.) Cav., an aromatic and medicinal plant widely used as a spice, as well as of the hydrodistillation residual water (HRW), a discarded by-product of EO hydrodistillation. The phytochemical characterization of EO and HRW was assessed by GC-MS and HPLC-PDA-ESI-MSn, respectively. The DPPH, ABTS, and FRAP assays were used to disclose the antioxidant properties. The anti-inflammatory potential was evaluated using lipopolysaccharide-stimulated macrophages by assessing NO production, iNOS, and pro-IL-1ß protein levels. Cell migration was evaluated using the scratch wound assay, and the etoposide-induced senescence was used to assess the modulation of senescence. The EO is mainly characterized by carvacrol, while the HRW is predominantly characterized by rosmarinic acid. The HRW exerts a stronger antioxidant effect in the DPPH and FRAP assays, whereas the EO was the most active sample in the ABTS assay. Both extracts reduce NO, iNOS, and pro-IL-1ß. The EO has no effect on cell migration and presents anti-senescence effects. In opposition, HRW reduces cell migration and induces cellular senescence. Overall, our study highlights interesting pharmacological properties for both extracts, EO being of interest as an anti-aging ingredient and HRW relevant in cancer therapy.

UHPLC-MS and GC-MS phytochemical profiling, amelioration of pain and inflammation with chloroform extract of Funaria hygrometrica Hedw. via modulation of inflammatory biomarkers.

People of Pakistan have undisturbed customs for the employment of medicinal plants for healthcare requisites. Chloroform extract of F. hygrometrica (CE FH) was examined for its ability to reduce inflammation and to produce analgesia. Carrageenan and formalin-induced paw edema model for inflammatory activity, hot-plate and tail-flick methods to assess analgesic activity were executed. Phytochemical analysis was done by UHPLC-MS and GC-mass spectrometer. The results demonstrated that in carrageenan-induced paw edema, maximum reduction in inflammation was observed at 5th hour at the dose 100 mg/kg; while at doses 250 and 500 mg/kg, maximum response was observed at 5th and 6th hours. Analgesic activity results indicated that maximum analgesia was observed up to 120 min at 100 mg/kg, while up to 90 min in case of 250 and 500 mg/kg doses. The formalin-induced rat paw edema showed significant (p < 0.05) anti-inflammatory activity after 5 days treatment. After, testing period of 10 days, the biochemical parameters such as CBC, CRP, serum enzymes like CAT, SOD, GSH and inflammatory mediators like TNF-α, IL-6, IL-4 and IL-10 were estimated. The administration of formalin resulted in an increase in the level of leucocytes, total WBC, CRP, serum enzymes and in the diameters of paw thickness, while pre-treatment with CE FH at dose levels of 100, 250 and 500 mg/kg exhibited a diminution in the levels of SOD, GSH, CAT, total RBC and HB. Acute inflammatory mediators such as TNFα, IL -6 and IL-4 were reduced, and IL-10 was upregulated in the treated group as compared to the control. Many phytoconstituents, i.e., chitobiose, chlorovulone III, γ-tocotrienol, emmotin, cassine, hexacosanedioic acid, neophytadiene, fumaric acid, neophytadiene, hexadecanoic acid, phytol and stigmasterol were detected during UHPLC-MS and GC-MS analysis seems to be responsible for the said activity in correlation with the already reported data about these compounds. The results concluded that CE FH possess noteworthy anti-inflammatory and central analgesic action at different doses (100, 250 and 500 mg/kg).

BAAE-AgNPs Improve Symptoms of Diabetes in STZ-induced Diabetic Rats.

OBJECTIVES: Nanoparticles can be employed to improve the therapeutic activity of natural products. Type 2 diabetes mellitus is a serious health condition that has spread like a "modern pandemic" worldwide. In the present study, we developed silver nanoparticles, Ag-NPs, with an aqueous extract from Balanites aegyptiaca to investigate their antioxidant and anti-inflammatory activity in STZ-induced diabetic rats. METHODS: Aqueous extracts of Balanites aegyptiaca seeds (BAAE) were used in the synthesis of BAAE-AgNPs, which were characterized using FTIR and TEM. Different doses of BAAE-AgNP (1/50 LD50; 29.4 mg/kg b.w. and 1/20 LD50: 73.5 mg/kg b.w.) were administered to STZ-induced diabetic rats to evaluate their potential antidiabetic activity. RESULTS: FTIR spectral data indicated the presence of flavonoids and polyphenols in BAAEAgNPs. The size of the BAAE-AgNPs, determined by TEM examination, was 49.33 ± 7.59 nm, with a zeta potential of +25.37. BAAE-AgNPs were characterized by an LD50 value of 1470 mg/kg b.w. In diabetic rats, the daily oral administration of both doses of BAAE-AgNPs (29.4 and 73.5 mg/kg b.w.) for 12 weeks resulted in a significant improvement in body weight, insulin homeostasis, HbA1c, HDL-C, MDA, and pancreatic SOD, CAT, and GSH. They reduced plasma glucose, cholesterol, and triglycerides. This treatment also resulted in a significant decrease in pancreatic IL-6, p53, and TNF-α in diabetic rats. Furthermore, BAAE-AgNPs down-regulated pancreatic TGF-ß1 and Akt gene expression in diabetic rats and resulted in a significant decrease in the regulation of hepatic GLUT-2, as well as an increase in the regulation of hepatic GK and pancreatic B-cl2 gene expression. The histopathological results obtained indicated that BAAEAgNPs improved pancreatic tissue metabolism by enhancing antioxidant enzymes, suppressing inflammatory cytokines, and scavenging free radicals. CONCLUSION: The findings implied that similar to the glibenclamide-treated groups, in the BAAEAgNPs treated group, the compromised antioxidant status normalized in STZ-induced diabetes. By scavenging free radicals, BAAE-Ag-NPs protected against lipid peroxidation while reducing the risk of complications from diabetes. Compared to the daily dose of 29.4 mg, the impact was more prominent at 73.5 mg.

Anti-inflammatory activity of caffeic acid derivatives from Ilex rotunda.

Ilex rotunda Thunb. has been used in traditional medicine for treating rheumatoid arthritis, relieving pain and indigestion. In the present study, we isolated three new caffeic acid benzyl ester (CABE) analogs (1-3) along with eight known compounds (4-11) from the extract of I. rotunda. The absolute configuration of α-hydoxycarboxylic acid in 1 was assigned with the phenylglycine methyl ester (PGME) method. We further investigated their anti-inflammatory activities in lipopolysaccharide (LPS)-induced macrophages (RAW 264.7) cells. Among them, compounds 2-4, 7, 8, 10, and 11 suppressed the production of nitric oxide (NO), pro-inflammatory mediators. It was additionally confirmed that the anti-inflammatory effect of active compound 2 was through significant suppression of cytokines, including interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and IL-8 in LPS-stimulated RAW 264.7 cells and colon epithelial (HT-29) cells. Western blot analysis revealed that compound 2 decreased the LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and phosphorylated extracellular regulated kinase (pERK)1/2. The following molecular docking simulations showed the significant interactions of compound 2 with the iNOS protein. These results suggested that the compound 2 can be used as potential candidate for treating inflammatory diseases such as inflammatory bowel disease (IBD).

Vitamin D receptor and STAT6 interactome governs oesophageal epithelial barrier responses to IL-13 signalling.

OBJECTIVE: The contribution of vitamin D (VD) deficiency to the pathogenesis of allergic diseases remains elusive. We aimed to define the impact of VD on oesophageal allergic inflammation. DESIGN: We assessed the genomic distribution and function of VD receptor (VDR) and STAT6 using histology, molecular imaging, motif discovery and metagenomic analysis. We examined the role of VD supplementation in oesophageal epithelial cells, in a preclinical model of IL-13-induced oesophageal allergic inflammation and in human subjects with eosinophilic oesophagitis (EoE). RESULTS: VDR response elements were enriched in oesophageal epithelium, suggesting enhanced VDR binding to functional gene enhancer and promoter regions. Metagenomic analysis showed that VD supplementation reversed dysregulation of up to 70% of the transcriptome and epigenetic modifications (H3K27Ac) induced by IL-13 in VD-deficient cells, including genes encoding the transcription factors HIF1A and SMAD3, endopeptidases (SERPINB3) and epithelial-mesenchymal transition mediators (TGFBR1, TIAM1, SRC, ROBO1, CDH1). Molecular imaging and chromatin immunoprecipitation showed VDR and STAT6 colocalisation within the regulatory regions of the affected genes, suggesting that VDR and STAT6 interactome governs epithelial tissue responses to IL-13 signalling. Indeed, VD supplementation reversed IL-13-induced epithelial hyperproliferation, reduced dilated intercellular spaces and barrier permeability, and improved differentiation marker expression (filaggrin, involucrin). In a preclinical model of IL-13-mediated oesophageal allergic inflammation and in human EoE, VD levels inversely associated with severity of oesophageal eosinophilia and epithelial histopathology. CONCLUSIONS: Collectively, these findings identify VD as a natural IL-13 antagonist with capacity to regulate the oesophageal epithelial barrier functions, providing a novel therapeutic entry point for type 2 immunity-related diseases.

Phillygenin from Forsythia suspensa leaves exhibits analgesic potential and anti-inflammatory activity in carrageenan-induced paw edema in mice.

Forsythia suspensa (Thunb.) Vahl (Oleaceae) leaves are valuable sources of phillygenin. This study aimed to isolate phillygenin from F. suspensa leaves and examine its analgesic and anti-inflammatory effects. Phillygenin was successfully extracted and isolated from F. suspensa leaves after fermentation. Phillygenin significantly reduced the number of writhing induced by acetic acid, prolonged the latency period in the hot plate test, and inhibited the xylene-induced ear edema and carrageenan-induced paw edema in mice. IL-6, TNF-α, IL-1ß, NO, and PGE2 levels in the carrageenan-induced paw edema were notably reduced after pretreatment with phillygenin. Phillygenin significantly decreased the iNOS and COX-2 protein expressions and the IκB-α and NF-κB p65 phosphorylation. This study demonstrated that phillygenin is a potential therapeutic candidate for managing pain and inflammation-mediated disorders. The study contributes to the comprehensive development and utilization of F. suspensa leaves for economic and health care. PRACTICAL APPLICATIONS: Phillygenin is one of the major active ingredients in Forsythia suspensa. But the content of phillygenin in F. suspensa is very low which limits its application. Phillygenin has potential pharmacological activity and anti-inflammatory properties. However, the potential effects of phillygenin on analgesic activity have not been clarified. Furthermore, the data on its anti-inflammatory activity in vivo are relatively limited. This study evaluated the analgesic activity for the first time and the acute anti-inflammatory effect of phillygenin from F. suspensa leaves by fermentation, which indicated phillygenin is a potential therapeutic candidate for managing pain and inflammation-mediated disorders.

How Curcumin Targets Inflammatory Mediators in Diabetes: Therapeutic Insights and Possible Solutions.

Diabetes mellitus is a multifactorial chronic metabolic disorder, characterized by altered metabolism of macro-nutrients, such as fats, proteins, and carbohydrates. Diabetic retinopathy, diabetic cardiomyopathy, diabetic encephalopathy, diabetic periodontitis, and diabetic nephropathy are the prominent complications of diabetes. Inflammatory mediators are primarily responsible for these complications. Curcumin, a polyphenol derived from turmeric, is well known for its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The regulation of several signaling pathways effectively targets inflammatory mediators in diabetes. Curcumin's anti-inflammatory and anti-oxidative activities against a wide range of molecular targets have been shown to have therapeutic potential for a variety of chronic inflammatory disorders, including diabetes. Curcumin's biological examination has shown that it is a powerful anti-oxidant that stops cells from growing by releasing active free thiol groups at the target location. Curcumin is a powerful anti-inflammatory agent that targets inflammatory mediators in diabetes, and its resistant form leads to better therapeutic outcomes in diabetes complications. Moreover, Curcumin is an anti-oxidant and NF-B inhibitor that may be useful in treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase and aldose reductase inhibitors. Through its anti-oxidant and anti-inflammatory effects, and its suppression of vascular endothelial development and nuclear transcription factors, curcumin has the ability to prevent, or reduce, the course of diabetic retinopathy. Curcumin improves insulin sensitivity by suppressing phosphorylation of ERK/JNK in HG-induced insulin-resistant cells and strengthening the PI3K-AKT-GSK3B signaling pathway. In the present article, we aimed to discuss the anti-inflammatory mechanisms of curcumin in diabetes regulated by various molecular signaling pathways.