Over the past few decades, complementary and alternative treatments have become increasingly popular worldwide. The purported therapeutic characteristics of natural products have come under increased scrutiny both in vitro and in vivo as part of efforts to legitimize their usage. One such product is tea tree oil (TTO), a volatile essential oil primarily obtained from the native Australian plant, Melaleuca alternifolia, which has diverse traditional and industrial applications such as topical preparations for the treatment of skin infections. Its anti-inflammatory-linked immunomodulatory actions have also been reported. This systematic review focuses on the anti-inflammatory effects of TTO and its main components that have shown strong immunomodulatory potential. An extensive literature search was performed electronically for data curation on worldwide accepted scientific databases, such as Web of Science, Google Scholar, PubMed, ScienceDirect, Scopus, and esteemed publishers such as Elsevier, Springer, Frontiers, and Taylor & Francis. Considering that the majority of pharmacological studies were conducted on crude oils only, the extracted data were critically analyzed to gain further insight into the prospects of TTO being used as a neuroprotective agent by drug formulation or dietary supplement. In addition, the active constituents contributing to the activity of TTO have not been well justified, and the core mechanisms need to be unveiled especially for anti-inflammatory and immunomodulatory effects leading to neuroprotection. Therefore, this review attempts to correlate the anti-inflammatory and immunomodulatory activity of TTO with its neuroprotective mechanisms.
Tea Tree Oil/therapeutic use* ; Melaleuca ; Neuroprotection ; Drug Repositioning ; Neuroinflammatory Diseases ; Australia ; Oils, Volatile ; Anti-Inflammatory Agents/pharmacology*

Dendrobium officinale can serve as Chinese medicinal material effective in nourishing yin, clearing heat, and producing fluid, and is used to treat throat diseases, but its active substances and mechanism are not clear. To clarify the active fraction and underlying mechanism of D. officinale against chronic pharyngitis(CP), the present study induced a CP model in rats by pepper water combined with low-concentration ammonia, and crude polysaccharides of D. officinale(DOP), non-polysaccharides of D. officinale(DON), and total extract of D. officinale(DOT)(0.33 g·kg~(-1), calculated according to the crude drug) were administered by gavage for six weeks. The changes in oral secretions and pharyngeal conditions of rats with CP were observed and rated. The hematological indicators were determined by an automatic hematology analyzer. The serum levels of pro-inflammatory factors, such as tumor necrosis factor-alpha(TNF-α), interleukin 1β(IL-1β), and interleukin 6(IL-6), and T-lymphocyte cytokines, including interferon γ(IFN-γ), interleukin 4(IL-4), interleukin 17(IL-17), and transforming growth factor β1(TGF-β1) were detected by the enzyme-linked immunosorbent assay(ELISA). The proportions of CD3~+, CD4~+, and CD8~+cells in peripheral blood T lymphocyte subsets were determined by the flow cytometry. The histomorphological changes of the pharynx were observed by hematoxylin-eosin(HE) staining. The protein expression of nuclear factor-κB P65(NF-κB P65), cyclooxygenase-2(COX-2), F4/80, and monocyte chemoattractant protein-1(MCP-1) in the pharynx were detected by immunohistochemistry and Western blot. The results showed that DOP and DON could significantly relieve pharyngeal lesions, reduce white blood cells(WBC) and lymphocytes(LYMP), decrease the levels of pro-inflammatory factors TNF-α, IL-6, and IL-1β, and inhibit the protein expression of NF-κB P65, COX-2, F4/80, and MCP-1 in the pharynx. DOP was superior in reducing oral secretions and serum IL-17 level and inferior in increasing CD4~+/CD8~+ratio to DON. It is suggested that both polysaccharides and non-polysaccharides of D. officinale have anti-PC effects and the anti-inflammatory mechanism may be related to the regulation of T lymphocyte distribution and inhibition of the inflammatory signaling pathways mediated by NF-κB P65. The anti-inflammatory effect of DOP may be related to the regulation of Th17/Treg balance, while that of DON may be related to the regulation of the Th/Tc ratio.
Ammonia/therapeutic use* ; Animals ; Anti-Inflammatory Agents/therapeutic use* ; Cyclooxygenase 2 ; Dendrobium/chemistry* ; Interleukin-17/therapeutic use* ; Interleukin-6 ; NF-kappa B/metabolism* ; Pharyngitis/drug therapy* ; Plant Extracts/chemistry* ; Polysaccharides/pharmacology* ; Rats ; Tumor Necrosis Factor-alpha ; Water

Abelmoschus manihot (L.) Medik. (A. manihot) is a traditional Chinese herbal medicine with a variety of pharmacological properties. It was first recorded in Jiayou Materia Medica dating back to the Song dynasty to eliminate urinary tract irritation by clearing away heat and diuretic effect. However, its pharmacological action on urinary tract infections has not been investigated. The present study aims to evaluate the anti-inflammatory activity of A. manihot on a mouse model of lipopolysaccharide (LPS)-induced cystitis. The results showed that A. manihot decreased white blood cell (WBC) count in urine sediments of the cystitis mice, alleviated bladder congestion, edema, as well as histopathological damage, reduced the expression levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β simultaneously. Moreover, A. manihot administration significantly downregulated the expression levels of TLR4, MYD88, IκBα, p-IκBα, NF-κB p65, and p-NF-κB p65 in LPS-induced cystitis mice. These findings demonstrated the protective effect of A. manihot against LPS-induced cystitis, which is attributed to its anti-inflammatory profile by suppressing TLR4/MYD88/NF-κB pathways. Our results suggest that A. manihot could be a potential candidate for cystitis treatment.
Abelmoschus/metabolism* ; Animals ; Anti-Inflammatory Agents/therapeutic use* ; Cystitis ; Female ; Humans ; Lipopolysaccharides/pharmacology* ; Male ; Mice ; Myeloid Differentiation Factor 88/metabolism* ; NF-KappaB Inhibitor alpha/metabolism* ; NF-kappa B/metabolism* ; Signal Transduction ; Toll-Like Receptor 4/metabolism*

OBJECTIVES: Because intracerebral hemorrhage (ICH) has high morbidity, disability and mortality, it is significant to find new and effective treatments for ICH. This study aims to explore the effect of butyphthalide (NBP) on neuroinflammation secondary to ICH and microglia polarization. METHODS: A total of 48 healthy male SD rats were randomly divided into 6 groups: a sham 24 h group, a sham 72 h group, an ICH 24 h group, an ICH 72 h group, an ICH+NBP 24 h group, and an ICH+NBP 72 h group (8 rats per group). After operation, the neurological deficiencies were assessed based on improved Garcia scores and corner test. The expressions of Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), aquaporin-4 (AQP4), zonula occludens-1 (ZO-1), occludin, CD68, CD86, and CD206 were observed by Western blotting. Inflammatory cytokines were detected by ELISA. The immunofluorescence was to detect the polarization of microglia. RESULTS: 1) Compared with the sham groups, the expression of TLR4 (24 h: P<0.05; 72 h: P<0.01), NF-κB (both P<0.01) and Nrf2 (both P<0.01) in the perihematoma of the ICH group was increased, leading to microglia activation (P<0.01). The expressions of IL-6 (24 h: P<0.05; 72 h: P<0.01) and TNF-α (both P<0.01), the pro-inflammatory cytokines were up-regulated, and the expression of anti-inflammatory cytokine IL-4 was down-regulated (both P<0.01). Besides, the expression of AQP4 was enhanced (both P<0.01). The protein level of tightly connected proteins (including ZO-1, occludin) was decreased (all P<0.01). The neurological function of the rats in the ICH group was impaired in the 2 time points (both P<0.01). 2) Compared with the sham group at 24 h and 72 h after the intervention of NBP, the expressions of TLR4 (both P<0.05) and NF-κB (both P<0.01) were significantly declined, and the expression of Nrf2 was further enhanced (both P<0.05) in the perihematoma of the ICH+NBP group. Furthermore, the expression of M1 microglia marker was inhibited (P<0.05), and the polarization of microglia to the M2 phenotype was promoted (P<0.01). 3) In terms of inflammation after ICH, the IL-4 expression in the ICH+NBP group was increased compared with the ICH group (24 h: P<0.05; 72 h: P<0.01); the expression of IL-6 was decreased significantly in the ICH+NBP 72 h group (P<0.01); the level of AQP4 was declined significantly in the ICH+NBP 24 h group (P<0.05), there was a downward trend in the 72-hour intervention group but without significant statistical difference. 4) Compared with the ICH group, the ZO-1 protein levels were increased (24 h: P<0.05; 72 h: P<0.01), and the symptoms of nerve defect were improved eventually (both P<0.05) in the ICH+NBP groups. CONCLUSIONS After ICH, the TLR4/NF-κB pathway is activated. The M1 microglia is up-regulated along with the release of detrimental cytokines, while the anti-inflammatory cytokines are down-regulated. The expression of AQP4 is increased, the tight junction proteins from the blood-brain barrier (BBB) is damaged, and the neurological function of rats is impaired. On the contrary, NBP may regulate microglia polarization to M2 phenotype and play a role in the neuroprotective effect mediated via inhibiting TLR4/NF-κB and enhancing Nrf2 pathways, which relieves the neuroinflammation, inhibits the expression of AQP4, repairs BBB, and improves neurological functional defects.
Animals ; Anti-Inflammatory Agents/therapeutic use* ; Cerebral Hemorrhage ; Cytokines/metabolism* ; Interleukin-4/therapeutic use* ; Interleukin-6/metabolism* ; Male ; Microglia/metabolism* ; NF-E2-Related Factor 2/metabolism* ; NF-kappa B/metabolism* ; Occludin/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Toll-Like Receptor 4/genetics*

Based on network pharmacology and in vivo experiment, this study explored the therapeutic effect of Tetrastigma hemsle-yanum(SYQ) on sepsis and the underlying mechanism. The common targets of SYQ and sepsis were screened out by network pharmacology, and the "SYQ-component-target-sepsis" network was constructed. The protein-protein interaction(PPI) network was established by STRING. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were performed based on DAVID to predict the anti-sepsis mechanism of SYQ. The prediction results of network pharmacology were verified by animal experiment. The network pharmacology results showed that the key anti-sepsis targets of SYQ were tumor necrosis factor(TNF), interleukin(IL)-6, IL-1β, IL-10, and cysteinyl asparate specific proteinase 3(caspase-3), which were mainly involved in Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappaB(NF-κB) signaling pathway. The results of animal experiment showed that SYQ can decrease the content of C-reactive protein(CRP), procalcitonin(PCT), lactate dehydrogenase(LDH), IL-6, TNF-α, and IL-1β, increase the content of IL-10, and down-regulate the protein levels of Bcl-2-associa-ted X(Bax)/B-cell lymphoma 2(Bcl2), cleaved caspase-3, TLR4, MyD88, and p-NF-κB p65/NF-κB p65. In summary, SYQ plays an anti-inflammatory role in the treatment of sepsis by acting on the key genes related to inflammation and apoptosis, such as TNF-α, IL-6, IL-lβ, IL-10, Bax, Bcl2, and cleaved caspase-3. The mechanism is the likelihood that it suppresses the TLR4/MyD88/NF-κB signaling pathway, which verifies relative prediction results of network pharmacology.
Animals ; Anti-Inflammatory Agents/therapeutic use* ; C-Reactive Protein ; Caspase 3/metabolism* ; Interleukin-10 ; Interleukin-6/metabolism* ; Lactate Dehydrogenases/metabolism* ; Myeloblastin/metabolism* ; Myeloid Differentiation Factor 88/metabolism* ; NF-kappa B/metabolism* ; Network Pharmacology ; Procalcitonin/therapeutic use* ; Sepsis/genetics* ; Toll-Like Receptor 4/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; bcl-2-Associated X Protein/metabolism*

Cardiovascular diseases seriously affect human health and their prevalence continues to increase with the aging of the population. The integrated therapy of traditional Chinese medicine(TCM) and western medicine for cardiovascular diseases has achieved certain results, but it is still faced with new challenges. Studies have shown that inflammation plays an important role in the development of cardiovascular diseases and some of these mechanisms have common features. For example, in cardiovascular diseases, C-C motif chemokine receptor 2(CCR2)-expressing macrophages increase and promote inflammation, and excessive activation of NOD-like receptor protein 3(NLRP3) inflammasome leads to the elevation of inflammatory factors. There is also new understanding of the pathogenesis and treatment of cardiovascular diseases in TCM. The heat-toxicity theory in cardiovascular diseases and the therapeutic principle of clearing heat and removing toxin have attracted attention. The clinical and pharmacological studies on the treatment of cardiovascular diseases such as Huanglian Jiedu Decoction and Simiao Yong'an Decoction are also gradually increasing. The present study analyzed the common features of the inflammatory response mechanisms in diverse cardiovascular diseases and discussed the significance of the prevention and treatment of diverse cardiovascular diseases by the treatment method of clearing heat and removing toxin to regulate inflammation, which is expected to provide new ideas and references for clinical treatment and drug research on cardiovascular diseases with the same treatment method for different diseases.
Humans ; Cardiovascular Diseases/drug therapy* ; Hot Temperature ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology* ; Inflammation/drug therapy* ; China ; Anti-Inflammatory Agents/therapeutic use*

The present study aimed to explore the regulatory targets and anti-inflammatory mechanism of Jingfang Mixture based on network pharmacology and animal tests. The active ingredients of Jingfang Mixture and the corresponding targets were screened out by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Inflammation-related targets were searched from GeneCards and DisGeNET, and the targets of active ingredients of Jingfang Mixture against inflammation were obtained. The protein-protein interaction(PPI) network was analyzed by STRING and plotted. Gene ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were carried out based on DAVID. The results of network pharmacology showed 159 active ingredients and 276 targets of Jingfang Mixture and 664 inflammation-related targets were screened out, and 90 targets of active ingredients of Jingfang Mixture against inflammation were obtained. As revealed by the PPI network, protein kinase B1(AKT1), caspase-3(CASP3), interleukin-1β(IL1 B), prostaglandin-endoperoxide synthase 2(PTGS2), and tumor necrosis factor(TNF) might be the key proteins for the anti-inflammatory effect of Jingfang Mixture. KEGG enrichment analysis demonstrated the pathways involved TNF, nuclear factor-kappa B(NF-κB), and mitogen-activated protein kinase(MAPK). The anti-inflammatory effect of Jingfang Mixture was explored through the mouse model of urticaria. The results indicated that Jingfang Mixture could down-regulate the phosphorylation levels of p38 MAPK, extracellular regulated protein kinases(ERK1/2), and NF-κB. The present study revealed the anti-inflammatory effect of Jingfang Mixture with multi-component and multi-target characteristics, which is expected to provide a scientific basis and important support for further research, development, and application.
Animals ; Mice ; Anti-Inflammatory Agents/therapeutic use* ; Cyclooxygenase 2 ; Drugs, Chinese Herbal/therapeutic use* ; Inflammation/drug therapy* ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Network Pharmacology ; NF-kappa B/genetics*

PURPOSE: The combined use of antibiotics and anti-inflammatory medicine to manage bacterial endotoxin-induced inflammation following injuries or diseases is increasing. The cytokine level produced by macrophages plays an important role in this treatment course. Ciprofloxacin and indomethacin, two typical representatives of antibiotics and anti-inflammatory medicine, are cost-effective and has been reported to show satisfactory effect. The current study aims to investigate the effect of ciprofloxacin along with indomethacin on the secretion of inflammatory cytokines by macrophages in vitro. METHODS: Primary murine peritoneal macrophages and RAW 264.7 cells were administrated with lipopolysaccharide (LPS) for 24 h. The related optimal dose and time point of ciprofloxacin or indomethacin in response to macrophage inflammatory response inflammation were determined via macrophage secretion induced by LPS. Then, the effects of ciprofloxacin and indomethacin on the secretory functions and viability of various macrophages were determined by enzyme-linked immunosorbent assay and flow cytometry analysis, especially for the levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF)-α. The optimal dose and time course of ciprofloxacin affecting macrophage inflammatory response were determined by testing the maximum inhibitory effect of the drugs on pro-inflammatory factors at each concentration or time point. RESULTS: According to the levels of cytokines secreted by various macrophages (1.2 × 10⁶ cells/well) after administration of 1 μg/mL LPS, the optimal dose and usage timing for ciprofloxacin alone were 80 μg/mL and 24 h, respectively, and the optimal dose for indomethacin alone was 10 μg/mL. Compared with the LPS-stimulated group, the combination of ciprofloxacin and indomethacin reduced the levels of IL-1β (p < 0.05), IL-6 (p < 0.05), IL-10 (p < 0.01)), and TNF-α (p < 0.01). Furthermore, there was greater stability in the reduction of inflammatory factor levels in the combination group compared with those in which only ciprofloxacin or indomethacin was used. CONCLUSION The combination of ciprofloxacin and indomethacin suppressed the levels of inflammatory cytokines secreted by macrophages in vitro. This study illustrates the regulatory mechanism of drug combinations on innate immune cells that cause inflammatory reactions. In addition, it provides a new potential antibacterial and anti-inflammatory treatment pattern to prevent and cure various complications in the future.
Humans ; Mice ; Animals ; Cytokines ; Lipopolysaccharides/pharmacology* ; Interleukin-10 ; Indomethacin/therapeutic use* ; Interleukin-6/therapeutic use* ; Ciprofloxacin/therapeutic use* ; Macrophages ; Tumor Necrosis Factor-alpha ; Inflammation/drug therapy* ; Anti-Inflammatory Agents/therapeutic use* ; Anti-Bacterial Agents/therapeutic use*

This study aimed to investigate the anti-inflammatory, antitussive, expectorant, and anti-asthmatic effects of Qinbaohong Oral Liquid in mouse experiments and explore its action mechanism based on network pharmacology. The mouse auricle swelling was induced by xylene for detecting the anti-inflammatory effect of Qinbaohong Oral Liquid, whose antitussive effect was then examined in mice with cough after exposure to ammonium hydroxide. The expectorant effect was determined based on the excretion of phenol red into the mouse trachea. The mouse model of asthma induced by histamine phosphate and acetylcholine chloride was used to observe the anti-asthmatic effect. The chemical components of Qinbaohong Oral Liquid were retrieved from TCMSP and literature, followed by target prediction based on BATMAN-TCM. The targets of inflammation, cough, expectoration, and asthma collected from GeneCards were intersected with drug targets for GO and KEGG enrichment analysis using Metascape. The results were imported into STRING for exploring protein-protein interactions and screening the key targets. As demonstrated by our findings, Qinbaohong Oral Liquid at 4.5 and 9.0 mL·kg~(-1) obviously decreased the weight(P<0.05) and thickness(P<0.01) of the right swelling ear and also the weight diffe-rence(swelling degree) between the two ears(P<0.05), prolonged the incubation period of cough(P<0.05), reduced the frequency of cough within 3 min(P<0.05), and increased the excretion of phenol red into the mouse trachea(P<0.01). Qinbaohong Oral Li-quid at 2.3, 4.5, and 9.0 mL·kg~(-1) dramatically prolonged the incubation period of asthma(P<0.05). A total of 324 chemical components and 1 245 targets were harvested for the Qinbaohong Oral Liquid, together with 10 272 inflammation targets, 4 400 cough targets, 192 expectoration targets, and 7 533 asthma targets. Their intersection revealed that the anti-inflammatory, antitussive, expectorant and anti-asthmatic effects of Qinbaohong Oral Liquid were correlated with such GO biological processes as the regulation of ion transport and blood circulation and such KEGG pathways as cancer-related signaling pathways and neuroactive ligand-receptor interaction. Qinbaohong Oral Liquid has been confirmed by both experiments and network pharmacology analysis to be efficient in anti-inflammation, stopping cough, eliminating phlegm, and relieving asthma.
Animals ; Anti-Inflammatory Agents/therapeutic use* ; Antitussive Agents/therapeutic use* ; Asthma/drug therapy* ; Cough/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Mice ; Network Pharmacology

Tripterygium wilfordii Hook F has significant anti-inflammatory and immunosuppressive properties and is widely used for treating autoimmune and inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and kidney disease, especially in traditional Chinese medicine. The mechanisms underlying its effects may be diverse but they remain unclear, and its toxicity and side effects limit its wider clinical application. This review summarizes the clinical application of Tripterygium wilfordii Hook F in recent years, as well as the results of studies into its mechanisms and toxicity, to provide a reference for its future clinical application.
Animals ; Anti-Inflammatory Agents/pharmacology* ; Arthritis, Rheumatoid/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Immunosuppressive Agents/pharmacology* ; Inflammation/drug therapy* ; Inflammatory Bowel Diseases/drug therapy* ; Medicine, Chinese Traditional ; Pyroptosis/drug effects* ; Tripterygium