Sodium houttuyfonate induces bacterial lipopolysaccharide shedding to promote macrophage M1 polarization against acute bacterial lung infection.

Sodium houttuyfonate (SH), derived from the widely utilized natural herb Houttuynia cordata, exhibits an effective therapeutic effect on various diseases, including bacterial and fungal infections, especially the respiratory tract infection. Therefore, the anti-microbial mechanisms of SH may be different from the single-target action mechanism of conventional antibiotics, and further research is needed to clarify this. Firstly, we discovered that SH can effectively intervene in mouse lung infections by reducing bacterial load and acute inflammation response related to pneumonia caused by Pseudomonas aeruginosa. Interestingly, our results confirmed that SH has surface activity and can directly induce changes in the cell wall the shedding of surface lipopolysaccharide (LPS). Additionally, we found that SH-induced shedding of LPS can induce M1 polarization of macrophages in the early stage, leading to the production of corresponding polarization effector molecules. Subsequently, we discovered that SH-induced M1 polarization cells can effectively phagocytose and kill bacterial cells. The protein expression results indicated that SH can enhance the expression of M1 polarization pathway of TLR4/MyD88/NF-κB during the initial phase of macrophage and pathogen interaction. In summary, our results imply that SH could directly induce the shedding of P. aeruginosa LPS in a surfactant-like manner. Afterwards, the SH induced abscisic LPS can initiate the TLR4/MyD88/NF-κB immune pathway to trigger the M1 polarization of macrophages, which might intervene the P. aeruginosa-caused acute lung infection at early stage. Based on these findings, we attempted to coin the term "immune feedback eradication mechanism against pathogen of natural product" to describe this potent antimicrobial mechanism of SH.

Sodium Houttuybonate Promotes the Browning of White Adipose Tissue by Inhibiting Ferroptosis via the AMPK-NRF2-HO1 Pathway.

The rising prevalence of obesity has resulted in an increased demand for innovative and effective treatment strategies. Houttuynia cordata Thunb. (H. cordata) has demonstrated promising potential in preventing obesity. However, the mechanism underlying the anti-obesity effects of H. cordata and its bioactive component, sodium houttuybonate (SH), remains unclear. Our study reveals that SH treatment promotes the browning of inguinal white adipose tissue (iWAT) and prevents the obesity induced by a high-fat diet. SH significantly mitigates ferroptosis by upregulating glutathione peroxidase 4 (Gpx4) and decreasing malondialdehyde (MDA) levels, while also enhancing superoxide dismutase (SOD) levels. Furthermore, SH promotes the phosphorylation of AMP-activated protein kinase (AMPK), which subsequently increases the expression of nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) in the iWAT. However, the effects of SH were attenuated by ML385, an Nrf2 inhibitor. Collectively, our findings suggest that SH induces iWAT browning and prevents diet-induced obesity primarily through the AMPK/NRF2/HO-1 pathway by inhibiting ferroptosis.

Sodium Houttuyfonate Ameliorates DSS-induced Colitis Aggravated by Candida albicans through Dectin-1/NF-κB/miR-32-5p/NFKBIZ Axis Based on Intestinal microRNA Profiling.

Our previous research indicated that Sodium houttuyfonate (SH) can effectively ameliorate dextran sulfate sodium (DSS)-induced colitis exacerbated by Candida albicans. However, the underlying protective mechanism of SH remains unclear. Therefore, in this study, a mice colitis model was infected with C. albicans, and the total colonic miRNAs were assessed. Furthermore, the differentially expressed miRNAs were enriched, clustered, and analyzed. Moreover, based on the dual luciferase analysis of NFKBIZ modulation by miR-32-5p, the in vitro and in vivo therapeutic effects of SH on inflammatory response, fungal burden, oxidative stress, and apoptosis were assessed at transcriptional and translational levels in the presence of agonist and antagonist. A total of 1157 miRNAs were identified, 84 of which were differentially expressed. Furthermore, qRT-PCR validated that SH treatment improved 17 differentially expressed miRNAs with > fourfold upregulation or > sixfold downregulation. Similar to most differentially altered miRNA, C. albicans significantly increased Dectin-1, NF-κB, TNF-α, IL-1ß, IL-17A, and decreased miR-32-5p which negatively targeted NFKBIZ. In addition, SH treatment reduced inflammatory response and fungal burden in a colitis model with C. albicans infection. Further analyses indicated that in C. albicans infected Caco2 cells, SH inhibited fungal growth, oxidative stress, and apoptosis by increasing Dectin-1, NF-κB, NFKBIZ, TNF-α, IL-1ß, IL-17A, and decreasing miR-32-5p. Therefore, SH can ameliorate the severity of colitis aggravated by C. albicans via the Dectin-1/NF-κB/miR-32-5p/NFKBIZ axis.

Sodium houttuyfonate modulates the lung Th1/Th2 balance and gut microbiota to protect against pathological changes in lung of ovalbumin-induced asthmatic mice.

OBJECTIVE: The gut-lung axis involves microbial and product interactions between the lung and intestine. Antibiotics for chronic asthma can cause intestinal dysbiosis, disrupting this axis. Sodium houttuyfonate (SH) has diverse biological activities, including modifying gut microbiota, antibacterial, and anti-inflammatory. This study aims to explore the relationship between SH, CD4+ T cells, and gut microbiota. METHODS: Allergic asthma was experimentally induced in mice through injection and inhalation of ovalbumin. After the administration of different amounts of SH, ELISA was utilized to ascertain the levels of inflammatory cytokines in the serum, flow cytometry was used to examine the levels of Th1/Th2 cytokines in CD4+ cells from lung tissues. The expression of T-bet and GATA3 in lung tissue was determined by Western blotting and quantitative real-time PCR assay. Gut microbiota was determined by 16S rRNA gene sequencing. RESULTS: The results showed that SH can alleviate pulmonary injury in asthmatic mice, reducing serum levels of IL-4, IL-5, and IL-13 while simultaneously increasing IFN-γ. Furthermore, SH has been observed to modulate the balance of Th1/Th2 cells by up-regulating the mRNA and protein expression of T-bet but down-regulating GATA3 in the lung tissues of asthmatic mice, thereby promoting the differentiation of Th1 cells. Additionally, SH can regulate the variety and composition of gut microbiota especially genus Akkermansia in asthmatic mice. CONCLUSION: SH can alleviate asthma through the regulation of Th1/Th2 cells and gut microbiota.

Sodium Houttuyfonate Prevents Seizures and Neuronal Cell Loss by Maintaining Glutamatergic System Stability in Male Rats with Kainic Acid-Induced Seizures.

The present study evaluated the antiseizure and neuroprotective effects of sodium houttuyfonate (SH), a derivative of Houttuynia cordata Thunb. (H. cordata), in a kainic acid (KA)- induced seizure rat model and its underlying mechanism. Sprague Dawley rats were administered normal saline, SH (50 or 100 mg/kg), or carbamazepine (300 mg/kg) by oral gavage for seven consecutive days before the intraperitoneal administration of KA (15 mg/kg). SH showed antiseizure effects at a dose of 100 mg/kg; it prolonged seizure latency and decreased seizure scores. SH also significantly decreased neuronal loss in the hippocampi of KA-treated rats, which was associated with the prevention of glutamate level increase, the upregulation of glutamate reuptake-associated proteins (excitatory amino acid transporters 1-3), glutamate metabolism enzyme glutamine synthetase, the downregulation of the glutamate synthesis enzyme glutaminase, and significant alterations in the expression of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor) and NMDA (N-methyl-D-aspartic acid receptor) receptor subunits in the hippocampus. Furthermore, the effects of SH were similar to those of the antiseizure drug carbamazepine. Therefore, the results of the present study suggest that SH has antiseizure effects on KA-induced seizures, possibly through the prevention of glutamatergic alterations. Our findings suggest that SH is a potential alternative treatment that may prevent seizures by preserving the normal glutamatergic system.

Sodium Houttuyfonate Alleviates Monocrotaline-induced Pulmonary Hypertension by Regulating Orai1 and Orai2.

An increased intracellular Ca2+ concentration ([Ca2+]i) is a key trigger for pulmonary arterial smooth muscle cell (PASMC) proliferation and contributes greatly to pulmonary hypertension (PH). Extracellular Ca2+ influx via a store-operated Ca2+ channel, termed store-operated Ca2+ entry (SOCE), is a crucial mechanism for [Ca2+]i increase in PASMCs. Calcium release-activated calcium modulator (Orai) proteins, consisting of three members (Orai1-3), are the main components of the store-operated Ca2+ channel. Sodium houttuyfonate (SH) is a product of the addition reaction of sodium bisulfite and houttuynin and has antibacterial, antiinflammatory, and other properties. In this study, we assessed the contributions of Orai proteins to monocrotaline (MCT)-enhanced SOCE, [Ca2+]i, and cell proliferation in PASMCs and determined the effect of SH on MCT-PH and the underlying mechanism, focusing on Orai proteins, SOCE, and [Ca2+]i in PASMCs. Our results showed that: 1) Orai1 and Orai2 were selectively upregulated in the distal pulmonary arteries and the PASMCs of MCT-PH rats; 2) knockdown of Orai1 or Orai2 reduced SOCE, [Ca2+]i, and cell proliferation without affecting their expression in PASMCs in MCT-PH rats; 3) SH significantly normalized the characteristic parameters in a dose-dependent manner in the MCT-PH rat model; and 4) SH decreased MCT-enhanced SOCE, [Ca2+]i, and PASMC proliferation via Orai1 or Orai2. These results indicate that SH likely exerts its protective role in MCT-PH by inhibiting the Orai1,2-SOCE-[Ca2+]i signaling pathway.

Physical impediment to sodium houttuyfonate conversely reinforces ß-glucan exposure stimulated innate immune response to Candida albicans.

Candida albicans is a dimorphic opportunistic pathogen in immunocompromised individuals. We have previously demonstrated that sodium houttuyfonate (SH), a derivative of medicinal herb Houttuynia cordata Thunb, was effective for antifungal purposes. However, the physical impediment of SH by C. albicans ß-glucan may weaken the antifungal activity of SH. In this study, the interactions of SH with cell wall (CW), extracellular matrix (EM), CW ß-glucan, and a commercial ß-glucan zymosan A (ZY) were inspected by XTT assay and total plate count in a standard reference C. albicans SC5314 as well as two clinical fluconazole-resistant strains Z4935 and Z5172. After treatment with SH, the content and exposure of CW ß-glucan, chitin, and mannan were detected, the fungal clearance by phagocytosis of RAW264.7 and THP-1 was examined, and the gene expressions and levels of cytokines TNF-ɑ and IL-10 were also monitored. The results showed that SH could be physically impeded by ß-glucan in CW, EM, and ZY. This impediment subsequently triggered the exposure of CW ß-glucan and chitin with mannan masked in a time-dependent manner. SH-induced ß-glucan exposure could significantly enhance the phagocytosis and inhibit the growth of C. albicans. Meanwhile, the SH-pretreated fungal cells could greatly stimulate the cytokine gene expressions and levels of TNF-ɑ and IL-10 in the macrophages. In sum, the strategy that the instant physical impediment of C. albicans CW to SH, which can induce the exposure of CW ß-glucan may be universal for C. albicans in response to physical deterrent by antifungal drugs.

Sodium houttuyfonate plays a protective role in the asthmatic airway by alleviating the NLRP3-related pyroptosis and Th1/Th2 immune imbalance.

BACKGROUND: Houttuynia cordata is an herbal compound that grows in China and exhibits anti-inflammatory, antiviral, and antioxidant properties. Additionally, pyroptosis is mediated by the activated NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome after stimulation by various inflammatory factors in asthma. OBJECTIVE: To investigate the effect of sodium houttuyfonate on NLRP3 inflammasome-related pyroptosis and Th1/Th2 immune imbalance in asthma. METHODS: Asthmatic mice model were made, sodium houttuyfonate was injected intraperitoneally to treat the asthmatic mice. Airway reactivity, cell classification and counting in the bronchoalveolar lavage fluid were measured. Hematoxylin-eosin and periodic acid-Schiff staining were used to analyze airway inflammation and mucus hypersecretion. Beas-2b cells were cultured, LPS, NLRP3 antagonist (Mcc950) and sodium houttuyfonate were used to intervene the Beas-2b cells, NLRP3, ASC, caspase-1, GSDMD, IL-1ß, and IL-18 expression in the lung tissue and cells were analyzed using immunohistochemistry and western blot, while qRT- PCR was performed to analyze the mRNA contents in the pulmonary and the cells, respectively. Th1 and Th2 cytokines (IL-4 and IFN-γ) were detected with ELISA and the proportions of Th1 and Th2 in splenocyte were detected by flow cytometry. RESULTS: Airway reactivity decreased in sodium houttuyfonate group when compared with asthmatic group mice. In the BALF, the numbers of leukocytes, eosinophils, neutrophils, lymphocytes, and macrophages were significantly lower in sodium houttuyfonate group mice than in asthmatic group mice. The proportion of TH1/TH2 cells in spleen cells and IFN-γ /IL-4 in plasma increased in sodium houttuyfonate treatment group when compared with asthma group. Immunohistochemistry, western blot and RT-PCR showed that the expressions of NLRP3, ASC, caspase-1, GSDMD, IL-1ß and IL-18 were decreased in the lung tissue of mice after treated with sodium houttuyfonate when compared with those in the asthma group. However, sodium houttuyfonate combined with dexamethasone induced a stronger effect on NLRP3-related pyroptosis and Th1/Th2 immune imbalance compared to sodium houttuyfonate or dexamethasone alone. Beas-2b cells were cultured in vitro, sodium houttuyfonate can alleviate LPS-induced ASC, casepase-1, GSDMD, IL-18 and IL-1ß increasing, especially in SH (10 µg/ml) treated group, but the effect less than Mcc950. CONCLUSIONS: Sodium houttuyfonate can alleviated NLRP3-related pyroptosis and Th1/Th2 immune imbalance to reduce asthma airway inflammation and airway reactivity.

Sodium houttuyfonate exerts its neuroprotection effect by inhibiting the M1 microglia polarization in a TLR4/NF-κB signal pathway.

Neuroinflammation plays an important role in secondary injury after spinal cord injury (SCI) and may aggravate neurological dysfunction. Several studies have indicated that sodium houttuyfonate (SH) can significantly inhibit macrophage- mediated inflammation; however, its effects on SCI still needs to be elucidated. We found that SH improved Basso, Beattie, and Bresnahan scores and performance in the inclined plane test of SCI model rats. The injured spinal cord exhibited less neuronal loss, cell apoptosis, and M1 microglial polarization after SH treatment. In vitro, SH reduced TLR4/NF-κB expression in cultured primary microglia and decreased M1 microglial polarization and cell apoptosis in a lipopolysaccharide (LPS)-pretreated microglia and neuron coculture system. These results indicated that SH may exert a neuroprotective effect by inhibiting M1 microglial polarization after SCI via the TLR4/NF-κB signalling pathway.

Sodium houttuyfonate against cardiac fibrosis attenuates isoproterenol-induced heart failure by binding to MMP2 and p38.

BACKGROUND: Heart failure (HF), caused by stress cardiomyopathy, is a major cause of mortality. Cardiac fibrosis is an essential structural remodeling associated with HF; therefore, preventing cardiac fibrosis is crucial to decelerating the progression of HF. Sodium houttuyfonate (SH), an extract of Houttuynia cordata, has a potent therapeutic effect on hypoxic cardiomyocytes in a myocardial infarction model. PURPOSE: To investigate the preventative and therapeutic effects of SH during isoproterenol (ISO)-induced HF and explore the pharmacological mechanism of SH in alleviating HF. METHODS: We analyzed the overlapping target genes between SH and cardiac fibrosis or HF using a network pharmacology analytical method. We verified the suppressive effect of SH on ISO-induced proliferation and activation of cardiac fibroblasts by immunohistochemical staining and histological analysis in an isoproterenol-induced HF mouse model. Additionally, we investigated the effect of SH by evaluating fibrosis and cardiac remodeling markers. To further decipher the pharmacological mechanism of SH against cardiac fibrosis and HF, we performed a molecular docking analysis between SH and hub common target genes. RESULTS: There were 20 overlapping target genes between SH and cardiac fibrosis and 32 overlapping target genes between SH and HF. The 16 common target genes of SH against cardiac fibrosis and HF included MMP2 (matrix metalloproteinase 2), and p38. SH significantly inhibited the ISO- or TGF-ß-induced expression of Col1α (collagen 1), α-SMA (smooth muscle actin), MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), TGF-ß (transforming growth factor), and Smad2 phosphorylation. Moreover, both ISO- and TGF-ß-induced p38 phosphorylation was inhibited. Molecular docking analysis showed that SH forms a stable complex with MMP2 and p38. CONCLUSIONS: In addition to protecting cardiomyocytes, SH directly inhibits cardiac fibroblast activation and proliferation by binding to MMP2 and p38, subsequently delaying cardiac fibrosis and HF progression. Our prevention- and intervention-based approaches in this study showed that SH inhibited the development of stress cardiomyopathy-mediated cardiac fibrosis and HF when SH was administered before or after the initiation of cardiac stress.

Sodium houttuyfonate effectively treats acute pulmonary infection of Pseudomonas aeruginosa by affecting immunity and intestinal flora in mice.

Introduction: Pseudomonas aeruginosa is a major nosocomial pathogen that frequently causes ventilator-associated pneumonia in specific populations. Sodium houttuyfonate (SH) has shown mild antibacterial activity against P. aeruginosa in vitro, but the mechanism of potent antimicrobial activity of SH against P. aeruginosa infection in vivo remains unclear. Methods: Here, using the mouse pneumonia model induced by P. aeruginosa nasal drip to explore the therapeutic effects of SH. Results: We found that SH exhibits dose-dependent therapeutic effects of reducing P. aeruginosa burden and systemic inflammation in pneumonia mice. SH ameliorates inflammatory gene expression and production of inflammatory proteins, such as interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB) and toll-like receptor 4 (TLR4), associated with the TLR4/NF-κB pathway in mice with P. aeruginosa pneumonia. Furthermore, we analyzed the intestinal flora of mice and found that compared with the model group, the abundance and diversity of beneficial bacterial flora of SH treatment groups increased significantly, suggesting that SH can improve the intestinal flora disorder caused by inflammation. In addition, SH improves alpha and beta diversity index and reduces species abundance differences of intestinal flora in pneumonia mice. Discussion: Taken together, our presented results indicate that SH may effectively alleviate the acute pulmonary infection induced by P. aeruginosa by reducing the disturbance of regulating immunity and intestinal flora in mice.

Sodium houttuyfonate protects against cardiac injury by regulating cardiac energy metabolism in diabetic rats.

Diabetic cardiomyopathy is a diabetic complication with complicated pathophysiological changes and pathogenesis and difficult treatment. Sodium houttuyfonate is the adduct of sodium bisulfite and houttuynin, the main volatile component in Houttuynia cordata Thunb, possesses a variety of activities including multiple interventions on inhibiting ventricular remodeling. The study aims to explore effect of sodium houttuyfonate on diabetic myocardial injury and its underlying mechanisms. The diabetes model was established by intraperitoneal injection of streptozotocin at a dose of 85 mg/kg. By intragastric administration for 26 days, sodium houttuyfonate (50 and 100 mg/kg/d) reversed the abnormal serum levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol and low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, improved the abnormal levels of serum aspartate aminotransferase and brain natriuretic peptide, reduced electrocardiogram P-R and QRS interval extension, accelerated the heart rate, decreased serum malondialdehyde content, up-regulated the myocardial energy metabolism including elevated the contents of ATP, ADP, total adenine nucleotides and phosphocreatine in myocardium, decreased AMP/ATP ratio, elevated myocardial Ca2+-Mg2+-ATPase activity, and down-regulated the mRNA expressions of AMP protein activation kinase α2 (AMPK-α2) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). In a conclusion, these results suggest that sodium houttuyfonate can improve cardiac energy metabolism disorder caused by diabetes by increasing cardiac Ca2+-Mg2+-ATPase activity and regulating AMPK signaling pathway, and then attenuates cardiac injury caused by hyperglycemia. In addition, sodium houttuyfonate also has the effects of anti-oxidation and improving abnormal levels of blood lipid.

The Immune Change of the Lung and Bowel in an Ulcerative Colitis Rat Model and the Protective Effect of Sodium Houttuyfonate Combined With Matrine.

Objective: To explore the immune change of lung injury of Ulcerative colitis (UC) by observing the changes of inherent immunity and adaptive immunity of the lung and bowel in UC rat models after the treatment of Sodium Houttuyfonate combined with Matrine. Method: UC rat models were established with the mucous membrane of colon allergize combined with TNBS-alcohol enteroclysis for 1 week and 5 weeks. 1-week experimental rats were divided into normal group and model group, 5/each group. 5-weeks experimental rats were divided into normal group, model group, Sodium Houttuyfonate (2.9mg/ml) combined with Matrine (1.47mg/ml), and positive control sulfasalazine (10mg/ml), 5/each group. All rats were administered by gavage for 5 weeks. The histopathological and fibrotic changes in the lung and bowel were observed, and the expressions of Tumor Necrosis Factor (TNF)- α, interleukin (IL)-8 in the lung, bowel, and serum were detected by radio-immunity and immunohistochemistry, and the mRNA expressions of Toll-like receptor (TLR)-4, nuclear factor kappa (NF-κB), Macrophage migration inhibitory factor (MIF), Mucosal addressing cell adhesion molecule-1 (MadCAM1) and Pulmonary surfactant protein-A (SP-A) in the lung and bowel were detected by Real time-PCR. Result: Compared with the normal group, the model rats had significant histopathological and fibrotic changes both in the lung and bowel, and all treatment groups were improved. After treatment, TLR4, IL-8, MIF, and TNF-α in the lung decreased (P<0.05); NF-KB, IL-8, and MIF in the bowel increased (P<0.05); MadCAM1 both in lung and bowel decreased (P<0.05); SP-A decreased in bowel and increased in the lung (P<0.05). Conclusion: The cause of lung injury in this model was found to be related to inherent immunity and adaptive immunity, while the cause of bowel injury in this model was found to be mainly related to adaptive immunity. Sodium Houttuyfonate combined with Matrine could improve bowel and lung injury.

Sodium houttuyfonate enhances the mono-therapy of fluconazole on oropharyngeal candidiasis (OPC) through HIF-1α/IL-17 axis by inhibiting cAMP mediated filamentation in Candida albicans-Candida glabrata dual biofilms.

Candida albicans and Candida glabrata are two common opportunistic fungi that can be co-isolated in oropharyngeal candidiasis (OPC). Hypha is a hallmark of the biofilm formation of C. albicans, indispensable for the attachment of C. glabrata, which is seldom in mycelial morphology. Increasing evidence reveals a hypoxic microenvironment in interior fungal biofilms, reminding of a fact that inflammation is usually accompanied by oxygen deprivation. As a result, it is assumed that the disaggregation of hypha-mediated hypoxia of biofilms might be a solution to alleviate OPC. Based on this hypothesis, sodium houttuyfonate (SH), a well-identified traditional herbal compound with antifungal activity, is used in combination with fluconazole (FLU), a well-informed synthesized antimycotics, to investigate their impact on filamentation in C. albicans and C. glabrata dual biofilms and the underlying mechanism of their combined treatment on OPC. The results show that compared with the single therapy, SH plus FLU can inhibit the hyphal growth in the mixed biofilms in vitro, decrease the fungal burden of oral tissues and internal organs, restore mucosal epithelial integrity and function, and reduce hypoxic microenvironment and inflammation in a mice OPC model. The possible mechanism of the combined therapy of SH plus FLU can be attributed to the regulation of HIF-1α/IL-17A axis through direct abrogation of the dual Candida biofilm formation. This study highlights the role of HIF-1α/IL-17A axis and the promising application of SH as a sensitizer of conventional antifungals in the treatment of OPC.

Sodium houttuyfonate attenuates neurological defects after traumatic brain injury in mice via inhibiting NLRP3 inflammasomes.

Sodium houttuyfonate (SH) is a chemical compound synthesized by houttuynin and sodium bisulfite. As it has antinflammatory effects, SH has been widely used to treat autoimmune diseases, including post events following traumatic brain injury (TBI). Meanwhile, NOD-like receptor with pyrin domain containing-3 (NLRP3) inflammasomes in microglia may play a central role in TBI. But to date, the intracellular mechanisms involved in the anti-inflammatory effects of SH in TBI remain unknown, especially whether regulating NLRP3. To gain an insight into this possibility, we conducted cell culture and biochemical studies on the effect of SH on NLRP3 inflammasome in microglia. The results showed that SH inhibited TLR4 and NLRP3 inflammasome activation in the microglia cell. In parallel, phosphorylation of ERK and NF-κB p65, which play a key role in NLRP3 inflammasome formation, was decreased. Intraperitoneal injection of SH into TBI mice significantly reduced the modified neurological severity score (mNSS), as well as the degree of microglia apoptosis post-controlled cortical impact (CCI). Immunohistochemistry, Western blot analysis, and reverse-transcription polymerase chain reaction (RT-PCR) revealed that SH markedly reduced NLRP3 inflammasome activation, TLR4 activity, phosphorylation of ERK and NF-κB. Moreover, SH significantly inhibited microglia activation post-CCI, but effectively promoted the astrocyte activation and angiopoiesis. Taken together, our research provides evidence that SH attenuated neurological deficits post TBI through inhibiting NLRP3 inflammasome activation, via influencing the TLR4/NF-κB signaling pathway. These findings explain the intracellular mechanism of the anti-inflammatory activity caused by SH treatment following TBI.

Effect and Mechanism Study of Sodium Houttuyfonate on Ventilator-Induced Lung Injury by Inhibiting ROS and Inflammation.

PURPOSE: Ventilator-induced lung injury (VILI) is a serious complication of mechanical ventilation (MV) that increases morbidity and mortality of patients receiving ventilator treatment. This study aimed to reveal the molecular mechanism of sodium houttuyfonate (SH) on VILI. MATERIALS AND METHODS: The male mice VILI model was established by high tidal volume ventilation. The cell model was established by performing cell stretch (CS) experiments on murine respiratory epithelial cells MLE-15. In addition, the JNK activator Anisomycin and JNK inhibitor SP600125 were used on VILI mice and CS-treated cells. RESULTS: VILI modeling damaged the structural integrity, increased apoptosis and wet-to-dry (W/D) ratio, enhanced the levels of inflammatory factors, reactive oxygen species (ROS) and malonaldehyde (MDA), and activated JNK pathway in lung tissues. SH gavage alleviated lung injury, decreased apoptosis and W/D ratio, and reduced levels of inflammatory factors, ROS and MDA, and p-JNK/JNK expression of lung tissues in VILI mice. However, activation of JNK wiped the protective effect of SH on VILI. Contrary results were found in experiments with JNK inhibitor SP600125. CONCLUSION: SH relieved VILI by inhibiting the ROS-mediated JNK pathway.

Sodium houttuyfonate: A review of its antimicrobial, anti-inflammatory and cardiovascular protective effects.

There is an almost unlimited interest in searching and developing new drugs, especially when we are in an era that are witnessing more and more emerging pathogens. Natural products from traditional medicines represent a large library for searching lead compounds with novel bioactivities. Sodium houttuyfonate is such one bioactive compound derived from Houttuynia cordata Thunb which has been employed in traditional medicine for treating infectious and inflammatory diseases. Sodium houttuyfonate has demonstrated multiple kinds of pharmacological effects, including antifungal, antibacterial, anti-inflammatory, and cardiovascular protective activities, which are discussed here to provide insights into our understanding of the pharmacological effects of SH and the underlying mechanisms.

Sodium Houttuyfonate Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice.

Pulmonary fibrosis (PF) could severely disrupt the normal lung architecture and function with fatal consequences. Currently, there is no effective treatment for PF or idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the effects of Sodium Houttuyfonate (SH) on bleomycin (BLM) induced PF mice model. Our results indicated that SH could attenuate BLM induced lung injury by reducing the inflammation, fibrogenesis and lung/body weight ratio. The proposed mechanisms for the protective effects of SH include: 1) improvement of pulmonary function in BLM mice, for instance, it can elevate the vital capacity (VC), increase the forced expiratory flow at 50% of forced vital capacity (FEF50) and improve other pulmonary function indices; 2) inhibition of collagen formation in BLM mice; 3) attenuation of the elevation of inflammatory cytokines, such as interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α), which are triggered by BLM administration; 4) reduction of the mRNA level and protein production of transforming growth factor-ß1 (TGF-ß1) in BLM mice. Furthermore, it was found that the protective effects of SH against BLM induced PF in mice was comparable to that of prednisone acetate (PA) tablets, a widely used drug for immunological diseases. Although Houttuynia Cordata Thunb has been widely used in China for lung infection and inflammation, the mechanism has not yet been fully elucidated. Our study provides the evidence that SH is an effective compound against pulmonary injury, irritation and fibrogenesis.

Sodium houttuyfonate attenuates dextran sulfate sodium associated colitis precolonized with Candida albicans through inducing ß-glucan exposure.

Inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis is a chronic intestinal disease most likely associated with gut dysbiosis. Candida related mycobiota has been demonstrated to play a role in IBD progression. Traditional Chinese herbal medicines (TCHMs) with antifungal activity have a potential in prevention and treatment of fungi-related IBD. Sodium houttuyfonate (SH) is a promising anti-Candida TCHMs. In this study, a dextran sulfate sodium induced colitis model with Candida albicans precolonization is established. SH gavage can significantly decrease the fungal burdens in feces and colon tissues, reduce disease activity index score, elongate colon length, and attenuate colonic damages. Moreover, SH markedly inhibits the levels of anti-Saccharomyces cerevisiae antibodies, ß-glucan, and proinflammatory cytokine (IL-1ß, IL-6, IL-8, TNF-α), and increases anti-inflammatory factor IL-10 level in serum and colon tissue. Further experiments demonstrate that SH could induce ß-glucan exposure, priming intestinal macrophages to get rid of colonized C. albicans through the collaboration of Dectin-1 and TLR2/4. With the decreased fungal burden, the protein levels of Dectin-1, TLR2, TLR4, and NF-κBp65 are fallen back, indicating the primed macrophages calm down and the colitis is alleviated. Collectively, these results manifest that SH can attenuate C. albicans associated colitis via ß-glucan exposure, deepening our understanding of TCHMs in the prevention and treatment of fungi associated IBD.

Sodium houttuyfonate enhances the intestinal barrier and attenuates inflammation induced by Salmonella typhimurium through the NF-κB pathway in mice.

Salmonella typhimurium (ST), as an aggressive bacterium, mainly causes intestinal inflammation and diarrhea. Sodium houttuyfonate (SH) is a derivative of houttuynin in the active oil of Houttuynia cordata, which is stable in nature and has anti-inflammatory activity. In this study, we used BALB/c mice infected with ST as experimental subjects and aimed to study the regulatory effect of SH on the intestinal tract and to explain its anti-inflammatory mechanism. Compared with the ST group, SH treatment improved the morphology of jejunum mucosa and alleviated the pathological damage to colon tissue. In addition, SH protected the intestinal barrier by regulating the localization and distribution of tight junction proteins. Meanwhile, SH significantly decreased the production of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) and inflammation-related enzymes (iNOS, COX-2). Moreover, further western blot results suggested that SH inhibited the expression of p-IκBα and p-p65 in intestinal tissues. These results demonstrated that SH maintained the intestinal barrier and attenuated the production of intestinal proinflammatory cytokines by regulating the NF-κB signaling pathway, thereby providing protection for the intestine.