Advances in traditional herbal formulation based nano-vaccine for cancer immunotherapy: Unraveling the enigma of complex tumor environment and multidrug resistance.

Cancer is attributed to uncontrolled cell growth and is among the leading causes of death with no known effective treatment while complex tumor microenvironment (TME) and multidrug resistance (MDR) are major challenges for developing an effective therapeutic strategy. Advancement in cancer immunotherapy has been limited by the over-activation of the host immune response that ultimately affects healthy tissues or organs and leads to a feeble response of the patient's immune system against tumor cells. Besides, traditional herbal medicines (THM) have been well-known for their essential role in the treatment of cancer and are considered relatively safe due to their compatibility with the human body. Yet, poor solubility, low bio-availability, and lack of understanding about their pathophysiological mechanism halt their clinical application. Moreover, considering the complex TME and drug resistance, the most precarious and least discussed concerns for developing THM-based nano-vaccination, are identification of specific biomarkers for drug inhibitory protein and targeted delivery of bioactive ingredients of THM on the specific sites in tumor cells. The concept of THM-based nano-vaccination indicates immunomodulation of TME by THM-based bioactive adjuvants, exerting immunomodulatory effects, via targeted inhibition of key proteins involved in the metastasis of cancer. However, this concept is at its nascent stage and very few preclinical studies provided the evidence to support clinical translation. Therefore, we attempted to capsulize previously reported studies highlighting the role of THM-based nano-medicine in reducing the risk of MDR and combating complex tumor environments to provide a reference for future study design by discussing the challenges and opportunities for developing an effective and safe therapeutic strategy against cancer.

Hypersampsonone H attenuates ulcerative colitis via inhibition of PDE4 and regulation of cAMP/PKA/CREB signaling pathway.

BACKGROUND AND OBJECTIVES: Ulcerative colitis (UC) is a recurrent intestinal inflammatory disease which poses a serious threat to the life of patients. However, there are no specific drugs for UC yet. Hypericum sampsonii Hance (HS) is a Chinese herbal medicine traditionally used to treat enteritis and dysentery. Our previous studies have demonstrated that HS holds potential anti-UC effects, and a novel compound named Hypersampsonone H (HS-1) isolated from HS possesses significant anti-inflammatory activity. However, the beneficial effects of HS-1 on UC remain unclear. This study aimed to investigate the therapeutic effects of HS-1 on UC and its potential mechanisms, both in vitro and in vivo. METHODS: The in vitro model was employed using LPS-induced RAW264.7 cells to investigate the anti-inflammatory effects of HS-1 and its possible mechanisms. Furthermore, the therapeutic efficacy and potential mechanisms of HS-1 against dextran sulfate sodium (DSS)-induced acute colitis were assessed through histopathological examination, biochemical analysis, and molecular docking. RESULTS: In vitro, HS-1 significantly reduced LPS-induced inflammatory responses, as indicated by inhibiting NO production, down-regulating the overexpression of COX-2 and iNOS, as well as regulating the imbalanced levels of IL-6, TNF-α, and IL-10. Moreover, HS-1 also inhibited the expression of PDE4, elevated the intracellular cAMP level, and promoted the phosphorylation of CREB, thereby activating the PKA/CREB pathway in RAW264.7 cells. In vivo, HS-1 demonstrated therapeutic capacity against DSS-induced colitis by alleviating the symptoms of colitis mice, regulating the abnormal expression of inflammatory mediators, protecting the integrity of intestinal epithelial barrier, and reducing tissue fibrosis. Consistently, HS-1 was found to decrease the expression of PDE4 isoforms, subsequently activating the cAMP/PKA/CREB signaling pathway. Furthermore, the molecular docking results indicated that HS-1 exhibited a high affinity for PDE4, particularly PDE4D. Further mechanistic validation in vitro demonstrated that HS-1 possessed a synergistic effect on forskolin and an antagonistic effect on H-89 dihydrochloride, thereby exerting anti-inflammatory effects through the cAMP/PKA/CREB signaling pathway. CONCLUSION: We disclose that HS-1 serves as a promising candidate drug for the treatment of UC by virtue of its ability to reduce DSS-induced colitis via the inhibition of PDE4 and the activation of cAMP/PKA/CREB signaling pathway.

Hypericum sampsonii Hance: a review of its botany, traditional uses, phytochemistry, biological activity, and safety.

Ethnopharmacological relevance: Hypericum sampsonii Hance, also known as Yuanbao Cao in Chinese, is a traditional medicinal herb from the Guttiferae family and has been widely used in China to treat various conditions, including dysentery, enteritis, mastitis, scrofula, and contusion. Aim of the review: This review aims to provide a comprehensive overview of the botany, traditional uses, phytochemistry, biological activity and safety of H. sampsonii and to highlight its potential for medical application and drug development. Materials and methods: We searched several databases, i.e., Web of Science, SciFinder, PubMed, CBM, CNKI, Google Scholar, etc., for relevant information on H. sampsonii. Additionally, we also consulted some books on Chinese medicine. Results: To date, 227 secondary metabolites have been isolated from H. sampsonii, including polycyclic polyprenylated acylphloroglucinols (PPAPs), benzophenones, xanthones, flavonoids, naphthodianthrones, anthraquinones and aromatic compounds. These metabolites exhibit various biological activities such as anti-inflammatory, anti-tumor, anti-depressant, anti-oxidant, anti-viral and anti-bacterial effects. PPAPs are considered the main active metabolites with rich biological activities. Despite being known as rich source of PPAPs, the full extent of H. sampsonii biological activities, including their potential as PDE4 inhibitors, remained unclear. Since, previous studies have mainly been based on structural identification of metabolites in H. sampsonii, and efficacy evaluations of these metabolites based on clinical applications of H. sampsonii lack sufficient data. However, current evidence suggest that PPAPs are the most likely material basis for efficacy. From the limited information available so far, there is no evidence of potential safety issues and the safety data are limited. Conclusion: Collectively, this review provides a comprehensive overview of the botany, traditional uses, phytochemistry, pharmacology, and safety of H. sampsonii, a valuable medicinal plant in China with various pharmacological activities. Based on pharmacological studies, H. sampsonii shows potential for treating gastrointestinal and gynecological disorders as well as traumatic injuries, which aligns with traditional medicinal use due to the presence of PPAPs, benzophenones, xanthones, and flavonoids. Therefore, further studies are needed to evaluate the pharmacological effects and elucidate the pharmacological mechanisms. In addition, pharmacological mechanisms and safety evaluation of PPAPs on animal models need to be clarified. Yet, further comprehensive studies are required to elucidate the phytochemical constituents, pharmacological mechanisms, structure-activity relationships, safety evaluation, and quality standards of this plant. Takentogether, this review highlights the potential of H. sampsonii for medical application and drug development.

Therapeutic potential of Litsea cubeba essential oil in modulating inflammation and the gut microbiome.

Inflammation, a sophisticated and delicately balanced physiological mechanism, is paramount to the host's immunological defense against pathogens. However, unfettered and excessive inflammation can be instrumental in engendering a plethora of chronic ailments and detrimental health repercussions, notably within the gastrointestinal tract. Lipopolysaccharides (LPS) from bacteria are potent endotoxins capable of instigating intestinal inflammation through the disruption of the intestinal epithelial barrier and the stimulation of a pro-inflammatory immune response. In this study, we sought to investigate the influence of Litsea cubeba essential oil (LCEO) on LPS-induced intestinal inflammation and associated changes in the gut microbiota. We investigated the therapeutic potential of LCEO for gut health, with particular emphasis on its gut protective properties, anti-inflammatory properties and modulation of the gut microbiome. LCEO exhibited protective effects on colonic tissue by protecting crypts and maintaining epithelial integrity, and anti-inflammatory properties by reducing TNF-α, IL-6, and IL-1ß levels in the liver and intestine. Citral, a major component of LCEO, showed robust binding to IL-1ß, IL-6, and TNF-α, exerting anti-inflammatory effects through hydrogen bonding interactions. Using community barplot and LEfSe analyses, we detected significant variation in microbial composition, identified discrete biomarkers, and highlighted the influence of essential oils on gut microbial communities. Our research suggests that LCEO may be a promising natural compound for ameliorating diarrhea and intestinal inflammation, with potential implications for modulating the gut microbiome. These observations provide invaluable insight into the potential therapeutic role of LCEO as a natural anti-inflammatory agent for treating intestinal inflammatory disorders, particularly in the setting of a dysregulated immune response and altered gut microbiota. Furthermore, our findings highlight the need to understand the complex interplay between the host, the gut microbiome and natural products in the context of inflammatory diseases.

Polycyclic polyprenylated acylphloroglucinols from Hypericum sampsonii Hance and their anti-inflammatory activity.

Phytochemical investigation of Hypericum sampsonii Hance resulted in the isolation of thirty-five polycyclic polyprenylated acylphloroglucinols including six new ones (1, 3, 5, and 15-17). Their structures were elucidated by UV, IR, NMR, HRESIMS, and calculated ECD analysis. Some compounds were evaluated for their anti-inflammatory effects in LPS-induced RAW264.7 cells. Compounds 1 and 26 showed significant inhibitory effects on LPS-induced NO production, and markedly suppressed the protein expression of iNOS and COX-2 in LPS-activated RAW264.7 cells.

New chemical structures and liver-protective activity of the diterpenoids from Callicarpa rubella.

Callicarpa rubella is a characteristic folk herb in the genus Callicarpa, and has abundant ethnobotanical usage as indigenous medicine in Lingnan area of P. R. China. However, the phytochemical and pharmacological properties of C. rubella was rarely investigated. Now, three new diterpenoids, named rubellapene A-C (1-3), along with five known analogues (4-8), were isolated from C. rubella. Their structures were determined by spectroscopic methods, quantum chemical electronic circular dichroism calculations and single-crystal X-ray diffraction analysis. Notably, the norditerpenoids C18 of clerodane type (rubellapene B) was rarely found in the genus Callicarpa. The liver protective effects of all of the isolates (1-8) were evaluated by the changes of cell viability and transaminase content of AST and ALT in H2O2-induced BRL cells. Compound 1, 3-8 exhibited that potent liver protective effects at different levels.

Protective effects of 4-geranyloxy-2,6-dihydroxybenzophenonel on DSS-induced ulcerative colitis in mice via regulation of cAMP/PKA/CREB and NF-κB signaling pathways.

Hypericum sampsonii Hance has traditionally been used to treat enteritis and diarrhea. As one of the main benzophenones isolated from H. sampsonii, 4-geranyloxy-2,6-dihydroxybenzophenonel (4-GDB) has been shown to possess anti-inflammatory effects. However, the therapeutic effect and potential mechanisms of 4-GDB in ulcerative colitis (UC) remain unclear. This study aimed to evaluate the role of 4-GDB in UC using a dextran sulfate sodium-induced colitis mouse model. Intragastric administration of 4-GDB (20 mg/kg/day) for 8 days significantly attenuated colonic injury, reduced the expression of inflammatory mediators, and improved colonic barrier function in mice with colitis. Furthermore, in vivo and in vitro experiments indicated that 4-GDB could activate cAMP/PKA/CREB and inhibit the NF-κB pathway. Collectively, 4-GDB may be a potential agent for treating UC by regulating the cAMP/PKA/CREB and NF-κB pathways.

Triterpenoids from the genus Ilex attenuate free fatty acid-induced lipid accumulation in HepG2 cells by regulating lipid metabolism disorder and the AMPK signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Various traditional Chinese medicines from the genus Ilex (Aquifoliaceae) have been reported to have excellent hypolipidaemic effects. Although triterpenoids have been found to be the main active components, the underlying mechanisms have not been clarified. AIM OF THE STUDY: This study aimed to investigate the lipid-lowering effect, structure-activity relationship and action mechanism of triterpenoids from the genus Ilex. MATERIALS AND METHODS: FFA was used to induce HepG2 cells to establish a classical lipid-lowering activity screening model for the activities of 31 triterpenoids, and the contents of intracellular lipids, TC, and TG were measured. Furthermore, the structure-activity relationship was discussed. Mechanistically, UPLC-Q/TOF-MS-based metabolomics and lipidomics studies were performed, and metabolic pathways were analysed to investigate the lipid-lowering mechanism. Moreover, western blotting was performed to analyse the expression of key proteins of lipid metabolism and predict the targets of action. RESULTS: Thirteen triterpenoids significantly reduced intracellular lipid accumulation and decreased the levels of TG and TC. Among them, rotundic acid (RA) showed stronger lipid-lowering activity than the simvastatin-positive group, and structure-activity relationship analysis indicated that the hydroxyl groups at C-3 and C-19, hydroxymethyl groups at C-23, and carboxyl groups at C-28 may be the key groups for biological activity. Twenty-two metabolites in the metabolomics study and 19 metabolites in the lipidomics study were identified. The identified biomarkers were primarily glycerophosphocholine, LysoPCs, PCs, TAGs, LysoPEs, LysoPIs and sphingolipids, which are involved in glycerophospholipid and sphingolipid metabolism. Moreover, western blotting analysis showed that the expression of SREBP-1 and HMGCR decreased, while AMPK and ACC phosphorylation and the expression of CPT1A and CYP7A1 increased in the RA-treated group. CONCLUSION: The results suggested that triterpenoids from the genus Ilex showed significant lipid-lowering effects and that RA may be a novel hypolipidaemic drug candidate. Moreover, the underlying mechanism indicated that RA showed a lipid-lowering effect by regulating glycerophospholipid and sphingolipid metabolism and activating the AMPK pathway.

A Dual-Channel Microfluidic Chip for Single Tobacco Protoplast Isolation and Dynamic Capture.

Protoplasts are widely used in gene function verification, subcellular localization, and single-cell sequencing because of their complete physiological activities. The traditional methods based on tissues and organs cannot satisfy the requirement. Therefore, the isolation and capture of a single protoplast are most important to these studies. In this study, a dual-channel microfluidic chip based on PDMS with multi-capture cavities was designed. The design theory of the dual-channel microfluidic chip's geometry was discussed. The capture mechanism of the single cell in a dual-channel microfluidic chip was studied by simulation analysis. Our results showed that a single polystyrene microsphere or tobacco protoplast was successfully isolated and trapped in this chip. The capture efficiency of the chip was 83.33% for the single tobacco protoplast when the inlet flow rate was 0.75 µL/min. In addition, the dynamic capture of the polystyrene microsphere and tobacco protoplasts was also presented. Overall, our study not only provided a new strategy for the subsequent high throughput single protoplast research, but also laid a theoretical foundation for the capture mechanism of the single cell.

Hypericumsampsonii attenuates inflammation in mice with ulcerative colitis via regulation of PDE4/PKA/CREB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum sampsonii Hance (Yuanbaocao), a traditional herbal medicine with various pharmacological properties, is traditionally used to treat diarrhea and enteritis in China for hundreds of years. Investigations have uncovered its anti-inflammatory effects and corresponding bioactive constituents in H. sampsonii, however, the mechanisms of action for the treatment of enteritis are still unclear. AIMS OF THE STUDY: This study aims to investigate the therapeutic effects and molecular mechanisms of H. sampsonii in a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model. MATERIALS AND METHODS: The major ingredients of the ethyl acetate extract (HS) in H. sampsonii were analyzed by UPLC-QTOF-MS. The inflammatory state of UC mice was caused by 3% DSS once daily for seven days. During DSS treatment, the mice in the positive drug group and the other three groups were orally administered 5-ASA (positive control) or HS daily. After treatment with HS or 5-ASA for a week, colonic pathological observation and the molecular biological index were performed for therapeutic evaluation, including visual inspection in the length and weight of colons and spleens, pathological morphology by hematoxylin and eosin (HE) staining, determination of oxidative markers, inflammatory cytokines and tumor necrosis factor-alpha (TNF-α) levels in colonic tissues as well as spleen index. Gene expression levels of inflammatory cytokines, antioxidant enzymes and PDE4 were detected using kits and PCR, while the expression of colonic tight junction proteins and relative signals of PKA/CREB signaling pathway were analyzed by Western blot. RESULTS: The main components in HS were found to be polycyclic polyprenylated acylphloroglucinols (PPAPs). HS distinctly alleviated DSS-stimulated UC-like lesions symptoms as evidenced by a significant recovery from body weight, colon lengths, and histological injuries of colons. HS reduced the accumulation of pro-inflammatory cytokines and improved the mRNA level of IL-10. Simultaneously, the colonic mRNA expression levels of IL-1ß, IL-17, iNOS and COX-2 were all significantly suppressed by HS in a dose-dependent manner. Furthermore, HS restored the protein expression of tight junction-associated protein (ZO-1 and occluding). Besides, HS significantly inhibited the protein level of PDE4 and decreased the expressions of PKA and phosphorylated CREB. CONCLUSION: This is the first work about main composition and anti-UC effect of Hypericum sampsonii Hance. For the first time, this study reveals HS is not toxic in a single dose and exert significantly protective effect in DSS-colitis mice. The underlying mechanisms may involve the improvement to inflammatory status, the protection for intestinal barrier function, the inhibition of PDE4, and the activation of PKA/CREB signaling pathway. This study provided an experimental basis for the traditional application of H. sampsonii Hance in the treatment of diarrhea and dysentery.

Rare cytochalasans isolated from the mangrove endophytic fungus Xylaria arbuscula.

Four new cytochalasans, arbuschalasins A-D (1-4), along with thirteen known analogues (5-17), were isolated from the solid rice medium of endophytic fungus Xylaria arbuscula. Arbuschalasins A-B feature a rare 5/6/6/6 fused ring system while arbuschalasin D was characterized as the first example of natural cytochalasans that possesses a 5/5/11 fused scaffold. The structures of 1-4 were assigned by spectroscopic data, with their absolute structures being determined by electronic circular dichroism (ECD) calculations. All of the isolates were evaluated against the human colorectal adenocarcinoma cell lines (HCT15). Compounds 6 and 7 showed significant inhibitory effects (IC50 values were 13.5 and 13.4 µM, respectively), being more active than those of the positive control, fluorouracil (103.1 µM).

Therapeutic role of d-pinitol on experimental colitis via activating Nrf2/ARE and PPAR-γ/NF-κB signaling pathways.

Ulcerative colitis is a recrudescent intestinal inflammation coupled with diarrhea, weight loss, pus, and blood stool, which seriously impacts the quality of patient life. d-Pinitol, which can be a food supplement isolated from the food plant-like soybeans, Ceratonia siliqua Linn and Bruguiera gymnorrhiza, has been proved to show anti-oxidative and anti-inflammatory effects. However, the potential mechanism of d-pinitol still remains ill-defined contemporarily. In the current study, the therapeutic effect and potential mechanisms of d-pinitol against colitis were investigated. Oxidative stress and inflammation of experimental colitis were caused by 3% DSS treatment once daily for 7 days. During DSS treatment, the mice of the positive drug group and three other groups were orally administered SASP or d-pinitol once daily. Clinical symptoms were analyzed, and macroscopic scores were calculated. The levels of oxidative and inflammatory cytokines were measured using assay kits and RT-PCR. Additionally, the protein expression of the Nrf2/ARE pathway and PPAR-γ was measured by Western blot. Results showed that d-pinitol enormously alleviated DSS-induced bodyweight loss, colon shortening, and histological injuries, achieving a therapeutic efficacy superior to SASP. Moreover, the oxidative stress and colonic inflammatory response were mitigated. d-pinitol not only significantly activated the Nrf2/ARE signaling pathway via facilitating the translocation of Nrf2 from sitoplazma to cytoblast, upregulating the protein expression levels of GCLC, GCLM, HO-1, and NQO1, but also improved the PPAR-γ level by binding to the active site of PPAR-γ, when suppressing NF-κB p65 and IκBα phosphorylation. In conclusion, d-pinitol exhibited a dramatic anti-colitis efficacy by activating the Nrf2/ARE pathway and PPAR-γ. Hence, d-pinitol may be a promising therapeutic drug against UC in the future.

Asymmetric Total Synthesis of the Highly Strained 4ß-Acetoxyprobotryane-9ß,15α-diol.

The first and asymmetric total synthesis of 4ß-acetoxyprobotryane-9ß,15α-diol, containing a rare and highly strained trans-fused bicyclo[3.3.0]octane ring system, has been achieved. The synthetically challenging [6-5-5] tricyclic ring system in the final product was efficiently and diastereoselectively synthesized via an asymmetric rhodium-catalyzed [4 + 2] cycloaddition reaction, followed by a unique benzilic acid type rearrangement under very mild conditions. The seven contiguous stereocenters were installed efficiently and diastereoselectively.

Polypropionate Derivatives with Mycobacterium tuberculosis Protein Tyrosine Phosphatase B Inhibitory Activities from the Deep-Sea-Derived Fungus Aspergillus fischeri FS452.

Fiscpropionates A-F (1-6), six new polypropionate derivatives featuring an unusual long hydrophobic chain, were isolated from the deep-sea-derived fungus Aspergillus fischeri FS452. Their structures were elucidated on the basis of spectroscopic analysis, and the absolute configurations were determined by J-HMBC analysis, electronic circular dichroism (ECD) calculations, and the modified Mosher's method. This is the first discovery of polypropionates from marine-derived fungi, and compounds 4 and 5 represent the first examples of polypropionate derivatives containing a 3-hydroxypiperidin-2-one as part of an imide linkage. In addition, compounds 1-4 exhibited significant inhibitory activities against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC50 values of 5.1, 12, 4.0, and 11 µM, respectively. Enzyme kinetic experiments suggested that they all acted through a noncompetitive mechanism. A preliminary structure-activity relationship is discussed.

Dechdigliotoxins A-C, Three Novel Disulfide-Bridged Gliotoxin Dimers from Deep-Sea Sediment Derived Fungus Dichotomomyces cejpii.

Dechdigliotoxins A-C (1-3), which represented the first examples of gliotoxin dimers with an unprecedented exocyclic disulfide linkage, were obtained from a deep-sea derived fungus Dichotomomyces cejpii FS110. The structures of these compounds were elucidated on the basis of spectroscopic analysis and the absolute configurations were unambiguously determined through quantum chemical calculations, as well as DP4+ probability simulations. The proposed biosynthetic pathway suggested 1-3 were generated from unusual L-Phe and D-Ser. All the isolates were evaluated for their cytotoxicity against four tumor cell lines.

Emission enhancement and high sensitivity of a π-conjugated dye towards pressure: the synergistic effect of supramolecular interactions and H-aggregation.

Piezoresponsive fluorescent (PRF) materials are highly promising for applications in deformation, flaw detection and haptic sensing. However, traditional PRF materials generally suffer from low sensitivity and fluorescence quenching processes. This study involved the preparation of H-aggregated dyes with weak supramolecular interactions, which showed enhanced emission under a low pressure.

Tigliane Diterpenoids as a New Type of Antiadipogenic Agents Inhibit GRα-Dexras1 Axis in Adipocytes.

The phytochemical study of Euphorbia prolifera led to the isolation of two tiglianes (1 and 2) and 23 mysrinanes (3-25). Most of these isolates showed significant antiadipogenic activity in 3T3-L1 adipocyte without apparent cytotoxicity. Subsequent structural modification yielded 10 derivatives, among which 1a, the 5- O-acetyl derivative of 1, turned out to be the most active compound with improved triglyceride-lowering activity (EC50 for 1 and 1a: 0.61 and 0.32 µM, respectively) and reduced cytotoxicity (selectivity index for 1 and 1a: 28 and 312, respectively). The structure-activity relationship study revealed that the trans-fused 5/7/6 ring system in an angular shape was important to the activity. A mechanistic study indicated that 1 and 1a could inhibit the glucocorticoid receptor α-Dexras1 axis in adipocyte, leading to the retardation of cell differentiation at the early stage. These findings may provide a new type of lipid-lowering agents for future antiobesity drug development.

Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against acetaminophen-induced liver injury: Role of CYP2E1 and Keap1-Nrf2 pathway.

Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.

Protective Effect of Bruguiera gymnorrhiza (L.) Lam. Fruit on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice: Role of Keap1/Nrf2 Pathway and Gut Microbiota.

Bruguiera gymnorrhiza (BG), a medicinal mangrove, and its fruit (a food material) (BGF), have traditionally been used to treat diarrhea (also known as ulcerative colitis) in folk medicine. However, the mechanism of action against colitis remains ambiguous. This study aimed to investigate the potential efficacy and mechanism of BGF on experimental colitis. Colitis was induced by oral intake of dextran sulfate sodium (DSS) and treated with aqueous extract of BGF (25, 50 and 100 mg/kg) for a week. The Disease Activity Index (DAI), colon length, and histological changes of colon were analyzed. The inflammatory and oxidative stress status was explored. The protein expression of Nrf2 and Keap1 in the colon was detected by Western blotting. The mRNA expression of Nrf2 downstream genes (GCLC, GCLM, HO-1 and NQO1) was determined by RT-PCR. Furthermore, the effect on intestinal flora was analyzed. Results indicated that BGF was rich in pinitol, and showed strong antioxidative activity in vitro. Compared with the DSS model, BGF effectively reduced the body weight loss and DAI, restored the colon length, repaired colonic pathological variations, and decreased the histological scores, which was superior to salicylazosulfapyridine (SASP) with smaller dosage. Moreover, BGF not only abated the levels of MDA and inflammatory mediators (TNF-α, IL-6, IL-1ß, and IFN-γ), increased the level of IL-10, but also prevented the depletion of SOD and GSH. BGF upregulated the protein level of nuclear Nrf2 and mRNA levels of GCLC, GCLM, HO-1 and NQO1, while significantly inhibited the protein expression of Keap1 and cytosolic Nrf2. Besides, BGF promoted the growth of probiotics (Bifidobacterium, Anaerotruncus, and Lactobacillus) in the gut, and inhibited the colonization of pathogenic bacteria (Bacteroides and Streptococcus), which contributed to the maintenance of intestinal homeostasis. BGF possessed protective effect against DSS-induced colitis. The potential mechanism of BGF may involve the amelioration of inflammatory and oxidative status, activation of Keap1/Nrf2 signaling pathway, and maintenance of micro-ecological balance of the host. This study provides experimental evidence for the traditional application of BGF in the treatment of diarrhea, and indicates that BGF may be a promising candidate against colitis.

Geospallins A⁻C: New Thiodiketopiperazines with Inhibitory Activity against Angiotensin-Converting Enzyme from a Deep-Sea-Derived Fungus Geosmithia pallida FS140.

Three new thiodiketopiperazines, geospallins A⁻C (1⁻3), together with nine known analogues (4⁻12), were isolated from the culture of the deep-sea sediment-derived fungus Geosmithia pallida FS140. Among them, geospallins A and B (1 and 2) represent rare examples of thiodiketopiperazines featuring an S-methyl group at C-10 and a tertiary hydroxyl group at C-11. Their structures were determined by high-resolution electrospray mass spectrometry (HRESIMS), spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Their angiotensin-converting enzyme (ACE) inhibitory activity was reported, and geospallins A⁻C (1⁻3) showed inhibitory activity with IC50 values of 29⁻35 µM.