Indole alkaloids isolated from the Nicotiana tabacum-derived Aspergillus fumigatus 0338 as potential inhibitors for tobacco powdery mildew and their mode of actions.

To explore active natural products against tobacco powdery mildew caused by Golovinomyces cichoracearum, an extract from the fermentation of endophytic Aspergillus fumigatus 0338 was investigated. The mechanisms of action for active compounds were also studied in detail. As a result, 14 indole alkaloid derivatives were isolated, with seven being newly discovered (1-7) and the remaining seven previously described (8-14). Notably, compounds 1-3 are rare linearly fused 6/6/5 tricyclic prenylated indole alkaloids, with asperversiamide J being the only known natural product of this kind. The isopentenyl substitutions at the 5-position in compounds 4 and 5 are also rare, with only compounds 1-(5-prenyl-1H-indol-3-yl)-propan-2-one (8) and 1-(6-methoxy-5-prenyl-1H-indol3-yl)-propan-2-one currently available. In addition, compounds 6 and 7 are new framework indole alkaloid derivatives bearing a 6-methyl-1,7-dihydro-2H-azepin-2-one ring. The purified compounds were evaluated for their activity against G. cichoracearum, and the results revealed that compounds 7 and 9 demonstrated obvious anti-G. cichoracearum activities with an inhibition rate of 82.6% and 85.2%, respectively, at a concentration of 250 µg/mL, these rates were better than that of the positive control agent, carbendazim (78.6%). The protective and curative effects of compounds 7 and 9 were also better than that of positive control, at the same concentration. Moreover, the mechanistic study showed that treatment with compound 9 significantly increased the structural tightness of tobacco leaves and directly affect the conidiospores of G. cichoracearum, thereby enhancing resistance. Compounds 7 and 9 could also induce systemic acquired resistance (SAR), directly regulating the expression of defense enzymes, defense genes, and plant semaphorins, which may further contribute to increased plant resistance. Based on the activity experiments and molecular dockings, the indole core structure may be the foundation of these compounds' anti-G. cichoracearum activity. Among them, the indole derivative parent structures of compounds 6, 7, and 9 exhibit strong effects. Moreover, the methoxy substitution in compound 7 can enhance their activity. By isolating and structurally identifying the above indole alkaloids, new candidates for anti-powdery mildew chemical screening were discovered, which could enhance the utilization of N. tabacum-derived fungi in pesticide development.

Rutaecarpine protects podocytes in diabetic kidney disease by targeting VEGFR2/NLRP3-mediated pyroptosis.

OBJECTIVE: Diabetic kidney disease (DKD) is the most common cause of the end-stage renal disease, which has limited treatment options. Rutaecarpine has anti-inflammatory effects, however, it has not been studied in DKD. Pyroptosis is a newly discovered mode of podocyte death related to inflammation. This study aimed to explore whether Rutaecarpine can ameliorate DKD and to clarify its possible mechanism. METHODS: In this study, we investigated the effects of Rutaecarpine on DKD using diabetic mice model (db/db mice) and high glucose (HG)-stimulated mouse podocyte clone 5 (MPC5) cells. Quantitative reverse transcription polymerase chain reaction and western blot were performed to detect the related gene and protein levels. We applied pharmacological prediction, co-immunoprecipitation assay, cellular thermal shift assay, surface plasmon resonance to find the target and pathway of the substances. Gene knockdown experiments confirmed this view in HG-stimulated MPC5 cells. RESULTS: Rutaecarpine significantly reduced proteinuria, histopathological damage, and pyroptosis of podocytes in a dose-dependent manner in db/db mice. Rutaecarpine also protected high glucose induced MPC5 injury in vitro experiments. Mechanistically, Rutaecarpine can inhibit pyroptosis in HG-stimulated MPC5 by reducing the expression of VEGFR2. VEGFR2 is a target of Rutaecarpine in MPC5 cells and directly binds to the pyroptosis initiation signal, NLRP3. VEGFR2-knockdown disrupted the beneficial effects of Rutaecarpine in HG-stimulated MPC5 cells. CONCLUSION: Rutaecarpine inhibits renal inflammation and pyroptosis through VEGFR2/NLRP3 pathway, thereby alleviating glomerular podocyte injury. These findings highlight the potential of Rutaecarpine as a novel drug for DKD treatment.

Gramine sensitizes Klebsiella pneumoniae to tigecycline killing.

BACKGROUND: The presence of plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 and its related variants has been associated with heightened resistance to tigecycline, thus diminishing its effectiveness. In this study, we explored the potential of gramine, a naturally occurring indole alkaloid, as an innovative adjuvant to enhance the treatment of infections caused by K. pneumoniae carrying tmexCD-toprJ-like gene clusters. METHODS: The synergistic potential of gramine in combination with antibiotics against both planktonic and drug-tolerant multidrug-resistant Enterobacterales was evaluated using the checkerboard microbroth dilution technique and time-killing curve analyses. Afterwards, the proton motive force (PMF) of cell membrane, the function of efflux pump and the activity of antioxidant system were determined by fluorescence assay and RT-PCR. The intracellular accumulation of tigecycline was evaluated by HPLC-MS/MS. The respiration rate, bacterial ATP level and the NAD+/NADH ratio were investigated to reveal the metabolism state. Finally, the safety of gramine was assessed through hemolytic activity and cytotoxicity assays. Two animal infection models were used to evaluate the in vivo synergistic effect. RESULTS: Gramine significantly potentiated tigecycline and ciprofloxacin activity against tmexCD1-toprJ1 and its variants-positive pathogens. Importantly, the synergistic activity was also observed against bacteria in special physiological states such as biofilms and persister cells. The mechanism study showed that gramine possesses the capability to augment tigecycline accumulation within cells by disrupting the proton motive force (PMF) and inhibiting the efflux pump functionality. In addition, the bacterial respiration rate, intracellular ATP level and tricarboxylic acid cycle (TCA) were promoted under the treatment of gramine. Notably, gramine effectively restored tigecycline activity in multiple animal infection models infected by tmexCD1-toprJ1 positive K. pneumoniae (RGF105-1). CONCLUSION: This study provides the first evidence of gramine's therapeutic potential as a novel tigecycline adjuvant for treating infections caused by K. pneumoniae carrying tmexCD-toprJ-like gene clusters.

Vincazalidine A, a unique bisindole alkaloid from Catharanthus roseus.

A new dimeric indole alkaloid, vincazalidine A consisting of an aspidosperma type and a modified iboga type with 1-azatricyclo ring system consisting of one azepane and two piperidine rings coupled with an oxazolidine ring was isolated from Catharanthus roseus, and the structure including absolute stereochemistry was elucidated on the basis of spectroscopic data as well as DP4 statistical analysis. Vincazalidine A induced G2 arrest and subsequent apoptosis in human lung carcinoma cell line, A549 cells.

An update review on monoterpene indole alkaloids and biological activities of Tabernaemontana species occurring in Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: The Tabernaemontana genus belongs to the Apocynaceae family of which 30 species are found in Brazil. Some Tabernaemontana species are used by Brazilian indigenous people and other communities, or are listed in the Yanomami Pharmacopeia. Ethnopharmacological data include use(s) for muscle problems, depressed sternum, back pain, abscess, indigestion, eye irritation, earache, itching, vaginal discharge, as an aid for older people who are slow and forgetful, mosquito and snake bites, infection by the human botfly larvae, calmative, and fever. Obviously, many of these uses are attributed to the alkaloids found in Tabernaemontana species. AIM OF THE REVIEW: The aim is to gather information on Tabernaemontana species occurring in Brazil, as sources of monoterpene indole alkaloids (MIAs). In addition, we aim to collect reported experimental demonstrations of their biological activity, which may provide the foundation for further studies, including phytochemistry, the development of medicinal agents, and validation of phytopreparations. MATERIAL AND METHODS: The Brazilian Flora 2020 database was used as source for Tabernamontana species occurring in Brazil. The literature review on these species was collected from Web of Science, Scopus, PubMed, and Scifinder. The keywords included names and synonyms of Tabernaemontana species found in Brazil, which were validated by the Word Flora Online Plant List. RESULTS: A literature survey covering the time frame from 1960 until June 2023 resulted in 121 MIAs, including 48 not yet reported in the last review published in 2016. Some alkaloid extracts, fractions, and isolated alkaloids present evidenced biological activity, such as anticancer, anti-inflammatory, antinociceptive, antimicrobial, antiparasitic, antiviral, and against snake venoms, among others. Notably, ethnopharmacological based information has been the basis of some reports on Tabernaemontana species. CONCLUSIONS: Our literature survey shows that Tabernaemontana species present bioactive MIAs, such as voacamine and affinisine, demonstrating significant cytotoxicity activity against several tumoral cell lines. Those compounds can be considered promising candidates in the search for new anticancer drugs. However, the Amazonian plant biome is increasingly damaged, which may lead to the extinction of biological diversity. This threat may also affect Tabernaemontana species, which have scarcely been investigated regarding the potential of their phytochemicals for the development of new drugs.

Novel anti-inflammatory diketopiperazine alkaloids from the marine-derived fungus Penicillium brasilianum.

Diketopiperazine alkaloids have proven the most abundant heterocyclic alkaloids up to now, which usually process diverse scaffolds and rich biological activities. In our search for bioactive diketopiperazine alkaloids from marine-derived fungi, two novel diketopiperazine alkaloids, penipiperazine A (1) and its biogenetically related new metabolite (2), together with a known analogue neofipiperzine C (3), were obtained from the strain Penicillium brasilianum. Their planar structures and absolute configurations were elucidated by extensive spectroscopic analyses, 13C NMR calculation, Marfey's, ECD, and ORD methods. Compound 1 featured a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system, and its plausible biogenetic pathway was also proposed. Additionally, compounds 1-3 have been tested for their inflammatory activities. 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells, suggesting they could be attracting candidate for further development as anti-inflammatory agent. KEY POINTS: • A novel diketopiperazine alkaloid featuring a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system was isolated from the marine fungus Penicillium brasilianum. • The structure of 1 was elucidated by detailed analysis of 2D NMR data, 13C NMR calculation, Marfey's, ECD, and ORD methods. • Compounds 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells.

STK214947, a novel indole alkaloids, inhibits HeLa and SK-HEP-1 cells survival and EMT process by blocking the Notch3 and Akt signals.

Apoptosis and epithelial-to-mesenchymal transition (EMT) are closely associated with tumor survival and metastasis. These are the basic events in tumor occurrence and progression. STK214947 is an indole alkaloid with a skeleton that is similar to that of indirubin. Indole alkaloids have attracted considerable attention because of their antitumor activity. However, the relationship between STK214947 and these basic events remains unknown. In this study, the effects of STK214947 on inducing apoptosis and reversing the EMT process in tumor cells were confirmed. Mild concentrations of STK214947 inhibited tumor cell migration by reversing EMT and significantly regulated the expression of EMT-related proteins, including Notch3, E-cadherin, N-cadherin and vimentin. In addition, STK214947 in high concentration could induce apoptosis by down-regulating Notch3, p-Akt/Akt, and NF-κB, and upregulating Caspase 3. These findings support the further development of STK214947 as a potential antitumor small molecule that targets Notch3 and Akt signal transduction in cancer.

Quinoline, Indole, and Isogranatanine Alkaloids from Malayan Leuconotis eugeniifolia.

Nine new alkaloids, eugeniinalines A-H (1-8) and (+)-eburnamenine N-oxide (9), comprising one quinoline, six indole, and two isogranatanine alkaloids, were isolated from the stem-bark extract of the Malayan Leuconotis eugeniifolia. The structures and absolute configurations of these alkaloids were established based on the analysis of the spectroscopic data, GIAO NMR calculations, DP4+ probability analysis, TDDFT-ECD method, and X-ray diffraction analysis. Eugeniinaline A (1) represents a new pentacyclic quinoline alkaloid with a 6/6/5/6/7 ring system. Eugeniinaline G (7) and its seco-derivative, eugeniinaline H (8), were the first isogranatanine alkaloids isolated as natural products. The known alkaloids leucolusine (10) and melokhanine A (11) were found to be the same compound, based on comparison of the spectroscopic data of both compounds, with the absolute configuration of (7R, 20R, 21S). Eugeniinalines A and G (1 and 7) showed cytotoxic activity against the HT-29 cancer cell line with IC50 values of 7.1 and 7.2 µM, respectively.

Two new indole alkaloids from Nauclea officinalis and their evaluation for cytotoxic activities.

Two new indole alkaloids, naucleamide H (1) and (±)-19-O-butylangustoline (8), along with seven known alkaloids, 3,14-dihydroangustine (2), (-)-naucleofficine D (3a), (+)-naucleofficine D (3b), nauclefine (4), angustidine (5),19-O-ethylangustoline (6) and angustine (7) were isolated from the water extract of Nauclea officinalis. The structures of these compounds were established by spectroscopic analysis. Among them, the cytotoxicity of 1, 2, 6 and 8 were evaluated against six human cancer cell lines (HepG-2, SKOV3, HeLa, SGC 7901, MCF-7 and KB) in vitro for the first time with 5-fluorouracil as a positive control drug. The new compound 1 had a strong inhibitory effect on the proliferation of HepG-2 with an IC50 value of 19.59 µg/mL. The new compound 8 had a strong inhibitory effect on HepG-2, SKOV3, HeLa, MCF-7 and KB, IC50 value was 5.530, 23.11, 31.30, 32.42 and 37.26 µg/mL, respectively.

Isovincathicine from Catharanthus roseus induces apoptosis in A549 cells.

A dimeric indole alkaloid, isovincathicine consisting of an aspidosperma type and modified iboga with C-7-C-20 connection type skeletons was first isolated from Catharanthus roseus, and the structure including stereochemistry was elucidated on the basis of spectroscopic data as well as DP4 statistical analysis. Isovincathicine inhibited cell proliferation in A549 cells. We investigated the detailed mode of action of isovincathicine-induced inhibitory effects on cell proliferation in A549 cells. Flow cytometric analysis showed that isovincathicine-treated cells accumulated in the G2 phase after 24 h, and the percentage of cells showing cell death increased after 48 h. Western blotting also showed increased expression of BimEL, an apoptosis-related protein, and decreased expression of Mcl-1 and Bcl-xL. Isovincathicine was suggested to induce apoptosis in A549 cells by a mechanism is similar to that of vinblastine.

New Monoterpenoid Indole Hybrids from Gelsemium elegans with Anti-Inflammatory and Osteoclast Inhibitory Activities.

Gelsegansymines A (1) and B (2), two new indole alkaloids along with six known analogues (3-8) were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques. Structurally, compounds 1 and 2 possessed the rare cage-like gelsedine skeleton hybrid with bicyclic monoterpenoid. The anti-inflammatory activities of isolated compounds (1-3) were tested on LPS induced RAW264.7 cells. Under the treated concentration without toxicity for cells, the cytokines levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were evaluated by Griess method and enzyme-linked immunosorbent assay (ELISA). The results showed that compounds 1-3 exhibited anti-inflammatory activities with dose-dependent manner range from 12.5 to 50 µmol/L. Furthermore, the inhibitory activities of compounds 1 and 2 on receptor activator of NF-κB ligand (RANKL) induced osteoclast formation were tested in vitro. Compounds 1 and 2 at 5 µmol/L exhibited the significant inhibitory effect on the osteoclastogenesis induced by RANKL. This work reported the anti-inflammatory and osteoclast inhibitory activities of new monoterpenoid indole hybrids, which may inspire the further light on the related traditional application research of G. elegans.

Alscholarines A and B, two rearranged monoterpene indole alkaloids from Alstonia scholaris.

Alscholarines A and B (1 and 2), two unprecedented rearranged monoterpene indole alkaloids, were isolated from Alstonia scholaris. Alscholarine A (1) features an imidazole ring fused with a rearranged vallesamine-type alkaloid possessing an unparalleled 6/5/6/6 tetracyclic skeleton through an unprecedented C7-C-19 connectivity. Alscholarine B (2), incorporating an unusual 7-oxa-1-azabicyclo[3.2.1]octane moiety, represents a unique rearranged vallesamine-type alkaloid with a 6/5/6/6/5 ring system via an unprecedented C-6-C-20 connectivity. Their structures were established by spectroscopic analysis, X-ray crystallography, and quantum-chemical calculations. Their plausible biosynthetic pathways were proposed. The vasorelaxant and anti-inflammatory activities of them were also evaluated. Compounds 1-3 showed moderate vasorelaxant activities.

A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues.

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure-activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.

Monoterpene indole alkaloids from the roots of Alstonia rupestris and their anti-inflammatory activity.

Four new monoterpene indole alkaloids (1-4) together with twelve known alkaloids (5-16) were isolated from the roots of Alstonia rupestris. Compound 1 was the first example of C2-symmetric heteroyohimbine-type indole alkaloid homodimer obtained from natural plant resource. Their structures were elucidated on the basis of spectroscopic data. The absolute configuration of 1 was determined by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra. All compounds were evaluated for their anti-inflammatory activities by measuring their NO inhibitory effects in LPS-stimulated RAW 264.7 cells. Compound 2 showed strong NO inhibition with IC50 value of 4.2 ± 1.3 µM. Moreover, compound 2 could decrease the expressions of cyclooxygenase-2 (COX-2) and transforming growth factor beta-1 (TGF-ß1).

Major Indole Alkaloids in Evodia Rutaecarpa: The Latest Insights and Review of Their Impact on Gastrointestinal Diseases.

Evodia rutaecarpa, the near-ripe fruit of Euodia rutaecarpa (Juss.) Benth, Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang, or Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang, is a famous herbal medicine with several biological activities and therapeutic values, which has been applied for abdominalgia, abdominal distension, vomiting, and diarrhea as a complementary and alternative therapy in clinic. Indole alkaloids, particularly evodiamine (EVO), rutaecarpine (RUT), and dedhydroevodiamine (DHE), are received rising attention as the major bioactivity compounds in Evodia rutaecarpa. Therefore, this review summarizes the physicochemical properties, pharmacological activities, pharmacokinetics, and therapeutic effects on gastrointestinal diseases of these three indole alkaloids with original literature collected by PubMed, Web of Science Core Collection, and CNKI up to June 2023. Despite sharing the same parent nucleus, EVO, RUT, and DHE have different structural and chemical properties, which result in different advantages of biological effects. In their wide range of pharmacological activities, the anti-migratory activity of RUT is less effective than that of EVO, and the neuroprotection of DHE is significant. Additionally, although DHE has a higher bioavailability, EVO and RUT display better permeabilities within blood-brain barrier. These three indole alkaloids can alleviate gastrointestinal inflammatory in particular, and EVO also has outstanding anti-cancer effect, although clinical trials are still required to further support their therapeutic potential.

Phytochemical Analysis and In Vitro Antileukemic Activity of Alkaloid-Enriched Extracts from Vinca sardoa (Stearn) Pignatti.

Vinca sardoa (Stearn) Pignatti, known as Sardinian periwinkle, is widely diffused in Sardinia (Italy). This species contains indole alkaloids, which are known to have a great variety of biological activities. This study investigated the antileukemic activity against a B lymphoblast cell line (SUP-B15) of V. sardoa alkaloid-rich extracts obtained from plants grown in Italy, in Iglesias (Sardinia) and Rome (Latium). All the extracts showed a good capacity to induce reductions in cell proliferation of up to 50% at the tested concentrations (1-15 µg/mL). Moreover, none of the extracts showed cytotoxicity on normal cells at all the studied concentrations.

Recent Developments of Gramine: Chemistry and Biological Activity.

The natural alkaloid gramine has attracted significant attention in both academic and industrial circles because of its potential and diverse biological activities, including antiviral, antibacterial, antifungal, anti-inflammatory and antitumor activities; application in therapy for Alzheimer's disease; serotonin-receptor-related activity; insecticidal activity; and application as an algicide. In this review, we focus on the research advances that have been made for gramine-based molecules since their discovery, providing key information on their extraction and separation, chemical synthesis and diverse biological activities. Data regarding their mechanisms of action are also presented. This comprehensive and critical review will serve as a guide for developing more drug candidates based on gramine skeletons.

Rutaecarpine ameliorates cardiomyocyte injury induced by high glucose by promoting TRPV1-mediated autophagy.

AIM: Diabetic cardiomyopathy (DCM) is a dominant factor contributing to diabetic death. Rutaecarpine has many cardiovascular biological effects and anti-high-glucose activity. Therefore, this paper aimed to investigate the impact of rutaecarpine on high glucose (HG)-elicited cardiomyocyte injury. METHOD: Cell counting kit 8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU), TdT-mediated dUTP Nick-End Labeling (TUNEL) assays judged H9c2 cell activity and apoptosis, and oxidative stress was assessed by corresponding assay kits. The expression of apoptosis, oxidative stress, autophagy-associated factors and TRPV1 were examined with western blot. IF assay tested GFP-LC3 expression. RESULTS: As a result, rutaecarpine had no obvious effect on the viability of H9c2 cells while elevated HG-exposed H9c2 cell viability. Rutaecarpine inhibited the apoptosis and oxidative stress of H9c2 cells induced by HG. In addition, rutaecarpine activated TRPV1 to induce autophagy. However, inhibition of TRPV1 inactivated the autophagy, which drove HG-evoked H9c2 apoptosis and oxidative stress. CONCLUSIONS: In conclusion, rutaecarpine suppressed HG-stimulated H9c2 cell viability injury, apoptosis as well as oxidative stress via promoting TRPV1-mediated autophagy (Fig. 10, Ref. 40).

Fumigaclavine C ameliorates liver steatosis by attenuating hepatic de novo lipogenesis via modulation of the RhoA/ROCK signaling pathway.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been well defined as a common chronic liver metabolism disorder. Statins as a first-line therapeutic treatment had some side effects. Here, we found that Fumigaclavine C (FC) was collected from endophytic Aspergillus terreus via the root of Rhizophora stylosa (Rhizophoraceae), had potential anti-adipogenic and hepatoprotective effects both in vitro and in vivo without obvious adverse side effects. However, the mechanisms of the prevention and management of FC for hepatic steatosis are incompletely delineated. METHODS: The pharmacodynamic effects of FC were measured in high-fat diet (HFD)-induced obese mice. Liver index and blood biochemical were examined. Histopathological examination in the liver was performed by hematoxylin & eosin or oil red O. The levels of serum TG, TC, LDL-c, HDL-c, FFA, T-bili, ALT, AST, creatinine, and creatine kinase were estimated via diagnostic assay kits. The levels of hepatic lipid metabolism-related genes were detected via qRT-PCR. The expression levels of hepatic de novo lipogenesis were quantitated with Western blot analysis.  RESULTS: FC-treatment markedly reduced hepatic lipid accumulation in HFD-induced obese mice. FC significantly attenuated the hepatic lipid metabolism and ameliorated liver injury without obvious adverse side effects. Moreover, FC also could dose-dependently modulate the expressions of lipid metabolism-related transcription genes. Mechanically, FC notably suppressed sterol response element binding protein-1c mediated de novo lipogenesis via interfering with the RhoA/ROCK signaling pathway by decreasing the levels of geranylgeranyl diphosphate and farnesyl diphosphate. CONCLUSIONS: These findings suggested that FC could improve hepatic steatosis through inhibiting de novo lipogenesis via modulating the RhoA/ROCK signaling pathway.