Paliurus spina-christi Mill fruit extracts improve glucose uptake and activate the insulin signaling pathways in HepG2 insulin-resistant cells.

BACKGROUND: Paliurus spina-christi Mill. (PSC) fruit is frequently used in the treatment of diabetes mellitus in Mediterranean regions. Here, we investigated the effects of various PSC fruit extracts (PSC-FEs) on glucose consumption and some key mediators of insulin signaling pathways in high glucose and high insulin-induced insulin-resistant HepG2 cells. METHODS: The effects of methanolic, chloroform and total extracts on cell proliferation were assessed by the MTT assay. The potential of non-toxic extracts on glucose utilization in insulin-resistant HepG2 cells was checked using a glucose oxidase assay. AKT and AMP-activated protein kinase (AMPK) pathway activation and mRNA expression levels of insulin receptor (INSR), glucose transporter 1 (GLUT1), and glucose transporters 4 (GLUT4) were determined by western blotting and real-time PCR, respectively. RESULTS: We found that high concentrations of methanolic and both low and high concentrations of total extracts were able to enhance glucose uptake in an insulin-resistant cell line model. Moreover, AKT and AMPK phosphorylation were significantly increased by the high strength of methanolic extract, while total extract raised AMPK activation at low and high concentrations. Also, GLUT 1, GLUT 4, and INSR were elevated by both methanolic and total extracts. CONCLUSIONS: Ultimately, our results shed new light on methanolic and total PSC-FEs as sources of potential anti-diabetic medications, restoring glucose consumption and uptake in insulin-resistant HepG2 cells. These could be at least in part due to re-activating AKT and AMPK signaling pathways and also increased expression of INSR, GLUT1, and GLUT4. Overall, active constituents present in methanolic and total extracts of PCS are appropriate anti-diabetic agents and explain the use of these PSC fruits in traditional medicine for the treatment of diabetes.

Pyranonaphthoquinones and Naphthoquinones from the Stem Bark of Ventilago harmandiana and Their Anti-HIV-1 Activity.

Seven previously undescribed compounds, including five pyranonaphthoquinones (ventilanones L-P) and two naphthoquinones (ventilanones Q and R), along with 15 known compounds were isolated from the stem bark of Ventilago harmandiana (Rhamnaceae). The structures were established by extensive analysis of their spectroscopic data. The absolute configuration of ventilanone L was established from single crystal X-ray crystallographic analysis using Cu Kα radiation and from its electronic circular dichroism data. Anti-HIV-1 activity using a syncytium inhibition assay and the cytotoxic activities of some isolated compounds were evaluated. Compounds 12, 13, 15, and 16 showed activity against syncytium formation with half maximal effective concentration (EC50) values ranging from 9.9 to 47 µM (selectivity index (SI) 2.4-4.5).

Characterisation of four new triterpenoid saponins with nitric oxide inhibitory activity from aerial parts of Gouania leptostachya.

Four new triterpenoid saponins (gouaniasides VII-IX [1-3] and joazeiroside C [4]) and one known triterpenoid (5) were isolated from the aerial parts of Gouania leptostachya DC. (Rhamnaceae). Their structures were elucidated via one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy, high-resolution electrospray ionisation-mass spectrometry, and analyses of hydrolytic cleavage results. The anti-inflammatory potential of compounds 1-3 was evaluated according to their ability to inhibit the production of nitric oxide (NO) by RAW 264.7 macrophages. All compounds at noncytotoxic concentrations significantly inhibited NO production by macrophages in a concentration-dependent manner.

New cyclopeptide alkaloid of Condalia buxifolia and the absolute stereochemistry of Condaline A.

During the course of a study of Condalia buxifolia (Rhamnaceae), one new cyclopeptide alkaloid condaline B (1), together with six known cyclopeptide alkaloids, condaline A (2), and the scutianines B (3), - D (4) and -E (5), frangulanine (6), and 3,4,28-tris-epi-scutianene N (7), were isolated from the rind bark of Condalia buxifolia. Their structures have been confirmed through spectroscopic analyses such as 1D and 2D NMR experiments. The absolute stereochemistry of condaline A (2), was elucidated by X-ray crystal structure determination of its HI salt. In addition, condaline B (1) was obtained synthetically through a structural transformation of condaline A. Meanwhile, the crude methanol extract, the basic ether fraction, and alkaloids 1-7 were tested against various strains of Gram-positive and Gram-negative bacteria and fungus, showing promising antimicrobial activity.

Four New Anthraquinones with Histone Deacetylase Inhibitory Activity from Ventilago denticulata Roots.

Chromatographic separation of the crude extracts from the roots of Ventilago denticulata led to the isolation of four new anthraquinones, ventilanones L-O (1-4), together with eight known anthraquinones (5-12). Their structures were elucidated by spectroscopic methods (UV, IR, 1H NMR, 13C NMR, and 2D NMR) and mass spectrometry (MS), as well as comparison of their spectroscopic data with those reported in the literature. HDACs inhibitory activity evaluation resulted that compound 2 exhibited moderate antiproliferative activity against HeLa and A549 cell lines but nontoxic to normal cell. Molecular docking indicated the phenolic functionality of 2 plays crucial interactions with class II HDAC4 enzyme.

Alkaloids from the stem barks of Scutia buxifolia Reissek (Rhamnaceae): Structures and antimicrobial evaluation.

A reinvestigation of the chemical constituents of the stem barks of Scutia buxifolia, a member of the Rhamnaceae, resulted, along with the known alkaloids scutianine C and scutianene L, in the isolation of three undescribed diastereoisomeric alkaloids - scutianine N, 27-epi-scutianine N and 3, 4, 7-tri-epi-scutianine N -, one undescribed non macrocyclic alkaloid - scutianine Q - and a neutral compound -scutianene M. Their structures were determined using extensive NMR techniques and HRMS. The absolute configurations of the stereogenic centers of the three diastereoisomeric alkaloids have been assigned by gas chromatography employing modified cyclodextrins as chiral stationary phases. Scutianine Q had its structure and stereochemistry defined by single crystal X-ray crystallographic analysis. All tested compounds showed good to moderate antibacterial activity (MICs between 1.56 and 100 µg mL-1) when evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria. Some stereochemistry-activity relationships have been identified for the antibacterial activity of diastereoisomeric alkaloids against the Gram-negative bacteria Enterobacter aerogenes. The alkaloid 27-epi-scutianine N was as active as the standard antibiotic chloramphenicol (MIC = 1.56 µg mL-1), while scutianine N and 3,4,27-tris-epi-Scutianine N were inactive (>100 µg mL-1).

Combined Water Extracts from Oxidation-Treated Leaves and Branches of Hovenia dulcis Has Anti-Hangover and Liver Protective Effects in Binge Alcohol Intake of Male Mice.

Hovenia dulcis, known as the oriental raisin tree, is used for food supplements and traditional medicine for the liver after alcohol-related symptoms. However, little information exists about the use of its leaves and branches. In this study, we established a method to use the leaves and branches to develop anti-hangover treatment and elucidated the underlying mechanisms. Oxidation-treated leaves (OL) exhibited high antioxidant content comparable to that of the peduncles and showed an anti-hangover effect in male mice. The branch extract (BE) was enriched in the flavonoid catechin, approximately five times more than OL extract. The mixture of OL and BE (OLB) was formulated in a 2:1 ratio with frozen-dried extract weight and was tested for anti-hangover effects and protective properties against binge alcohol-induced liver injury. OLB showed better anti-hangover effect than OL. In addition to this anti-hangover effect, OLB protected the liver from oxidative/nitrosative damage induced by binge alcohol intake.

Quality control of Semen Hoveniae by high-performance liquid chromatography coupled to Fourier transform-ion cyclotron resonance mass spectrometry.

A method based on high-performance liquid chromatography and Fourier transform-ion cyclotron resonance mass spectrometry was developed to control the quality of Semen Hoveniae. First, the chromatographic fingerprint was established in combination with the chemometrics methods such as similarity analysis, cluster analysis, principal component analysis, and orthogonal partial least squares discriminant analysis to discover the qualitative markers. Then, an high-performance liquid chromatography mass spectrometry method was developed to identify the chemical constituents in Semen Hoveniae. Moreover, the content of dihydromyricetin and dihydroquercetin in Semen Hoveniae were determined by high-performance liquid chromatography. As a result, nine common peaks were assigned in the fingerprints and the similarity of the 13 batch samples varied from 0.425 to 0.993, indicating an obviously different quality. Dihydromyricetin and dihydroquercetin were the main qualitative markers to differ the quality of Semen Hoveniae. Meanwhile, a total of 21 chemical compounds were characterized by high-performance liquid chromatography mass spectrometry and six of them were identified by comparing with information of reference standards. Finally, the content of dihydromyricetin and dihydroquercetin in 13 batch samples varied from 0.824  to 7.499 mg/g and from 0.05941  to 4.258 mg/g , respectively. In conclusion, the methods developed here will provide sufficient qualitative and quantitative information for the quality control of Semen Hoveniae.

Approaches to Cyclophane-Types of Cyclopeptide Alkaloids.

The cyclopeptide alkaloids are cyclic depsipeptides incorporating cyclophanes with polyamide units 13-, 14- and 15-membered macrocyclic systems. Although various pharmacological activities have been ascribed to cyclopeptide alkaloids from plants of the Rhamnacea family, these studies have been hampered by their low availability due to the lack of reasonable amounts distributed in nature. Therefore, novel and efficient synthetic approaches should be an important aim, which inspired us to examine how to diversely construct the unique structures of this type of natural products. In this account, several typical strategies are presented in terms of efficient, stereocontrolled and regioselective synthesis of cyclopeptide alkaloids.

Hovenia dulcis Thumberg: Phytochemistry, Pharmacology, Toxicology and Regulatory Framework for Its Use in the European Union.

Hovenia dulcis Thunberg is an herbal plant, belonging to the Rhamnaceae family, widespread in west Asia, USA, Australia and New Zealand, but still almost unknown in Western countries. H. dulcis has been described to possess several pharmacological properties, such as antidiabetic, anticancer, antioxidant, anti-inflammatory and hepatoprotective, especially in the hangover treatment, validating its use as an herbal remedy in the Chinese Traditional Medicine. These biological properties are related to a variety of secondary metabolites synthesized by the different plant parts. Root, bark and leaves are rich of dammarane-type triterpene saponins; dihydrokaempferol, quercetin, 3,3',5',5,7-pentahydroflavone and dihydromyricetin are flavonoids isolated from the seeds; fruits contain mainly dihydroflavonols, such as dihydromyricetin (or ampelopsin) and hovenodulinol, and flavonols such as myricetin and gallocatechin; alkaloids were found in root, barks (frangulanin) and seeds (perlolyrin), and organic acids (vanillic and ferulic) in hot water extract from seeds. Finally, peduncles have plenty of polysaccharides which justify the use as a food supplement. The aim of this work is to review the whole scientific production, with special focus on the last decade, in order to update phytochemistry, biological activities, nutritional properties, toxicological aspect and regulatory classification of H. dulcis extracts for its use in the European Union.

Hypoglycemic effect of low-sugar juice derived from Hovenia dulcis on type 1 diabetes mellitus rats.

BACKGROUND: Fruit juice is usually rich in monosaccharides and disaccharides. A reverse osmosis separation machine was used to remove monosaccharides and disaccharides from Hovenia dulcis fruit juice, leaving behind most of the bioactive substances in a low-sugar fruit juice (LSFJ), so as to provide a more effective treatment for diabetic patients. METHOD: This study was carried out with type 1 diabetes mellitus model induced with high dose of streptozotocin (60 mg kg-1 ), and oral administration of LSFJ for 4 weeks. RESULTS: LSFJ treatment led to significant gain in body weight and increased serum insulin level, insulin-like growth factor-1 level, blood urea nitrogen level, creatinine level, and hepatic glycogen level. Meanwhile, fasting blood glucose, fructosamine level, and glucose tolerance were also observably enhanced. Additional, LSFJ treatment significantly improved lipid metabolism, islet quality, and islet oxidative stress. The messenger RNA levels of glucose metabolism genes in the pancreas of diabetic rats decreased in the diabetes model group, whereas messenger RNA expression of these genes was significantly increased with LSFJ treatment. CONCLUSION: These findings indicate that LSFJ can improve symptoms associated with type 1 diabetes mellitus. The research also suggests new strategies for diabetes prevention and treatment. © 2021 Society of Chemical Industry.

Ethyl acetate extract of Tibetan medicine Rhamnella gilgitica ameliorated type II collagen-induced arthritis in rats via regulating JAK-STAT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhamnella gilgitica Mansf. et Melch. (སེང་ལྡེང་།, RG) is a traditional Tibetan medicinal plant that is currently grown throughout Tibet. According to the theory of Tibetan medicine, RG is efficient for removing rheumatism, reducing swelling, and relieving pain. Hence, it has been used for the treatment of rheumatoid arthritis (RA) in Tibet for many years. However, there are no previous reports on the anti-RA activities of ethyl acetate extract of RG (RGEA). AIM OF THE STUDY: This study aimed to explore the anti-RA effect and mechanism of RGEA on collagen-induced arthritis (CIA) in rats. MATERIALS AND METHODS: The CIA model was established in male Wister rats by intradermal injection of bovine type II collagen and Complete Freund's Adjuvant at the base of the tail and left sole, respectively. The rats were orally administered with RGEA (9.71, 19.43, or 38.85 mg/kg) for 23 days. The body weight, swelling volume, arthritis index score, thymus and spleen indices, and pathological changes were observed to evaluate the effect of RGEA on RA. Furthermore, the inflammatory cytokines in serum, such as interleukin1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), interleukin6 (IL-6), interleukin17 (IL-17), interferon-γ (INF-γ), interleukin4 (IL-4), and interleukin10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA) to explore the anti-inflammatory effects of RGEA. The terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was used to examine apoptosis. Finally, the protein and gene expression of B-cell lymphoma-2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase3, janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling1 (SOCS1), and 3 (SOCS3) in synovial tissue were detected using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: After the treatment with RGEA, the body weight of rats was restored, both the arthritis index and paw swelling were suppressed, and spleen and thymus indices were decreased. RGEA reduced the inflammatory cells and synovial hyperplasia in the synovial tissue of the knee joint, and suppressed bone erosion. Meanwhile, RGEA decreased the levels of IL-1ß, IL-6, IL-17, TNF-α, and INF-γ, while increased the levels of IL-4 and IL-10. TUNEL fluorescence apoptosis results confirmed that RGEA obviously promoted the apoptosis of synovial cells. Further studies showed that RGEA inhibited the proteins and mRNAs expression of JAK2 and STAT3 as well as increased the proteins and mRNAs expression of SOCS1 and SOCS3. In addition, RGEA upregulated the expression of Bax and Caspase3, and downregulated the expression of Bcl-2. CONCLUSION: The anti-RA effectof RGEA might be related to the promotion of apoptosis and inhibition of inflammation, which regulated the JAK-STAT pathway.

A new dammarane type triterpene glucoside from the aerial parts of Gouania longipetala (Rhamnaceae).

3-O-ß-D-glucopyranosyl gouanogenin A (1), a new naturally occurring dammarane class of triterpene glucoside, has been isolated from the aerial parts of Gouania longipetala along with six known secondary metabolites 2-7. Their structure was elucidated through spectroscopic data including 1 D- and 2 D-NMR. The compounds 1 and 6 showed significant antioxidant potential in DPPH radical scavenging assay. On the other hand, the compound 4 revealed potent inhibitory potential against the enzyme urease, while 1 and 3 were significantly active.

Phytochemical analysis and evaluation of antioxidant and antimycobacterial activity of Colletia paradoxa from Brazil.

Colletia paradoxa (Spreng.) Esc. (Rhamnaceae, Colletieae) is a medicinal plant, threatened with extinction in Brazil, presenting great morphological variability. Our objective is to investigate the phytochemical components, antioxidant capacity and antimycobacterial activity of different morphotypes of C. paradoxa in different environments. For this, the crude extract of the leaves and branches of the individuals sampled was used. The elimination capacity of the free radicals was determined by the DPPH method, the antimycobacterial activity by the broth microdilution method and the phenolic content by the spectrophotometric method using the Folin-Ciocalteu reagent and by HPLC. The extracts of C. paradoxa and its morphotypes showed significant amounts of phenolic compounds, including quercetin, quercitrin and rutin, besides considerable antioxidant and antimycobacterial activity No connection was detected between the phytochemical composition and different morphotypes of C. paradoxa.

Components characterisation of Berchemia lineata (L.) DC. by UPLC-QTOF-MS/MS and its metabolism with human liver microsomes.

Investigations were performed on the determination of the main components in Berchemia lineata (L.) DC. (BL) and its metabolism with human liver microsomes (HLM). A total of 35 compounds were detected in BL extracts and 25 of them including 6 naphthopyrones, 10 flavonoids, 2 phenolic acids, 2 phenols, 4 fatty acids and 1 quinone were unambiguously or tentatively identified by UPLC-QTOF-MS/MS. Among them, naphthopyrones were first identified in BL extracts and labelled in chromatography. In addition, the weak inhibitory effects of BL extracts (IC50＝149.25 µg/mL) and rubrofusarin-6-O-α-L-rhamnosyl-(1-6)-O-ß-D-glu-copyranside (the main component of BL extracts, M0; IC50＝82.14 µM) on CYP3A4 were also proved using testosterone as specific probe drug. The main metabolic pathway of M0 by HLM was hydroxylation in its aglycone, the metabolite was tentatively identified as 10-hydroxy-rubrofusarin-6-O-α-L-rhamnosyl-(1-6)-O-ß-D-glucopyranside. Components characterisation and the metabolism with HLM could help the further development and application of BL.

Assessment of Insecticidal Activity of Benzylisoquinoline Alkaloids from Chilean Rhamnaceae Plants against Fruit-Fly Drosophila melanogaster and the Lepidopteran Crop Pest Cydia pomonella.

The Chilean plants Discaria chacaye, Talguenea quinquenervia (Rhamnaceae), Peumus boldus (Monimiaceae), and Cryptocarya alba (Lauraceae) were evaluated against Codling moth: Cydia pomonella L. (Lepidoptera: Tortricidae) and fruit fly Drosophila melanogaster (Diptera: Drosophilidae), which is one of the most widespread and destructive primary pests of Prunus (plums, cherries, peaches, nectarines, apricots, almonds), pear, walnuts, and chestnuts, among other. Four benzylisoquinoline alkaloids (coclaurine, laurolitsine, boldine, and pukateine) were isolated from the above mentioned plant species and evaluated regarding their insecticidal activity against the codling moth and fruit fly. The results showed that these alkaloids possess acute and chronic insecticidal effects. The most relevant effect was observed at 10 µg/mL against D. melanogaster and at 50 µg/mL against C. pomonella, being the alteration of the feeding, deformations, failure in the displacement of the larvae in the feeding medium of D. melanogaster, and mortality visible effects. In addition, the docking results show that these type of alkaloids present a good interaction with octopamine and ecdysone receptor showing a possible action mechanism.

Laxative Activity of the Hot-Water Extract Mixture of Hovenia dulcis Thunb. and Phyllostachys pubescens Mazel in Chronic Constipation Model SD Rats.

This study examined the laxative effects of hot-water extracts of Hovenia dulcis Thunb. (HD), Phyllostachys pubescens Mazel (PM), and a 2:8 mixture of both (HP) in two chronic constipation models. For the loperamide-induced constipation model, animals were divided into an untreated group, negative control group (loperamide 4 mg/kg), positive control group (bisacodyl 4 mg/kg) group, and six treatment groups (HP 100 or 400, HD 50 or 100, and PM 100 or 400 mg/kg). For the lowfiber diet-induced constipation model, animals were divided into an untreated group (normal diet), negative control group (low-fiber diet), positive control group (Agio granule, 620 mg/kg), and the same treatment groups. Fecal number, weight, fecal water content, and intestinal transit ratio were higher in the groups treated with HP, HD, and PM than in the groups treated with loperamide or lowfiber diet. Thickness of colon mucosa and muscle layers were increased in the treated groups. Colon tension increased in the HP groups, and [Ca2+]i measurements using fura-2 as an indicator showed that HP inhibits ATP-mediated Ca2+ influx in IEC-18 cells. These results showed that the HP mixture has laxative activity by increased mucin secretion and inducing contractile activity and relaxation. It may be a useful therapeutic strategy for ameliorating in chronic constipation.

Fruit of Hovenia dulcis Thunb. Induces Nonshivering Thermogenesis through Mitochondrial Biogenesis and Activation by SIRT1 in High-Fat Diet-Fed Obese Mice and Primary Cultured Brown Adipocytes.

Brown adipocytes, which contain abundant mitochondria, use stored energy as fuel during a process named nonshivering thermogenesis. Thus, the pharmacological activation of thermogenesis in brown adipose tissue (BAT) has become a promising target for treating obesity. We investigated the effect of fruit of Hovenial dulcis Thunb. (FHD), a frequently used herbal treatment for liver diseases, on thermogenesis and its mechanism using primary cultured brown adipocytes and BAT of high-fat-diet (HFD)-induced obese mice. Thermogenesis-related factors including UCP1 and PGC1α increased with FHD treatment. FHD also increased mitochondrial biogenesis and activation factors such as nuclear respiratory factor (NRF)1 and oxidative phosphorylation (OXPHOS) complex. Furthermore, FHD increased the intercellular nicotinamide adenine dinucleotide (NAD+) level and sirtuin 1 (SIRT1) activity, which may be responsible for the activation of the thermogenic reaction. Overall, our results suggest that FHD can be a novel option for obesity treatment due to its thermogenic action through mitochondrial biogenesis and activation.

Three new bisflavonols from the seeds of Hovenia dulcis Thunb. and their anti-RSV activities.

Three novel bisflavonol derivatives, Hovenianins A-C, along with 12 known flavonoids were isolated and identified from the seeds of Hovenia dulcis Thunb. Their structures were established on the basis of spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and electronic circular dichroism experiments. Hovenianin A (1) was the first dimer of flavonol linked dihydroflavonol via the B rings at C-2' and C-2″'positions to be found in nature. While Hovenianins BC (2-3) were a pair of diastereoisomeric bis-dihydroflavonols firstly reported in the Hovenia genus. The in vitro antiviral activity against respiratory syncytium virus (RSV) were evaluated by cytopathic effect (CPE) reduction assay. As a result, compounds 4, 5, and 10 displayed better antiviral effect against RSV A2 strains.

Hepatoprotective effects of gamma-aminobutyric acid-enriched fermented Hovenia dulcis extract on ethanol-induced liver injury in mice.

BACKGROUND: Various extracts of Hovenia dulcis have been commonly used in Asia for cases of alcohol-related disorders. Fermentation is reported to enhance the level and biological activities of various bio-constituents of plant extracts. Therefore, this study was undertaken to evaluate the effects of fermented H. dulcis extract (FHDE) on ethanol-induced liver injury in mice. METHODS: FHDE was prepared using Bacillus subtilis and Lactobacillus plantarum. The effects of FHDE on ethanol-induced liver injury were evaluated in C57BL/6 N CrSlc mice. A mixed feed preparation containing the fermented extract with and without ethanol was given to mice for 29 days, according to its group. At the end of the experiment, blood and liver samples were collected from all mice in the group. Plasma biochemical analysis and histopathological investigation were performed to evaluate the impacts of treatment on the biomarkers of hepatic damage and inflammatory changes. Besides, the expression of genes that regulate the activities of enzymes associated with alcohol metabolism, antioxidant activity, and fatty acid oxidation was assessed using a quantitative real-time polymerase chain reaction. Moreover, the amino acid contents and the active ingredients of the extract were evaluated before and after fermentation. RESULTS: Fermentation resulted in a marked increase and decrease in the amount of Gamma-Amino-n-butyric acid (GABA) and glutamic acid, respectively. FHDE enhanced the body weight gain of mice compared to ethanol. Besides, plasma levels of triglyceride, low-density lipoprotein, the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly (P < 0.05) reduced in the FHDE-treated groups relative to the ethanol-treated control. FHDE upregulated the expression of genes associated with enzymes involved in alcohol dehydrogenation (Adh1 and Aldh2), antioxidant activity (SOD and CAT), and fatty acid oxidation (PPAR-α and PGC-1α). However, the expressions of Cytochrome peroxidase Cyp2E1 and genes related to lipogenesis (SREBP-1c, FAS, SCD-1, and ACC) were significantly (P < 0.05) downregulated following treatment with the FHDE. Histopathological investigation demonstrated a slight degree of inflammatory cell infiltration and occasional fatty changes in the FHDE-treated groups. CONCLUSION: The GABA-enriched fermented H. dulcis extract prevented ethanol-induced hepatic damage by enhancing the antioxidant defense system, fatty acid oxidation, and reducing lipogenesis.