Antinociceptive and anti-inflammatory activity of extracts and α-pyrones isolated from Cantinoa stricta.

This study evaluated the composition and the antinociceptive and anti-inflammatory activity of the crude extracts and two isolated compounds, anamarine (ANA) and 10-epi-olguine (eOL), obtained from the leaves of Cantinoa stricta (Lamiaceae). Crude ethanolic extract (EEt) and dichloromethane extract (DCM), selected based on NMR data, were submitted to pharmacological tests in male Swiss mice. The oral administration of EEt and DCM significantly reduced the second phase of formalin-induced nociception (60%), lipopolysaccharide (LPS)-induced mechanical hyperalgesia (90%), and carrageenan (Cg)-induced edema (25%). ANA and eOL, the major compounds in EEt and DCM extracts, administered orally or locally (in the paw), also reduced the LPS-induced mechanical hyperalgesia (Oral ID50 1.9 and 3.9 mg/kg; Local ID50 93.4 and 677.3 ng, respectively) without changing the thermal acute nociception or the motor performance of the animals. Local administration of ANA and eOL also reduced Cg-induced edema (40 and 23%, respectively). These isolated compounds did not change the mechanical hyperalgesia induced by tumor necrosis factor-α, interleukin-1ß, prostaglandin E2, dibutyryl cyclic AMP, or forskolin but reversed the hyperalgesia induced by dopamine, epinephrine, and phorbol 12-myristate 13-acetate. The hyperalgesia induced by epinephrine was reversed in male but not in female mice, in which this response is not dependent on protein kinase C (PKC). These results suggest that C. stricta extracts possess antinociceptive and anti-inflammatory activity which is related to the presence of ANA and eOL. Differently from the known analgesics, these substances seem to exert their action mainly interfering with the sympathetic component of pain, possibly with PKC.

Clinically Approved Ferric Maltol: A Potent Nanozyme with Added Effect for High-Efficient Catalytic Disinfection.

Nanozyme has been proven to be an attractive and promising candidate to alleviate the current pressing medical problems. However, the unknown clinical safety and limited function beyond the catalysis of the most reported nanozymes cannot promise an ideal therapeutic outcome in further clinical application. Herein, we find that ferric maltol (FM), a clinically approved iron supplement synthesized through a facile scalable method, exhibits excellent peroxidase-like activity than natural horseradish peroxidase-like (HRP) and commonly reported Fe-based nanozymes, and also shows high antibacterial performance for methicillin-resistant Staphylococcus aureus (MRSA) elimination (100%) and wound disinfection. In addition, with added effects inherited from contained maltol, FM can accelerate skin barrier recovery. Therefore, the exploration of FM as a safe and desired nanozyme provides a timely alternative to current antibiotic therapy against drug-resistant bacteria.

Hyperhenrones: Prenylated α-pyrones with anti-inflammatory activity from Hypericum henryi.

Fourteen previously undescribed α-pyrone derivatives (1-14) together with four known analogs (15-18) were isolated from a traditional Chinese medicinal plant Hypericum henryi. Compounds (+)/(-)-1, 2, and 3 share a rare 6/6/4/6/6 polycyclic skeleton. Compound 14 was the first example of a 7,7-dimethyl-pyran-4-one moiety. Their structures were elucidated using comprehensive spectroscopic analyses and electronic circular dichroism calculations. The anti-inflammatory activities of 1-18 were screened in lipopolysaccharide-induced RAW264.7 cells. Among them, compounds 14, (+)-18, and (-)-18 exhibited inhibitory effects against nitric oxide production in LPS-induced RAW264.7 cells. Additionally, compound 14 suppressed the expression of cyclooxygenase-2 and inducible nitric oxide synthase in LPS-induced RAW264.7 cells. Furthermore, preliminary mechanism studies indicated that compound 14 suppressed the phosphorylation and degradation of the inhibitor of NF-κB, and this led to the inhibition of NF-κB activation.

Identification of KU-55933 as an anti-atherosclerosis compound by using a hemodynamic-based high-throughput drug screening platform.

Several compounds have been used for atherosclerosis treatment, including clinical trials; however, no anti-atherosclerotic drugs based on hemodynamic force-mediated atherogenesis have been discovered. Our previous studies demonstrated that "small mothers against decapentaplegic homolog 1/5" (Smad1/5) is a convergent signaling molecule for chemical [e.g., bone morphogenetic proteins (BMPs)] and mechanical (e.g., disturbed flow) stimulations and hence may serve as a promising hemodynamic-based target for anti-atherosclerosis drug development. The goal of this study was to develop a high-throughput screening (HTS) platform to identify potential compounds that can inhibit disturbed flow- and BMP-induced Smad1/5 activation and atherosclerosis. Through HTS using a Smad1/5 downstream target inhibitor of DNA binding 1 (Id-1) as a luciferase reporter, we demonstrated that KU-55933 and Apicidin suppressed Id-1 expression in AD-293 cells. KU-55933 (10 µM), Apicidin (10 µM), and the combination of half doses of each [1/2(K + A)] inhibited disturbed flow- and BMP4-induced Smad1/5 activation in human vascular endothelial cells (ECs). KU-55933, Apicidin, and 1/2(K + A) treatments caused 50.6%, 47.4%, and 73.3% inhibitions of EC proliferation induced by disturbed flow, respectively, whereas EC inflammation was only suppressed by KU-55933 and 1/2(K + A), but not Apicidin alone. Administrations of KU-55933 and 1/2(K + A) to apolipoprotein E-deficient mice inhibited Smad1/5 activation in ECs in athero-susceptible regions, thereby suppressing endothelial proliferation and inflammation, with the attenuation of atherosclerotic lesions in these mice. A unique drug screening platform has been developed to demonstrate that KU-55933 and its combination with Apicidin are promising therapeutic compounds for atherosclerosis based on hemodynamic considerations.

Uncovering the key pharmacodynamic material basis and possible molecular mechanism of Xiaoke formulation improve insulin resistant through a comprehensive investigation.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoke formulation (XKF) has been utilized in clinical practice for decades in China as a treatment option for mild to moderate type 2 diabetes. However, there is still a need for systematic research to uncover the key pharmacodynamic material basis and mechanism of XKF. AIM OF THE STUDY: Aim of to investigate the distribution and metabolism of XKF in normal and insulin resistant (IR) mice were different, and elucidate its key pharmacodynamic material basis and mechanism of action. MATERIALS AND METHODS: Ultra performance liquid chromatography/time of flight mass spectrometry technology was employed to investigate the differences in XKF absorption, distribution, and metabolism between normal and IR mice across blood, liver, feces, and urine samples. Further, network pharmacology was used to predict target proteins and their associated signaling pathways. Then, molecular docking was utilized to validate the activity of key pharmacodynamic components and targets. Finally, IR HepG2 cells were used to detect the glucose consumption under the action of key pharmacodynamic material basis. In addition, the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and phospho-protein kinase B (p-AKT) was determined using western blotting. RESULTS: The study demonstrates significant distinctions in plasma and liver number and abundance of alkaloids, organic acids, flavonoids, iridoids and saponins between normal and IR mice when XKF was administered. Further analysis has shown that the representative components of XKF, including berberine, chlorogenic acid, calycosin, swertiamarin and astragaloside IV have significantly different metabolic pathways in plasma and liver. Prototypes and metabolites of these components were rarely detected in the urine and feces of mice. According to the network pharmacological analysis, these differential components are predicted to improve IR by targeting key factors such as SRC, JUN, HRAS, NOS3, FGF2, etc. Additionally, the signaling pathways involved in this process include PI3K-AKT pathway, GnRH signaling pathway, and T cell receptor signaling pathway. In addition, in vitro experiments indicate that berberine and its metabolites (berberine and demethyleneberine), chlorogenic acid and its metabolites (3-O-ferulic quinic acid and 5-O-ferulic quinic acid), calycosin and swertiamarin could improve IR in IR-HepG2 cells by elevating the expression of PI3K and AKT, leading to an increase in glucose consumption. CONCLUSION: The key pharmacodynamic material basis of XKF, such as berberine and its metabolites (berberrubine and demethyleneberberine), chlorogenic acid and its metabolites (3-O-feruloylquinic acid and 5-O-feruloylquinic acid), calycosin and swertiamarin influence the glucose metabolism disorder of IR-HepG2 cells by regulating the PI3K/AKT signalling pathway, leading to an improvement in IR.

Cytospotones A-D, four new polyketones from the endophytic fungus Cytospora sp. A879.

Three new α-pyrone derivatives cytospotones A-C (1-3) and a new cyclohexenone derivative cytospotone D (4) together with four known α-pyrones were isolated from the endophytic fungus Cytospora sp. A879 of Pogostemon cablin (Blanco) Benth. The structures of 1-4 were elucidated primarily by spectroscopic methods (1D, 2D NMR and HRESIMS), ECD spectra analyses, and ECD calculations. Furthermore, the four new compounds (1-4) were evaluated for their anti-inflammatory and α-glucosidase inhibitory activities. The results showed that compound 1 had moderate inhibitory effect on LPS-induced NO production in RAW 264.7 macrophages.

CRISPR/Cas9-based genome editing of 14 lipid metabolic genes reveals a sporopollenin metabolon ZmPKSB-ZmTKPR1-1/-2 required for pollen exine formation in maize.

Lipid biosynthesis and transport are essential for plant male reproduction. Compared with Arabidopsis and rice, relatively fewer maize lipid metabolic genic male-sterility (GMS) genes have been identified, and the sporopollenin metabolon in maize anther remains unknown. Here, we identified two maize GMS genes, ZmTKPR1-1 and ZmTKPR1-2, by CRISPR/Cas9 mutagenesis of 14 lipid metabolic genes with anther stage-specific expression patterns. Among them, tkpr1-1/-2 double mutants displayed complete male sterility with delayed tapetum degradation and abortive pollen. ZmTKPR1-1 and ZmTKPR1-2 encode tetraketide α-pyrone reductases and have catalytic activities in reducing tetraketide α-pyrone produced by ZmPKSB (polyketide synthase B). Several conserved catalytic sites (S128/130, Y164/166 and K168/170 in ZmTKPR1-1/-2) are essential for their enzymatic activities. Both ZmTKPR1-1 and ZmTKPR1-2 are directly activated by ZmMYB84, and their encoded proteins are localized in both the endoplasmic reticulum and nuclei. Based on protein structure prediction, molecular docking, site-directed mutagenesis and biochemical assays, the sporopollenin biosynthetic metabolon ZmPKSB-ZmTKPR1-1/-2 was identified to control pollen exine formation in maize anther. Although ZmTKPR1-1/-2 and ZmPKSB formed a protein complex, their mutants showed different, even opposite, defective phenotypes of anther cuticle and pollen exine. Our findings discover new maize GMS genes that can contribute to male-sterility line-assisted maize breeding and also provide new insights into the metabolon-regulated sporopollenin biosynthesis in maize anther.

OsTKPR1 proteins with a single amino acid substitution fail the synthesis of a specific sporopollenin precursor and cause abnormal exine and pollen development in rice.

Fatty acid derivatives are key components of rice pollen exine. The synthesis of aliphatic sporopollenin precursors are initiated in the plastids of the tapetal cells, followed by multiple-step reactions conducted in the endoplasmic reticulum (ER). However, the relative contribution of different precursors to the precise structure of sporopollenin remains largely elusive, let alone the underlying mechanism. Here, we report that two complete male sterile mutants ostkpr1-3 (Tetraketide α-pyrone reductase 1-3, with OsTKPR1P124S substitution) and ostkpr1-4 (with truncated OsTKPR1stop) are defective in pollen exine, Ubisch body and anther cuticle development where ostkpr1-4 display severer phenotypes. Remarkably, OsTKPR1 could produce reduced hydroxylated tetraketide α-pyrone and reduced tetraketide α-pyrone, whereas OsTKPR1P124S fails to produce the latter. Pairwise interaction assays show that mutated OsTKPR1P124S is able to integrate into a recently characterized metabolon, thus its altered catalytic activity is not due to dis-integrity of the metabolon. In short, we find that reduced tetraketide α-pyrone is a key sporopollenin precursor required for normal exine formation, and the conserved 124th proline of OsTKPR1 is essential for the reduction activity. Therefore, this study provided new insights into the sporopollenin precursor constitution critical for exine formation.

Inhibition of Aß aggregation by naphtho-γ-pyrone derivatives from a marine-derived fungus, Aspergillus sp. MPUC239.

Alzheimer's disease (AD) is an important human disease that mainly causes cognitive impairments. Growing evidence has shown that amyloid-ß (Aß) peptide plays a key role in AD pathogenesis in what is known as the Aß cascade hypothesis. This hypothesis suggests the importance of suppressing Aß aggregation and Aß production. The latter process is governed by ß-site APP Cleaving Enzyme1 (BACE1) and γ-secretase. We, therefore, focused on Aß aggregation inhibitory activity, initially assessing numerous extracts derived from our marine-derived fungus collections. One EtOAc extract derived from an Aspergillus sp. exhibited Aß aggregation inhibitory activity. Eleven known compounds (1-11) were isolated from CHCl3 and EtOAc extracts derived from the fungus, and the structures were identified based on MS, NMR, and ECD spectra. Compounds 2, 6, and 10 inhibited Aß aggregation with IC50 values of 2.8, 3.9, and 8.1 µM, respectively. The protective effect on SH-SY5Y cells against Aß toxicity was also evaluated, and compounds 6 and 10 significantly alleviated Aß toxicity. BACE1 inhibitory activity was also examined, and compounds 4, 5, 7, 10, and 11 inhibited BACE1 activity with IC50 values of 14.9, 70.0, 36.5, 28.0, and 72.8 µM, respectively. These data suggest that compound 10 could be useful in AD treatment.

In vitro DPPH Radical Scavenging Activity of α-Pyrones from Odontonema strictum (Acanthaceae).

An ethyl acetate leaf extract from Odontonema strictum has been reported to have potent antihypertensive activity by inhibiting coronary artery contractions in porcine heart. However, the phytochemistry of the active fraction was unknown. Here we report, for the first time, the isolation and characterization of four known α-pyrones from the active fraction. The antioxidant activity of umuravumbolide (IC50 = 55.7±0.027 µg/mL), deacetylumuravumbolide (IC50 = 0.24±0.0002 µg/mL), dideacetylboronolide (IC50 = 149±0 µg/mL) and deacetylboronolide (IC50 = 24±0 µg/mL) was evaluated in vitro against 2,2-diphenyl-1-picrylhydrazyl radicals. Ascorbic acid was used as a positive control (IC50 = 1.73×10-3±0.3 µg/mL). The presence of 6-substituted 5,6-dihydro-α-pyrones and phenylpropanoid glucosides in the active fraction was suggested to be responsible for the antihypertensive activity. This is the first time that the antioxidant potential of these phytochemicals has been evaluated, and the results indicate that O. strictum has potential as an herbal medicine. Thus, further chemotaxonomic studies among the genera Odontonema and Tetradenia, a known source of α-pyrones, are recommended.

Five new verrucosidin derivatives from Penicillium polonicum, a deep-sea cold-seep sediment isolated fungus.

Five new verrucosidin derivatives, poloncosidins G-K (1-5), were isolated from the deep sea cold-seep sediment-derived fungus Penicillium polonicum CS-252. Their planar structures were elucidated by discreet analysis of the NMR spectroscopic and HRESIMS spectrometric data. The absolute configurations of compounds 1-5 were deduced from the combination of the modified Mosher's method and quantum chemical calculations of their ECD and NMR (with DP4+ probability analysis) data. The antimicrobial activities against several human- and aquatic-pathogenic bacteria of all the isolated compounds were evaluated and the structure-bioactivity relationship was briefly discussed.

Cytospones E-J from the endophytic fungus Cytospora rhizophorae.

Cytospones E-J (1-6), six unreported α-pyrone derivatives, together with six known ones (7-12) were isolated from the solid culture of the endophytic fungus Cytospora rhizophorae A761, an endophytic fungus from Gynochthodes officinalis. The structures of the unreported compounds were unambiguously elucidated through spectroscopic analyses (1D, 2D NMR and HRESIMS), and their absolute configurations were assigned by single-crystal X-ray diffraction (Cu Kα) analyses. Furthermore, cytospones E-J were evaluated for anti-inflammatory and α-glucosidase inhibitory activities.

New Aclyphloroglucinols and geranyl-α-pyrones from Hypericum hengshanense.

Hypericum hengshanense is a previously uninvestigated endemic plant species of China. Three new aclyphloroglucinols, hengshanols A-C (1-3), and two new geranyl-α-pyrones, hengshanpyol D and E (4 and 5), together with three known compounds were isolated from the aerial parts of H. hengshanense. The structure of these compounds were elucidated by NMR, MS, optical rotation, and ECD data. All compounds were isolated from H. hengshanense for the first time. Among them, compounds 2-4 may have anti-laryngeal cancer activity. Compounds isolated were tested for glucose uptake in L6 cells, and compound 4 showed the most potent glucose uptake with 1.62-fold enhancement.

Biopharmaceutical evaluation of kavain in Piper methysticum G. Forst dried extract: Equilibrium solubility and intestinal permeability in Caco-2 cell model.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper methysticum G. Forst, popularly known as kava, is a traditional medicinal plant native from South Pacific islands and widely used to treat anxiety, depression and stress. The psychoactive properties are related to the kavalactones, mainly kavain. AIM OF THE STUDY: To evaluate the biopharmaceutical properties of synthetic kavain and when present in kava dried extracts by means of equilibrium solubility and intestinal permeability studies in the Caco-2 cell model. MATERIALS AND METHODS: The equilibrium solubility of kavain was performed using a shake flask incubator at 37 °C in different media at physiological pH range (1.2-6.8). The intestinal permeability of kavain evaluated in Caco-2 cells in the presence and absence of the P-glycoprotein inhibitor verapamil. Kavain concentrations were determined by reversed phase high performance liquid chromatography (HPLC). RESULTS: HPLC methods were developed and fully validated for kavain quantitation. Kavain demonstrated low solubility and the pH of the aqueous media did not affect its solubility. Kavain was found to be highly permeable and efflux of kavain mediated by P-glycoprotein was not significant during intestinal permeation. CONCLUSION: The results of biopharmaceutical studies provided useful information for predicting availability of kavain from the gastrointestinal tract and this compound was ranked as BCS Class II, exhibiting dissolution rate-limited absorption.

Protective effect of kavain in meristematic cells of Allium cepa L.

Kavain is one of the main kavalactones of Piper methysticum (Piperaceae) with anxiolytic, analgesic, and antioxidant activities. Therefore, the aim of the study was to evaluate the cytotoxic, mutagenic, and antimutagenic potential of kavain in Allium cepa cells. Roots of A. cepa were transferred to the negative (2% acetone) and positive (10 µg/mL of Methylmethanesulfonate, MMS) controls and to the concentrations of kavain (32, 64 and 128 µg/mL) for 48 h. A total of 5,000 meristematic cells were analyzed under an optical microscope to determine the mitotic index, mean number of chromosomal alterations and percentage of damage reduction. Data were analyzed by Kruskal-Wallis test (p <0.05). All concentrations of kavain were not cytotoxic and did not show significant chromosomal changes when compared to 2% acetone. Kavain showed a cytoprotective effect in the pre (128 µg/mL) and in the post-treatment (32 and 64 µg/mL) and reduced damage against the mutagenic action of MMS in all concentrations of the pre and simultaneous and at the highest of post (128 µg/mL). Kavain promoted a significant reduction in micronuclei, nuclear buds and chromosomal losses in relation to MMS. The observed data indicate the importance of kavain for the inhibition of damage and chemoprevention.

Activated Carbon-Based Immunochromatographic Strip Test for the Rapid Qualitative Analysis of Swertiamarin and Sweroside.

BACKGROUND: Swertia japonica (S. japonica) is a medicinal plant that belongs to the Gentianaceae family. Several reports confirm the biological effects of the S. japonica extract. This plant is used mainly as a digestive stimulant, appetite stimulant, and gastrointestinal disease remedy in Japan. Secoiridoid glycosides are a group of compounds related to the beneficial effects of this plant. OBJECTIVE: We developed an immunochromatographic strip test for major secoiridoid glycosides, such as swertiamarin (SM) and sweroside (SS) detection. METHODS: We fabricated an immunoprobe using activated carbon as a reporter molecule and a monoclonal antibody against SM and SS (MAb D2) as a detection molecule. The test and control zones of the strip test contained SM-cBSA and Goat pAb anti-mouse IgM HRP conjugate, respectively. The immunoprobe reacted competitively with free SM and/or SS and immobilized SM-cBSA. The results were read and interpreted by the black spot intensity in the test zone. RESULTS: We succeeded in developing a strip test system with a detection limit (LOD) of 12.5 µg/mL. The selectivity and reliability evaluation revealed that the strip test is suitable for detecting SM and SS in S. japonica. The result was ready to be read in 30 min. CONCLUSIONS: This method can be a useful tool for the screening of biologically active S. japonica samples for further preparation of traditional medicine. HIGHLIGHTS: To the best of our knowledge, this is the first immunochromatographic strip test developed for the detection of SM and SS in S. japonica samples.

Optimal Liquid Inoculum Conditions and Grain Medium Enhanced Hispidin Production by Species of Genus Phellinus (Agaricomycetes) in Solid-State Fermentation.

This study aimed 1) to screen a high hispidin production strain from 12 strains of genus Phellinus and 2) to evaluate the effects of liquid inoculum conditions and grain medium on this strain's hispidin production levels after solid-state fermentation. The results showed that Ph. linteus 04 led to the highest hispidin production; this strain was then selected to elucidate the optimal liquid inoculum conditions and grain medium for hispidin production. Various liquid inoculum conditions were evaluated, and the highest hispidin yield, specific productivity of hispidin, and total content of hispidin were found to be optimal at 1 week of liquid inoculum culture time, cultured with potato dextrose broth, and using a 10% inoculum rate, with each condition resulting in 0.350, 0.325, and 0.328 mg/g dry weight of mycelium, 0.352, 0.251, and 0.249 µg/mg of specific productivity per week, and 57.90, 60.23, and 61.77 mg/kg dry weight of brown rice medium, respectively. These liquid inoculum conditions were then used to determine the appropriate grain medium for hispidin production. The highest hispidin yield and total content of hispidin were observed in pearl barley (1.107 mg/g dry weight of mycelium and 199.76 mg/kg dry weight of pearl barley), which led to results that were 4.73-fold and 5.35-fold higher than those of the control (brown rice medium). Overall, this study shows that Ph. linteus hispidin production can be enhanced by solid-state fermentation using optimal liquid inoculum conditions and the appropriate grain medium.

Swertiamarin, an active iridoid glycoside from Swertia pseudochinensis H. Hara, protects against alpha-naphthylisothiocyanate-induced cholestasis by activating the farnesoid X receptor and bile acid excretion pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Swertiamarin (SW), which belongs to iridoid glycosides, is one of the main components of Swertia plants in Gentianaceae family, including Swertia pseudochinensis H. Hara and Swertia mileensis T. N. Ho et W. L. Shi. There are mainly used in traditional Chinese medicine for the treatment of hepatic and biliary disease such as jaundice. AIM OF THIS STUDY: This experiment aimed to explore the protective mechanism of SW on cholestasis induced by alpha-naphthylisothiocyanate in rats. MATERIALS AND METHODS: Healthy rats were randomly divided into the control, model (ANIT, 50 mg/kg), ursodeoxycholic acid (UDCA, 80 mg/kg), and low-dose (SW, 80 mg/kg), medium-dose (SW, 100 mg/kg), and high-dose (SW, 150 mg/kg) groups. The hepatic protective effect of SW was preliminarily evaluated by measurement of serum biochemical indicators and liver morphological evaluation. Moreover, metabolomics and proteomics analysis were used to explore the protective mechanism of SW on cholestasis. The expression of related proteins was determined by Western blot and polymerase chain reaction, and the important proteins were verified by cell experiments in vitro. RESULTS: SW (100 mg/kg) can reduce the serum levels of the model group. The hepatocyte of the medium-dose treatment group was arranged neatly without evident inflammation. SW can partially reverse the changes in cholestasis metabolites, such as taurocholic acid, SM (d18:1/16:0), all-trans-retinoic acid and other products of rats. The main metabolic pathways affected were primary bile acid synthesis, glycerophospholipid metabolism, sphingolipid metabolism and retinol metabolism. SW medium-dose treatment group showed effective reversal of 25 related proteins and it can remarkably reduce the contents of NTCP and CYP27A1 in rat liver and increase the protein expressions of CYP7A1, CYP8B1, bile salt export pump, multidrug resistance-associated protein and FXR. CONCLUSIONS: SW can alleviate ANIT-induced cholestasis, which by activating the farnesoid X receptor and bile acid excretion pathway.

Sodium dehydroacetate confers broad antibiotic tolerance by remodeling bacterial metabolism.

Antibiotic tolerance has been a growing crisis that is seriously threatening global public health. However, little is known about the exogenous factors capable of triggering the development of antibiotic tolerance, particularly in vivo. Here we uncovered that an previously approved food additive termed sodium dehydroacetate (DHA-S) supplementation remarkably impaired the activity of bactericidal antibiotics against various bacterial pathogens. Mechanistic studies indicated that DHA-S induced glyoxylate shunt and reduced bacterial cellular respiration by inhibiting the enzymatic activity of α-ketoglutarate dehydrogenase (α-KGDH). Furthermore, DHA-S mitigated oxidative stress imposed by bactericidal antibiotics and enhanced the function of multidrug efflux pumps. These actions worked together to induce bacterial tolerance to antibiotic killing. Interestingly, the addition of five exogenous amino acids, particularly cysteine and proline, effectively reversed antibiotic tolerance elicited by DHA-S both in vitro and in mouse models of infection. Taken together, these findings advance our understanding of the potential risks of DHA-S in the treatment of bacterial infections, and shed new insights into the relationships between antibiotic tolerance and bacterial metabolism.

Maltol mitigates cisplatin-evoked cardiotoxicity via inhibiting the PI3K/Akt signaling pathway in rodents in vivo and in vitro.

Our current research aims to evaluate the efficiency of a flavor enhancer, maltol (produced by heating ginseng) against cisplatin-evoked cardiotoxicity by establishing cisplatin-induced heart injury in vivo and H9C2 rat cardiomyocyte model. The cisplatin-treated mice at 3 mg/kg for four times on the 7th, 9th, 11th and 13th day, and in them appeared a serious cardiac damage accompanied with the increase in indicators of heart damage. Multiple exposure of 3 mg/kg for four times of cisplatin increased cardiac cells apoptosis with increased expression of Bax and cleaved-caspase 3, and decreased expression of Bcl-2. Interestingly, supplement of maltol at doses of 50 and 100 mg/kg for 15 days significantly suppressed the cardiac disturbance. In cultured H9C2 cells, maltol enhanced PI3K/Akt expression level during cisplatin treatment, and reduced cisplatin-induced apoptosis. Notably, inhibition of PI3K/Akt by LY294002 and HY-10249A lessened the efficacy of maltol. In mice, maltol apparently induced PI3K/Akt in heart tissues and protected against cisplatin-induced cardiotoxicity. In conclusion, maltol exerted the protective effects against cisplatin-induced cardiotoxicity, at least partially by inhibiting the activation of PI3K/Akt signaling pathways in cardiomyocytes, to ease oxidative stress, and alleviate reactive oxygen species-mediated apoptosis.