Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow.

Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.

Two new guaiane-type sesquiterpenes from Curcuma wenyujin.

Two new guaiane-type sesquiterpenes, wenyujinolides A (1) and B (2), were isolated from the ethanol extract of Curcuma wenyujin, together with 10 known compounds. Their structures were established by extensive spectroscopic methods (IR, ESIMS, HRESIMS, ECD, 1D and 2D NMR) and comparison of their NMR data with literatures. Compounds 1 and 2 were evaluated for the inhibition of NO production in LPS induced RAW 264.7 macrophages.

Sesquiterpenoids from Alpinia oxyphylla with GLP-1 Stimulative Effects through Ca2+/CaMKII and PKA Pathways and Multiple-Enzyme Inhibition.

Six new sesquiterpenoids (1-6), a pair of enantiomers (7a and 7b), and six known ones (8-13) were isolated from the fruits of Alpinia oxyphylla. The structures of the new compounds were elucidated by extensive spectroscopic data and ECD calculations. The stereochemistry of 7a and 7b was reported for the first time. All compounds showed significant GLP-1 stimulation in NCI-H716 cells with promoting ratios ranging from 90.4 to 668.9% at 50 µM. Mechanism study indicated that compound 6 stimulated GLP-1 secretion mainly by regulating the transcription and the shearing process of proglucagon, while compound 13 exerted its effects through up-regulating prkaca levels. Interestingly, the GLP-1 stimulative effects of 6 and 13 were both closely related with Ca2+/CaMKII and PKA pathways but irrelevant to TGR5 and GPR119 receptors. Moreover, most compounds exhibited inhibitory activity against α-glucosidase and PTP1B at concentrations of 100 and 200 µM, while showing no activity against GPa. Compounds 3, 9, 11, and 13 could suppress α-glucosidase with IC50 values of 190.0, 204.0, 181.8, and 159.6 µM, equivalent to acarbose (IC50 = 212.0 µM). This study manifests that A. oxyphylla contains diverse sesquiterpenoids with multiple activities.

Artemiprinolides A-M, thirteen undescribed sesquiterpenoid dimers from Artemisia princeps and their antihepatoma activity.

Bioassay-guided investigation of the active fraction of Artemisia princeps led to 13 undescribed sesquiterpenoid dimers, artemiprinolides A-M (1-13), together with 11 known ones (14-24). Their structures were elucidated by comprehensive spectroscopic data and absolute configurations were assigned based on single crystal X-ray diffraction data and ECD calculations. Structurally, all compounds were postulated to be derived from the Diels-Alder cycloaddition. The isolated dimers except 11 and 15 were assayed for their cytotoxicity against HepG2, Huh7, and SK-Hep-1 cell lines, of which four compounds (3, 13, 17, 18) exhibited obvious cytotoxicity with IC50 values ranging from 8.8 to 20.1 µM. Interestingly, the most active compounds 1 and 16 manifested significant cytotoxicity on the three tested hepatoma cell lines with IC50 values of 5.4, 4.1 (HepG2), 7.7, 5.6 (Huh7), and 11.8, 15.7 µM (SK-Hep-1), respectively, which were better than sorafenib. Compound 1 dose-dependently inhibited cell migration and invasion, and significantly induced the HepG2 cell arrest in G2/M phase by downregulating cdc2 and pcdc2 and upregulating cyclinB1; and induced apoptosis by downregulating Bcl-2 expression and upregulating Bax level. The molecular docking study implied that the carbonyl at the C-12' of 1 had a strong binding affinity with PRKACA.

Rubiginosin B selectively inhibits Treg cell differentiation and enhances anti-tumor immune responses by targeting calcineurin-NFAT signaling pathway.

BACKGROUND: The accumulation of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment (TME) dampens anti-tumor immune responses and promotes tumor progression. Therefore, the elimination of Tregs has become a strategy to enhance the efficacy of tumor immunotherapy, although it is still a daunting challenge. Rhododendron brachypodum (R. brachypodum) is a perennial shrub mainly distributed in Southwestern China, whereas the chemical constituents in this plant remain elusive. PURPOSE: To identify small-molecule inhibitors of Tregs from R. brachypodum. METHODS: Meroterpenoids in R. brachypodum were isolated by column chromatography under the guidance of LCMS analyses. The structures of isolates were identified by spectroscopic data and quantum calculations. The activities of compounds were first evaluated on CD4+ T cell differentiation by flow cytometry in Th1, Th2, Th17, and Treg polarizing conditions, and then on CT26 and MC38 murine colorectal carcinoma cells-allografted mice models. The mechanism of action was first investigated by determining Foxp3 degradation in Jurkat T cells transfected with pLVX-TetOne-Puro-Foxp3-tGFP, and then through analyses of Foxp3 expression on several pre-transcriptional signaling molecules. RESULTS: Two new prenylated phenolic acids (1 and 2) and a chromane meroterpenoid, rubiginosin B (RGB, 3) were obtained from R. brachypodum. The structure of S-anthopogochromene C (1) was rectified according to the electronic circular dichroism (ECD) experiment, and rhodobrachypodic acid (2) was proposed as the precursor of RGB by photochemical transformation. In this investigation, we first found that RGB (3) selectively suppressed the de novo differentiation of TGFß-induced CD4+Foxp3+ regulatory T cells (iTregs), overcome the immunosuppressive TME, and consequently inhibited the growth of tumor in mouse models. The mechanistic study revealed that RGB could target calcineurin, inhibited the nuclear factor of activated T cells (NFAT) dephosphorylation, and down-regulated Foxp3 expression. The hypothetical binding modes of RGB with calcineurin were predicted by molecular docking, and the interactions were mainly hydrophobic effects and hydrogen bonds. CONCLUSION: These results suggest that RGB enhances anti-tumor immune responses by inhibiting Treg cell differentiation through calcineurin-NFAT signaling pathway, and therefore RGB or its analogs may be used as adjuvant agents meriting further investigation.

Diarylheptanoids with hypoglycemic potency from the rhizomes of Kaempferia galanga.

Five new diarylheptanoids, kaemgalangins A-E (1-5), and seven known ones were isolated from the rhizomes of Kaempferia galanga. The structures of new compounds were identified by spectroscopic analyses involving 1D and 2D NMR, HRESIMS, IR, UV, [α]D, ECD calculations, and chemical methods. All compounds were tested for their hypoglycemic effects against α-glucosidase, Gpa and PTP1B enzymes, and stimulative effects on GLP-1 secretion. Kaemgalangins A (1) and E (5) showed significant inhibition on α-glucosidase with IC50 values of 45.3 and 116.0 µM; renealtin B (8) showed inhibition on GPa with an IC50 value of 68.1 µM; whereas all compounds were inactive to PTP1B. Docking study manifested that 1 well located in the catalytic pocket of α-glucosidase and OH-4″ played important roles in maintaining activity. Moreover, all compounds showed obviously stimulative effects on GLP-1 with promoting rates of 826.9%-1738.3% in NCI-H716 cells. This study suggests that the diarylheptanoids in K. galanga have antidiabetic potency by inhibiting α-glucosidase and Gpa enzymes, and promoting GLP-1 secretion.

[Terpenoids from fruits of Amomum villosum and their hypoglycemic activity].

Eight terpenoids were isolated from the fruits of Amomum villosum by silica gel, Sephadex LH-20, Rp-C_(18), MCI GEL CHP20 P column chromatography, preparative TLC, and HPLC. Their structures were identified by HR-ESI-MS, ~1H and ~(13)C-NMR, IR, UV, [α]_D, and ECD spectroscopic data as kravanhin A 3-O-ß-D-glucopyranoside(1), kravanhin B(2), 6-eudesmene-1ß,4ß-diol(3), oplodiol(4), vicodiol(5),(1R,2S,4R,7S)-vicodiol 9-O-ß-D-glucopyranoside(6),(1R,2S,4S,5R)-angelicoidenol 2-O-ß-D-glucopyranoside(7), and(1S,2S,4R,6S)-bornane-2,6-diol 2-O-ß-D-glucopyranoside(8). Compound 1 was a new compound, and compounds 2-5 were isolated from A. villosum for the first time. Their hypoglycemic activity was tested based on STC-1 cell model and two enzymatic models(GPa and PTP1 B). The results showed that compounds 1, 7, and 8 could stimulate GLP-1 with the secretion rates of 692.8%, 398.6%, and 483.3% at 25.0 µmol·L~(-1), and compound 6 showed inhibitory activity against GPa with an IC_(50) value of 78.6 µmol·L~(-1).

Synthesis and biological evaluation of paeoveitol D derivatives as new melatonin receptor agonists with antidepressant activities.

Our previous study demonstrated that paeoveitol D, a benzofuran compound isolated from Paeonia veitchii, displayed activity on MT1 and MT2 receptors with agonistic ratios of 57.5% and 51.6% at a concentration of 1 mM. To explore the structure-activity relationships, 34 paeoveitol D derivatives were synthesized and evaluated for their MT1 and MT2 agonistic activities using the Fluo-8 calcium assay. Among them, 16 and 18 derivatives increased agonistic activities on the MT1 and MT2 receptors, respectively. Compound 18 indicated EC50 values of 21.0 and 298.9 µM on MT1 and MT2 receptors in agonistic dose response curves with Tango assays and shortened immobility time in the forced swim test. The preliminary mechanism-of-action investigation manifested that the antidepressant activity of compound 18 may be mediated by promoting serotonin (5-HT) and dopamine (DA) levels in the mice brain. Compound 18 also showed favorable pharmacokinetic profiles and low toxicity in vivo. These results suggest that compound 18 could be a potential antidepressant agent.

Distepharinamide, a novel dimeric proaporphine alkaloid from Diploclisia glaucescens, inhibits the differentiation and proliferative expansion of CD4+Foxp3+ regulatory T cells.

BACKGROUND: CD4+Foxp3+ regulatory T cells (Tregs) represent the primary cellular mechanism of tumor immune evasion. Elimination of Treg activity by the pharmacological agent may enhance anti-tumor immune responses. However, Treg-eliminating agents, especially those with small molecules, are rarely reported. PURPOSE: To identify small molecule inhibitors of Treg cells from natural products. METHODS: Compounds from Diploclisia glaucescens were isolated by column chromatography, and structures were identified by spectroscopic evidence and quantum calculations. The tet-On system for Foxp3-GFP expression in Jurkat T cells was generated to screen Treg inhibitors based on Foxp3 expression. The effect of the compound on TNF-induced proliferative expansion of naturally occurring Tregs (nTregs) and TGF-ß-induced generation of Tregs (iTregs) from naive CD4+ Tcells was further examined. RESULTS: A novel dimeric proaporphine alkaloid, designated as distepharinamide (DSA) with a symmetric structure isolated from the stems of D. glaucescens, restrained the doxycycline (Doxy)-induced Foxp3-tGFP expression, decreased the half-life of Foxp3 mRNA as well as reduced the mRNA levels of chemokine receptors (CCR4, CCR8 and CCR10) in Jurkat T cells with inducible Foxp3-tGFP expression. In lymphocytes or purified Tregs from wild-type C57BL/6 mice or from C57BL/6-Tg(Foxp3-DTR/EGFP)23.2Spar/Mmjax mice, DSA markedly inhibited TNF-induced proliferative expansion of Tregs present in the unfractionated CD4+ T cells, accompanied by the down-regulation of TNFR2, CD25 and CTLA4 expression on Tregs. Furthermore, DSA potently inhibited TGF-ß-induced differentiation of Foxp3-expressing iTregs. Importantly, the expression of Foxp3 mRNA by both nTregs and iTregs was decreased by DSA treatment. Nevertheless, DSA at the same concentrations did not inhibit the proliferation of conventional CD4+ and CD8+ T cells stimulated by anti-CD3/CD28 antibodies. CONCLUSION: DSA, a novel dimeric proaporphine alkaloid, potently inhibited the expansion of nTregs and generation of iTregs. Therefore, DSA or its analogs may merit further investigation as novel immunotherapeutic agents.

Oligostilbenes from the seeds of Paeonia lactiflora as potent GLP-1 secretagogues targeting TGR5 receptor.

One unusual stilbene trimer-flavonoid hybrid, paeonilactiflobenoid (1), together with six known stilbenes (2-7) were isolated from the seeds of Paeonia lactiflora. The structure of 1 was elucidated with the aid of HRESIMS, 1D and 2D NMR, [α]D spectroscopic data and ECD calculation. Compounds 2-7 showed stimulative effects on GLP-1 secretion with promoting rates of 79.8%-880.4% (25 µM) and 217.6%-1089.4% (50 µM), more potent than the positive control, oleoylethanolamide (250.2% at 50 µM). Moreover, compounds 4 and 6 exhibited agonistic activity on the G protein-coupled receptor (GPCR) TGR5 with stimulative ratios of 40.2% and 40.5% at 50 µM, and 54.2% and 49.1% at 100 µM, respectively. Docking study manifested that 6 well located in the catalytic pocket of TGR5 by hydrogen-bond and hydrophobic interactions. The GLP-1 promotion of 6 could be attenuated by IP3, Ca2+/CaMKII and MEK/ERK pathway inhibitors, suggesting that these pathways played important roles in GLP-1 secretion. Thus, stilbenes in peony seeds maybe regarded as potential GLP-1 secretagogues through TGR5-IP3-Ca2+/CaMKII-MEK/ERK pathways.

Synthesis and biological evaluation of (+)-paeoveitol derivatives as novel antidepressants.

The antidepressant activity of (+) and (-)-paeoveitol was first evaluated using the forced swimming test (FST), and (+)-paeoveitol showed potential antidepressant activity by decreasing immobility time of mice (by approximately 26.4%) in the FST at a dose of 20 mg/kg. To explore the structure-activity relationships (SARs) and obtain more potent compounds, twenty derivatives of (+)-paeoveitol were synthesized and evaluated for their agonistic activities on melatonin type I (MT1) and type II (MT2) receptors. As a results, compound 13 with an N-methylpiperazine fragment exhibited obvious effect on MT1 and MT2 receptors with EC50 values of 0.20 and 0.24 mM. Moreover, compound 13 dose-dependently decreased the immobility of mice in the FST and showed an inverted U-shaped dose-effect, and the most efficacious dose (at 40 mg/kg) was comparable to fluoxetine (20 mg/kg) with a reduced immobility time of 29.2% and 34.5%, respectively. In vivo neurochemical assays suggested that compound 13 obviously increased 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in the mice brain, indicating that its antidepressant effects might be related to the monoaminergic system. In silico ADMET study revealed that 13 has favorable pharmacokinetic properties. These findings suggest that compound 13 could be a potential antidepressant agent. Graphical abstract.

Artemzhongdianolides A1-A21, antihepatic fibrosis guaiane-type sesquiterpenoid dimers from Artemisia zhongdianensis.

In the search for new antihepatic fibrosis candidates, it was observed that the EtOH extract of Artemisia zhongdianensis and EtOAc fraction had cytotoxicity against hepatic stellate cell line LX2 (HSC-LX2) with the inhibitory ratios of 85.7 % and 83.9 % at 400 µg/mL. 21 new guaianolide dimers, artemzhongdianolides A1 - A21 (1-21) were isolated from the active fractions under the guidance of bioassay, and elucidated by spectral analyses (HRESIMS, 1D and 2D NMR, IR, ECD). The absolute stereochemistry of compounds 1, 13, and 14 was determined by single-crystal X-ray diffraction analyses. Cytotoxicity evaluation suggested that nine compounds exhibited activity against HSC-LX2 with IC50 values ranging from 14.0 to 95.2 µM. Of them, compounds 2, 6, and 13 displayed significant cytotoxicity against HSC-LX2 with IC50 values of 22.1, 24.3 and 14.0 µM, which were 6 to 10 times more active than the positive drug silybin (IC50, 148.6 µM). Preliminary mechanism study revealed that compounds 2, 6, and 13 could markedly inhibited the deposition of human collagen type Ⅰ (Col Ⅰ), human hyaluronic acid (HA), and human laminin (HL) with IC50 values of 37.9, 54.8, and 28.0 µM (Col Ⅰ), 29.5, 25.3, and 42.9 µM (HL), 31.2, 94.6, and 12.4 µM (HA), which were 1.5 to 13-fold more potent than silybin.

Artemidubolides A-T, cytotoxic unreported guaiane-type sesquiterpenoid dimers against three hepatoma cell lines from Artemisia dubia.

A random bioassay revealed that the EtOH extract and EtOAc fraction of Artemisia dubia Wall. (Asteraceae) exhibited cytotoxic activity against HepG2 cells with inhibitory ratios of 57.1% and 84.2% at a concentration of 100.0 µg/mL. Bio-guided isolation combined by LC-MS-IT-TOF analyses of the active fractions led to the isolation of 20 previously undescribed guaiane-type sesquiterpenoid dimers named artemidubolides A-T (1-20). Their structures and the absolute configurations were determined by comprehensive spectral analyses, comparison of the experimental and calculated ECD spectra, and seven compounds (artemidubolides A, B, D, F, K, O and R) were confirmed unequivocally by single crystal X-ray diffraction analysis. Structurally, artemidubolides A-Q were [4 + 2] Diels-Alder adducts of two monomeric guaianolides, and artemidubolides R-T were linked though an ester bond. All the isolated compounds were evaluated for their hepatomatic cytotoxicity against HepG2, Huh7, and SK-Hep-1 cell lines to demonstrate that 18 compounds exhibited obvious cytotoxicity against three tested hepatoma cell lines with IC50 values in the range of 5.4-87.6 µM. Importantly, artemidubolides B, D, and M exhibited hepatoma cytotoxicity with IC50 values of 5.4, 5.7, and 9.7 (HepG2), 8.2, 4.3, and 12.2 (Huh7), and 13.4, 8.4, and 12.9 µM (SK-Hep-1), respectively. Mechanism investigation in HepG2 cells suggested the most active artemidubolide D dose-dependently inhibited cell migration and invasion, induced G1/M cell cycle arrest by down-regulating proteins CDK4, CDK6 and CyclinD1 and up-regulating the level of protein P21; and induced apoptosis by down-regulated of PARP-1 and BCL-2 expression and up-regulating Bax and cleaved PARP-1 levels.

Artemyrianosins A-J, cytotoxic germacrane-type sesquiterpene lactones from Artemisia myriantha.

Ten new germacrane-type sesquiterpenoids, artemyrianosins A-J (1-10), were isolated from the aerial parts of Artemisia myriantha. Their structures were elucidated by spectral analyses including UV, IR, HRESIMS, 1D and 2D NMR, ECD and the absolute configurations of compounds 1 and 7-9 were characterized using X-ray crystallography. All isolates were tested their cytotoxicity against three human hepatoma cell lines (HepG2, Huh7, and SK-Hep-1), and compounds 1-3, 7, and 10 showed cytotoxicity with IC50 values ranging from 43.7 to 89.3 µM. Among them, the most active compound 3 exhibited activity against three human hepatoma cell lines with IC50 values of 43.7 µM (HepG2), 47.9 µM (Huh7), and 44.9 µM (SK-Hep-1).

Norlignans as potent GLP-1 secretagogues from the fruits of Amomum villosum.

The dried fruit of Amomum villosum (Amomi Fructus) is an important spices and traditional Chinese medicine. In this study, the EtOH extract of Amomi Fructus was revealed with hypoglycemic effects on db/db mice by increasing plasma insulin levels. After extracted with EtOAc, the EtOAc fraction showed increased activity in stimulating glucagon-like peptide-1 (GLP-1) secretion compared with the EtOH extract. In order to clarify the antidiabetic constituents, four undescribed norlignans, amovillosumins A‒D, were isolated from the EtOAc fraction, and the subsequent chiral resolution yielded three pairs of enantiomers. Their structures were determined by extensive spectroscopic data (1D and 2D NMR, HRESIMS, IR, UV and [α]D) and ECD calculations. Amovillosumins A and B significantly stimulated GLP-1 secretion by 375.1% and 222.7% at 25.0 µM, and 166.9% and 62.7% at 12.5 µM, representing a new type of GLP-1 secretagogues.

New diarylheptanoid dimers as GLP-1 secretagogues and multiple-enzyme inhibitors from Alpinia katsumadai.

Ten new diarylheptanoid dimers, katsumadainols C1 - C10 (1-10), were isolated from the seeds of Alpinia katsumada and elucidated by extensive spectroscopic methods, ECD calculations, and single-crystal X-ray diffraction. Their antidiabetic effects were evaluated by the stimulation of GLP-1 secretion in STC-1 cells and inhibition against four diabetes-related enzymes, GPa, α-glucosidase, PTP1B, and DPP4. Compounds 1-5 and 7-10 significantly stimulated GLP-1 secretion by 267.5-433.1% (25.0 µM) and 117.8-348.2% (12.5 µM). Compounds 1-4 exhibited significant inhibition on GPa with IC50 values of 18.0-31.3 µM; compounds 1-5 showed obvious inhibition on α-glucosidase with IC50 values of 6.9-18.2 µM; compounds 1-5 and 10 possessed PTP1B inhibitory activity with IC50 values ranging from 35.5 to 80.1 µM. This investigation first disclosed compounds 1-4 as intriguing GLP-1 secretagogues and GPa, α-glucosidase, and PTP1B inhibitors, which provided valuable clues for searching multiple-target antidiabetic candidates from Zingiberaceae plants.

Synthesis and biological evaluation of (20S,24R)-epoxy-dammarane-3ß,12ß,25-triol derivatives as α-glucosidase and PTP1B inhibitors.

The dammarane triterpenoid (20S,24R)-epoxy-dammarane-3ß,12ß,25-triol obtained from Cyclocarya paliurus in our previous study showed inhibitory activity on α-glucosidase in vitro with an inhibitory ratio of 32.2% at the concentration of 200 µM. In order to reveal the structure-activity relationships (SARs) and get more active compounds, 42 derivatives of (20S,24R)-epoxy-dammarane-3ß,12ß,25-triol were synthesized by chemical modification on the hydroxyls (C-3 and C-12), rings A and E, and assayed for their α-glucosidase and PTP1B inhibitory activities. Two compounds (8, 26) increased activity against α-glucosidase, and four compounds (8, 15, 26, 42) significantly inhibited PTP1B. It was noted that compounds 8 and 26 could inhibit both α-glucosidase and PTP1B as dual-target inhibitors with IC50 values of 489.8, 467.7 µM (α-glucosidase) and 319.7, 269.1 µM (PTP1B). Compound 26 was revealed to be a mix-type inhibitor on α-glucosidase and a noncompetitive-type inhibitor on PTP1B based on enzyme kinetic study. Furthermore, compound 42 could selectively inhibited PTP1B as a mix-type inhibitor with IC50 value of 134.9 µM, which was 2.5-fold higher than the positive control, suramin sodium (IC50 339.0 µM), but not inhibit α-glucosidase.

Lipid Disorders in NAFLD and Chronic Kidney Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and is characterized by exaggerated lipid accumulation, inflammation and even fibrosis. It has been shown that NAFLD increases the risk of other chronic diseases, particularly chronic kidney disease (CKD). Lipid in excess could lead to liver and kidney lesions and even end-stage disease through diverse pathways. Dysregulation of lipid uptake, oxidation or de novo lipogenesis contributes to the toxic effects of ectopic lipids which promotes the development and progression of NAFLD and CKD via triggering oxidative stress, apoptosis, pro-inflammatory and profibrotic responses. Importantly, dyslipidemia and release of pro-inflammatory cytokines caused by NAFLD (specifically, nonalcoholic steatohepatitis) are considered to play important roles in the pathological progression of CKD. Growing evidence of similarities between the pathogenic mechanisms of NAFLD and those of CKD has attracted attention and urged researchers to discover their common therapeutic targets. Here, we summarize the current understanding of molecular aberrations underlying the lipid metabolism of NAFLD and CKD and clinical evidence that suggests the relevance of these pathways in humans. This review also highlights the orchestrated inter-organ cross-talk in lipid disorders, as well as therapeutic options and opportunities to counteract NAFLD and CKD.

Biomimetic Synthesis of Lavandiolides H, I, and K and Artematrolide F via Diels-Alder Reaction.

The biomimetic synthesis of guaianolide dimers lavandiolides H, I, and K and artematrolide F containing a spirolactone moiety has been accomplished for the first time from naturally abundant arglabin in four to six steps with an overall yield up to 60%, and a series of natural product-like guaianolide dimers, trimer, and tetramer were also successfully synthesized. Notably, the trimeric compound exhibited antihepatoma cytotoxicity more potent than that of sorafenib with IC50 values of 6.2 µM (HepG2), 6.8 µM (Huh7), and 7.2 µM (SK-HEP-1).

Artemicapillasins A-N, cytotoxic coumaric acid analogues against hepatic stellate cell LX2 from Artemisia capillaris (Yin-Chen).

Under the guidance of bioassay against HSC-LX2, the EtOH extract and the EtOAc fraction of Artemisia capillaris (Yin-Chen) exhibited cytotoxic activity against HSC-LX2 with inhibitory ratios of 39.7% and 68.7% at the concentration of 400.0 µg/mL. Bioassay-guided investigation of Fr. D (the active fraction) yielded 14 new coumaric acid analogues, artemicapillasins A-N (1-14). The structures of the isolates were elucidated by spectroscopic analyses involving UV, IR, MS, 1D and 2D NMR spectra and ECD calculations. Cytotoxic activity against HSC-LX2 cells of these isolates was performed to reveal that 12 compounds demonstrated cytotoxicity with inhibitory ratios more than 50% at 400 µM. The most active artemicapillasin B (2) gave an IC50 value of 24.5 µM, which was about 7 times more toxic than the positive drug silybin (IC50, 162.3 µM). Importantly, artemicapillasin B (2) showed significant inhibition on the deposition of human collagen type I (Col I), human laminin (HL) and human hyaluronic acid (HA) with IC50 values of 11.0, 14.4 and 13.8 µM, which was about 7, 11 and 5 times more active than silybin. Artemicapillasin B (2) as an interesting antihepatic fibrosis candidate is worth in-depth study.