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Anaplastic thyroid cancer (ATC) is a rare but highly lethal disease. ATCs are resistant to standard therapies and are extremely difficult to manage. The stepwise cell dedifferentiation results in the impairment of the iodine-metabolizing machinery and the infeasibility of radioiodine treatment in ATC. Hence, reinducing iodine-metabolizing gene expression to restore radioiodine avidity is considered as a promising strategy to fight against ATC. In the present study, capsaicin (CAP), a natural potent transient receptor potential vanilloid type 1 (TRPV1) agonist, was discovered to reinduce ATC cell differentiation and to increase the expression of thyroid transcription factors (TTFs including TTF-1, TTF-2, and PAX8) and iodine-metabolizing proteins, including thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase, and sodium iodine symporter (NIS), in two ATC cell lines, 8505C and FRO. Strikingly, CAP treatment promoted NIS glycosylation and its membrane trafficking, resulting in a significant enhancement of radioiodine uptake of ATC cells in vitro. Mechanistically, CAP-activated TRPV1 channel and subsequently triggered Ca2+ influx, cyclic adenosine monophosphate (cAMP) generation, and cAMP-responsive element-binding protein (CREB) signal activation. Next, CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription. Moreover, the TRPV1 antagonist CPZ, the calcium chelator BAPTA, and the PKA inhibitor H-89 effectively alleviated the redifferentiation exerted by CAP, demonstrating that CAP might improve radioiodine avidity through the activation of the TRPV1‒Ca2+/cAMP/PKA/CREB signaling pathway. In addition, our study indicated that CAP might trigger a novel cascade to redifferentiate ATC cells and provide unprecedented opportunities for radioiodine therapy in ATC, bypassing canonical TSH‒TSHR pathway.

Populusene A (1), an unprecedented carbon skeleton featuring a bicyclo[8.4.1]pentadecane nucleus and a bridgehead double bond (anti-Bredt system), and populusin A (2), a cembrane-type diterpenoid possessing an uncommon dioxatricyclo[6.6.1.12,5]hexadecane scaffold, were isolated from the exudates of Populus euphratica. Their structures were elucidated by spectroscopic, computational, and crystallographic methods. A plausible biosynthetic route for 1 and 2 was proposed. Compounds 1 and 2 were found to significantly inhibit the production of TNF-α and IL-6 and the expression of iNOS, COX-2, and p-NF-κB at 125 nM in RAW264.7 cells.

It is widely accepted that anaplastic thyroid carcinoma (ATC), a rare, extremely aggressive malignant, is enriched by cancer stem cells (CSCs), which are closely related to the pathogenesis of ATC. In the present study, we demonstrated that diallyl trisulphide (DATS), a well-known hydrogen sulphide (H2 S) donor, suppressed sphere formation and restored the expression of iodide-metabolizing genes in human ATC cells, which were associated with H2 S generation. Two other H2 S donors, NaHS and GYY4137, could also suppress the self-renewal properties of ATC cells in vitro. Compared with normal thyroid tissues and papillary thyroid carcinomas (PTCs), the elevated expressions of SOX2 and MYC, two cancer stem cell markers, in ATCs were validated in the combined Gene Expression Omnibus (GEO) cohort. DATS decreased the expression of SOX2, which was mediated by H2 S generation. Furthermore, knockdown of AKT or inhibition of AKT by DATS led to a decrease of SOX2 expression in ATC cells. AKT knockdown phenocopied restoration of thyroid-specific gene expression in ATC cells. Our data suggest that H2 S donors treatment can compromise the stem cell phenotype and restore thyroid-specific gene expression of ATC cells by targeting AKT-SOX2 pathway, which may serve as a therapeutic strategy to intervene the CSC progression of ATC.

(±)-Periplactam A (1), a rare ten-membered macrolactam composed of lignan and putrescine, (±)-periplanol E (2), a dimeric phenethyl alcohol derivative formed via morpholine, and periplactams B (3) and C (4), epimeric adducts composed of isocoumarin and urea, were isolated from American cockroach (Periplaneta americana). Their structures were identified by spectroscopic analyses, X-ray diffraction, and computational methods. The biological assay revealed that (+)-2 exhibits antiangiogenic activity in HUVECs in a dose-dependent manner.

Radioactive iodine (RAI) is commonly used to treat differentiated thyroid cancer (DTC). A major challenge is the dedifferentiation of DTC with the loss of radioiodine uptake. Patients with distant metastases have persistent or recurrent disease and develop resistance to RAI therapy due to tumor dedifferentiation. Hence, tumor redifferentiation to restore sensitivity to RAI therapy is considered a promising strategy to overcome RAI resistance. In the present study, curcumin, a natural polyphenolic compound, was found to re-induce cell differentiation and increase the expression of thyroid-specific transcription factors, TTF-1, TTF-2 and transcriptional factor paired box 8 (PAX8), and iodide-metabolizing proteins, including thyroid stimulating hormone receptor (TSHR), thyroid peroxidase (TPO) and sodium iodide symporter (NIS) in dedifferentiated thyroid cancer cell lines, BCPAP and KTC-1. Importantly, curcumin enhanced NIS glycosylation and its membrane trafficking, resulting in a significant improvement of radioiodine uptake in vitro. Additionally, AKT knockdown phenocopied the restoration of thyroid-specific gene expression; however, ectopic expressed AKT inhibited curcumin-induced up-regulation of NIS protein, demonstrating that curcumin might improve radioiodine sensitivity via the inhibition of the PI3K-AKT-mTOR signaling pathway. Our study demonstrates that curcumin could represent a promising adjunctive therapy for restoring iodide avidity and improve radioiodine therapeutic efficacy in patients with RAI-refractory thyroid carcinoma.

Commiphoranoids A-E (1-5), five novel sesquiterpenoids, dinorditerpenoids, and heterodimers with unprecedented carbon skeletons, were isolated from Resina Commiphora. The structure of 1 was secured by X-ray crystallography. Compound 4 represents the first example of C38 terpenoids, whereas 5 is a C30 terpenoid formed by two types of sesquiterpenoids. These metabolites possess lipid regulatory activities via activating PPARα and CPT1.

(±)-Dispirocochlearoids A-C (1-3), meroterpenoids with a 6/6/5/6/6/6 ring system, were isolated from Ganoderma cochlear. 1-3 are selective COX-2 inhibitors with an IC50 value of (-)-2 at 386 nM. Site-directed mutagenesis identified His351 as a COX-2 active site. In vivo anti-inflammatory activities of (-)-2 were performed against acute lung injury in mice.

Sphingomyelin synthase is responsible for the production of sphingomyelin (SGM), the second most abundant phospholipid in mammalian plasma, from ceramide, a major sphingolipid. Knowledge of the effects of cigarette smoke on SGM production is limited. In the present study, we examined the effect of chronic cigarette smoke on sphingomyelin synthase (SGMS) activity and evaluated how the deficiency of Sgms2, one of the two isoforms of mammalian SGMS, impacts pulmonary function. Sgms2-knockout and wild-type control mice were exposed to cigarette smoke for 6 months, and pulmonary function testing was performed. SGMS2-dependent signaling was investigated in these mice and in human monocyte-derived macrophages of nonsmokers and human bronchial epithelial (HBE) cells isolated from healthy nonsmokers and subjects with chronic obstructive pulmonary disease (COPD). Chronic cigarette smoke reduces SGMS activity and Sgms2 gene expression in mouse lungs. Sgms2-deficient mice exhibited enhanced airway and tissue resistance after chronic cigarette smoke exposure, but had similar degrees of emphysema, compared with smoke-exposed wild-type mice. Sgms2-/- mice had greater AKT phosphorylation, peribronchial collagen deposition, and protease activity in their lungs after smoke inhalation. Similarly, we identified reduced SGMS2 expression and enhanced phosphorylation of AKT and protease production in HBE cells isolated from subjects with COPD. Selective inhibition of AKT activity or overexpression of SGMS2 reduced the production of several matrix metalloproteinases in HBE cells and monocyte-derived macrophages. Our study demonstrates that smoke-regulated Sgms2 gene expression influences key COPD features in mice, including airway resistance, AKT signaling, and protease production.

Aims Diseases caused by pathogenic fungi was a major constrain in increasing productivity and improving quality of Panax notoginseng. The aim of this research was to evaluate the inhibitory activity of essential oils (EOs) from Asteraceae family, Chrysanthemum indicum and Laggera pterodonta, against pathogenic fungi of P. notoginseng. Methods and results The antifungal activity was investigated using multiple methods, disclosing that the EOs from C. indicum and L. pterodonta are active against hypha growth of different fungi but with different degrees of potency. Checkerboard testing indicated that the combination of EOs with hymexazol had synergistic effect against Pythium aphanidermatum, and exhibited additive effects against bulk of targeted pathogenic fungi. Besides, we found that the baseline sensitivity of Fusarium oxysporum to L. pterodonta EOs was higher than those of C. indicum by means of mycelium growth rate method. Finally, the practicability of those EOs as plant pesticide was confirmed by in vivo model showing that EOs can significantly inhibit the occurrence of root rot of P. notoginseng caused by F. oxysporum. Conclusion Those studies suggest that the EOs from C. indicum and L. pterodonta had the potential to develop into new pollution-free pesticides for the protection of precious Chinese herbal medicines. Significance and impact of the study This study provided a new way of biological control for overcoming the frequent diseases occurrence of P. notoginseng.

The structures and stereochemistry of spiromyrrhenes A–D (1–4), isolated from Commiphora exudates, were elucidated using NMR and ECD methods. They are the first examples of hepta- and octa-cyclic heterodimers possessing C35 skeletons, for the biosynthesis of which intermolecular [4 + 2] cycloaddition has been proposed. Biological studies show that they suppress tumor stemness in esophageal cancer by inactivating the Hippo/Yap pathway.

Ganoderma mushrooms are not only traditional Chinese medicine, but also dietary supplements and functional foods worldwide. In this work, six new meroterpenoids, ganodercins A − F (2, 3, and 6–9), and three known compounds ganomycin C (1), cochlearin I (4), and fornicin D (5) were isolated from Ganoderma mushrooms. An approach characteristic of the chemical shift for H-8 to assign the geometry of meroterpenoids was developed and successfully used for structure revisions of 1, 5, and previous analogues. Biological evaluation found that 4 selectively inhibits Smad3 phosphorylation in TGF-β1-induced NRK-52E cells. Moreover, 1 and 7 could increase glucose uptake in a dose dependent manner in palmitic acid induced C2C12 cells. Further, 1 was found to activate AMPKα(Thr-172) and AKT(Ser-473) phosphorylation, while 7 could activate AKT(Ser-473) phosphorylation. This study demonstrates the potential of Ganoderma to be developed as new anti-renal fibrosis and improve insulin resistance functional food and medicine.

Summary Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment (in vitro and in vivo) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate cells. Additionally, GluCer promoted more β-catenin translocation into the nucleus, thus promoting tumorigenesis. Importantly, human NASH patients had higher liver GluCer synthase and higher plasma GluCer. These findings implicated that GluCer accumulation is one of triggers promoting the development of NAFLD into NASH, then, fibrosis, and tumorigenesis., Graphical abstract, Highlights • Sphingomyelin synthase 1 deficiency causes glucosylceramide accumulation • Glucosylceramide accelerates liver steatosis, steatohepatitis, and tumorigenesis • Glucosylceramide stimulates TGFβ1 activation, which mediates liver fibrosis • Human NASH patients have higher glucosylceramide synthase in their livers, Genetics; Molecular genetics; Omics

Ganoderma fungi as popular raw materials of numerous functional foods have been extensively investigated. In this study, five pairs of meroterpenoid enantiomers beyond well-known triterpenoids and polysaccharides, dayaolingzhiols I−M (1–5), were characterized from Ganoderma lucidum. Their structures were identified using spectroscopic and computational methods. Structurally, compound 1 features a novel dioxabicyclo[2.2.2]octan-3-one motif in the side chain. Ethnoknowledge-derived biological evaluation found that (+)-5 could activate Akt and AMPK phosphorylation in insulin-stimulated C2C12 cells, and (+)-5 could activate glucose uptake dose dependently in C2C12 cells. Furthermore, we found that (+)-1 (+)-4, and (–)-4 could significantly inhibit cell migration of the MDA-MB-231 cell line, of which (+)-4 showed significant inhibitory effects against cell migration of the MDA-MB-231 cell line in a dose-dependent manner. These findings revealed the meroterpenoidal composition of G. lucidum and its roles in the prevention of chronic diseases such as diabetes mellitus and triple-negative breast cancer.

Many studies have confirmed the enzymatic activity of a mammalian phosphatidylcholine phospholipase C (PC-PLC), which produces diacylglycerol (DAG) and phosphocholine through the hydrolysis of phosphatidylcholine (PC) in the absence of ceramide. However, the protein(s) responsible for this activity have never yet been isolated. Based on the fact that tricyclodecan-9-yl-potassium xanthate (D609) can inhibit both PC-PLC and sphingomyelin synthase (SMS) activities, and SMS1 and SMS2 have a conserved catalytic domain which could mediates a nucleophilic attack on the phosphodiester bond of PC, we hypothesized that both SMS1 and SMS2 might have PC-PLC activity. In the current study, we found that purified recombinant SMS1 and SMS2 but not SMSr (sphingomyelin synthase related protein) have PC-PLC activity. Moreover, we prepared liver-specific Sms1/global Sms2 double knockout (dKO) mice. We found that liver PC-PLC activity was significantly reduced and steady state levels of PC and DAG in the liver were regulated by the deficiency, in comparison with control mice. Using adenovirus, we expressed Sms1 and Sms2 genes in the liver of the dKO mice, respectively, and found that expressed SMS1 and SMS2 can hydrolyze PC to produce DAG and phosphocholine. Thus, SMS1 and SMS2 exhibit PC-PLC activity in vitro and in vivo.

Increased phospholipid transfer protein (PLTP) activity has been found to be associated with obesity, and metabolic syndrome in humans. However, whether or not PLTP has a direct effect on insulin sensitivity and obesity is largely unknown. Here we analyzed the effect by using PLTP knockout (PLTP-/-) mouse model. Although, PLTP-/- mice have normal body-weight-gain under chow diet, these mice were protected from high-fat-diet-induced obesity and insulin resistance, compared with wild type mice. In order to understand the mechanism, we evaluated insulin receptor and Akt activation and found that PLTP deficiency significantly enhanced phosphorylated insulin receptor and Akt levels in high-fat-diet fed mouse livers, adipose tissues, and muscles after insulin stimulation, while total Akt and insulin receptor levels were unchanged. Moreover, we found that the PLTP deficiency induced significantly more GLUT4 protein in the plasma membranes of adipocytes and muscle cells after insulin stimulation. Finally, we found that PLTP-deficient hepatocytes had less sphingomyelins and free cholesterols in the lipid rafts and plasma membranes than that of controls and this may provide a molecular basis for PLTP deficiency-mediated increase in insulin sensitivity. We have concluded that PLTP deficiency leads to an improvement in tissue and whole-body insulin sensitivity through modulating lipid levels in the plasma membrane, especially in the lipid rafts.

In this study, taking Ni enriched water hyacinth (WH, Eichhornia crassipes) as an example, we prepared porous Ni–N doped carbon material (WHPC@Ni) with high supercapacitive performance via fast pyr...

To develop natural fungicides against Panax notoginseng disease, the antifungal effects of Syzygium aromaticum essential oils (EOs) against the pathogenic fungi causing P. notoginseng disease were investigated. The effects of EOs from S. aromaticum buds and fruits on the growth of pathogenic mycelia were determined with in vitro antifungal experiments using the Oxford cup method. The results suggested that S. aromaticum EOs had a strong inhibitory effect on the growth of pathogenic fungi. At a dose of 50 mg/mL, the inhibitory effects of S. aromaticum buds EOs was greater than those of S. aromaticum fruits. Then the chemical constituents of the S. aromaticum EOs were analyzed by GC–MS. The results indicated that the eugenol content was the highest, accounting for 57.95% of the total constituents in the S. aromaticum buds EOs and 39.26% in the S. aromaticum fruits EOs. The minimum inhibitory concentration (MIC) of EOs, the major constituents, and hymexazol were evaluated. In addition, the antifungal effect of their combination was also determined by the fractional inhibitory concentration (FIC). When the buds EOs were combined with hymexazol, they had a synergistic effect in inhibiting Pythium aphanidermatum, Botrytis cinerea, and Colletotrichum gloeosporioides. The combination of S. aromaticum fruit EOs with hymexazol showed an additive effect on Fusarium solani, P. aphanidermatum, and B. cinerea. The preventive effect of S. aromaticum bud EOs combined with hymexazol was up to 60.77% in in vivo experiments. Overall, S. aromaticum EOs had a broad spectrum of antifungal activities against pathogenic fungi influencing the growth of P. notoginseng, which would provide a scientific basis for the ecological control of P. notoginseng disease.

BACKGROUND AND AIMS: To investigate the effect of cholesteryl ester transfer protein (CETP) inhibitor on subclasses of HDL in patients with atherosclerotic cardiovascular disease or diabetes. CETP inhibitor-mediated a dramatic induction of HDL-cholesterol has no effect on the protection of cardiovascular disease (CVD). However, the mechanism is still unknown. Data on the effects of this class of drugs on subclasses of HDL are either limited or insufficient. METHODS: Baseline and 3-month post-treatment samples from the atorvastatin 40 mg plus evacetrapib 130 mg (n=70) and atorvastatin 40 mg plus placebo (n=30) arms were utilized for this purpose. Four subclasses of HDL (large HDL1, medium HDL2, small HDL3, and Preβ-1 HDL) were separated according to their size and quantified by densitometry using a recently developed native polyacrylamide gel electrophoresis (PAGE) system. RESULTS: Relative to placebo, while evacetrapib treatment dramatically increased HDL1 and HDL2 subclasses, it significantly reduced small dense HDL3 (27%) as well as Preβ-1 HDL (36%) particles. Evacetrapib treatment reduced total LDL, but also resulted in polydisperse LDL with LDL particles larger and smaller than the LDL subclasses of the placebo group. CONCLUSION: Evacetrapib reduced Preβ-1 HDL and small dense HDL3 in patients with ASCVD or diabetes on statin. Preβ-1 HDL and HDL2 are negatively interrelated. The results could give a clue to understand the effect of CETP inhibitors on cardiovascular outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02227784.

Ganoderma mushrooms are widely used as effective medicines for treating and preventing chronic diseases. In this study, five new meroterpenoids, dayaolingzhiols A (1) and B (2) featuring a 6/6/6 ring system, dayaolingzhiols C−E (3–5) harboring a γ-lactone motif, along with eight known ones (6–13), were purified from G. lucidum. To clarify their chemical structures, spectroscopic and ECD and OR computational methods were used. In addition, the inhibition of all the new meroterpenoids against AChE was evaluated, disclosing that (+)-4 and (±)-5 possess potent AChE inhibitory activities with respective IC50 values of 8.52 ± 1.90 μM and 7.37 ± 0.52 μM.

Two new coumarins (1 and 2), two new lignans (3 and 4), one new phloroglucinol derivative (5), together with eleven known compounds, were isolated from Artemisia annua. Their structures were identified by spectroscopic methods with 1 to be secured by X-ray diffraction. Antifungal activities of the isolates against Fusarium oxysporum, Fusarium solani, and Cylindrocarpon destrutans were evaluated. It was found that compound 1 could inhibit all the fungal strains with respective MIC values of 18.75, and 25.00 μg/mL. In contrast, compounds 4, 5, 7, and 8 are active toward C. destrutans and 14 displays inhibitory property toward F. solani.

The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.

Context: Radix Tripterygium wilfordii Hook. f. (Celastraceae) (LGT) has outstanding curative efficacy; however, side effects include high toxicity, particularly hepatotoxicity and nephrotoxicity. Objective: To investigate detoxification mechanisms of LGT through processing separately with each of these medicinal herbs including Flower Lonicera japonica Thunb. (Caprifoliaceae) (JYH), Radix Paeonia lactiflora Pall. (Ranunculaceae) (BS), Herba Lysimachia christinae Hance (Primulaceae) (JQC), Radix et Rhizoma Glycyrrhiza uralensis Fisch. (Fabaceae) (GC) and Seed Phaseolus radiatus L. (Fabaceae) (LD) in S180-bearing mice by involving nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Materials and methods: LGT raw and processed products were orally administered at 60 mg/kg to KM male mice inoculated with S180 tumour cells for 14 consecutive days, and blood, tumour, liver and kidney were taken to observe the detoxifying effects and biological mechanisms. Results: Herbal-processing technology significantly weakened hepatotoxicity and nephrotoxicity evoked by LGT with ED50 of the converted triptolide in each processed-herb product for serum alanine transaminase, aspartate transaminase, creatinine and urea nitrogen of 9.3, 16.6, 2.5 and 4.2 μg/kg, for liver glutathione, glutathione S-transferase, catalase, tumour necrosis factor-α and interleukin-10 of 114.9, 67.8, 134.1, 7.7, 4171.6 μg/kg, and for kidney 21.9, 20.5, 145.0, 529.7, 19.4 μg/kg, respectively. Moreover, herbal-processing technology promoted the accumulation of Nrf2 into the nucleus, and upregulated mRNA expression of Nrf2 and heme oxygenase-1. Additionally, herbal-processing technology enhanced the tumour inhibition rate with ED50 12.2 μg/kg. Discussion and conclusions: Herbal-processing technology improves the safety and effectiveness of LGT in cancer treatment, and future research may be focused on the Nrf2-related molecules.

Nine multifarious new meroterpenoids, cochlearols E-M (1-9), along with seven known meroterpenoids 10-16, were isolated from the fruiting bodies of Ganoderma cochlear. Racemic 1, 6-8, 10 and 13 were separated by chiral HPLC. The structures were elucidated based on detailed spectroscopic analyses (HRESIMS, 1D/2D-NMR) and calculated electronic circular dichroism (ECD). Their biological activities against renal fibrosis were evaluated by using rat normal and diseased renal interstitial fibroblast cells (NRK49F). The results show that compounds 7a, 7b, and 10a exhibit potent proliferation inhibition in TGF-β1-induced NRK-49F cells.

Commiphorines A (1), an unprecedented sesquiterpenoid heterodimer featuring a 5/7(5)/4/10/5 ring system, and B (2), a dimeric sesquiterpenoid possessing an unusual 1,4-dioxin motif and a 6/6/5/6/6/6 polycyclic system, and two intermediates 3 and 4 were isolated from Resina Commiphora. A plausible biosynthetic route for 1 and 2 was proposed. Compound 2 could significantly suppress LPS-induced inflammation through NF-κB and MAPK signaling pathways in mouse peritoneal macrophages. Compounds 1 and 2 could inhibit lipid synthesis in HepG2 cells.

(+)- and (−)-gancochlearols A (1) and B (2), two pairs of dimeric mertoterpenoid enantiomers were isolated from the fruiting bodies of Ganoderma cochlear. Their structures were identified by spectr...

Duchenne muscular dystrophy (DMD) is a lethal genetic muscle disorder caused by recessive mutations in dystrophin gene, affecting 1/3000 males. Gene therapy has been proven to ameliorate dystrophic pathology. To investigate therapeutic benefits from long-term effect of human mini-dystrophin and functional outcomes, transgenic mdx mice (Tg-mdx) containing a single copy of human mini-dystrophin (∆hDys3849) gene, five rods (Rods1-2, Rods22-24), and two hinges (H1 and H4) driven by a truncated creatine-kinase promoter (dMCK) in a recombinant adeno-associated viral vector (rAAV) backbone, were generated and used to determine gene expression and improvement of muscle function. Human mini-dystrophin gene expression was found in a majority of the skeletal muscles, but no expression in cardiac muscle. Dystrophin-associated glycoproteins (DAGs) such as sarcoglycans and nNOS were restored at the sarcolemma and coincided with human mini-dystrophin gene expression at the ages of 6, 10, and 20 months; Morphology of dystrophic muscle expressing the human mini-dystrophin gene was improved and central nuclei were reduced. Myofiber membrane integrity was improved by Evans blue dye test. Improvement in treadmill running and grip force was observed in transgenic mice at 6 months. Tetanic force and specific force of tibialis anterior (TA) muscle were significantly increased at the ages of 6, 10, and 20 months. Pseudohypertrophy was not found in TA muscle at 10 and 20 months when compared with wild-type C57 (WT) group. This study demonstrated that the long-term effects of human mini-dystrophin effectively ameliorated pathology and improved the functions of the dystrophic muscles in the transgenic DMD mouse model.

Background: As part of the innate immune system, natural killer (NK) cells can directly kill virus-infected cells and malignant cells without pre-immunization. NK cell-based immunotherapy has attracted tremendous attention as a practical treatment for cancer and other diseases. In order to provide unlimited “off-the-shelf” NK cells to serve many recipients, we designed and demonstrated an overall manufacturing scheme for mass production of NK cells from physically reprogrammed somatic cells. Methods: Different somatic cells would be reprogrammed into induced pluripotent stem cells (iPSCs) by physical-dynamic suspension culture system, which was non-viral, non-integrated, non-compound-induced, feeder-free, and serum-free. The pluripotency of iPSCs was assessed by immunofluorescence, flow cytometry analysis, western blot, and teratoma assay. By using a combination of cytokines, iPSCs would be further differentiated into NK cells. Immunofluorescence, flow cytometry analysis, and lactate dehydrogenase (LDH) release method were performed to evaluate the characteristics of NK cells. Results: Starting from human somatic cells, we obtained iPSCs in the form of spherical embryoids (SEs) through physical reprogramming. iPSCs were similar to embryonic stem cells (ESCs) in their characteristics, including morphology, expression of pluripotency-associated markers, and teratoma formation. NK cells were efficiently generated from SEs by a combination of cytokines under feeder-free conditions. SEs-NK cells share similar phenotypic and functional characteristics with human NK cells, including morphology, cell surface markers, and cytotoxicity. Conclusions: We have not only established a practical approach for large-scale production of universal NK cells, but also provided a platform for generating good manufacturing practice (GMP)-compliant iPSCs through physical dynamics, thus suggesting that the physical reprogramming will become a more promising strategy for future biotherapies.

Commiphorane K (1), a new dinorditerpenoid, commiphoranes L-N (2-4), three new germacrane-type sesquiterpenoids, and commiphorane O (5), one new guaiane-type sesquiterpenoid, were isolated from Resina Commiphora. Their structures were characterized by spectroscopic and computational methods. In particular, the structure of 4 was confirmed by X-ray crystallography. Compounds 2-5 were evaluated for their anti-inflammatory activities. The result shows that compound 2 suppresses lipopolysaccharide (LPS)-stimulated production of TNF-α in RAW264.7 cells in a dose-dependent manner.

Background and aims Atherosclerosis progression and regression studies are related to its prevention and treatment. Although we have gained extensive knowledge on germline phospholipid transfer protein (PLTP) deficiency, the effect of inducible PLTP deficiency in atherosclerosis remains unexplored. Methods We generated inducible PLTP (iPLTP)-knockout (KO) mice and measured their plasma lipid levels after feeding a normal chow or a Western-type diet. Adenovirus associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9) was used to induce hypercholesterolemia in the mice. Collars were placed around the common carotid arteries, and atherosclerosis progression and regression in the carotid arteries and aortic roots were evaluated. Results On a normal chow diet, iPLTP-KO mice exhibited decreased cholesterol, phospholipid, apoA-I, and apoB levels compared with control mice. Furthermore, the overall amount of high-density lipoprotein (HDL) particles was reduced in these mice, but this effect was more profound for larger HDL particles. On a Western-type diet, iPLTP-KO mice again exhibited reduced levels of all tested lipids, even though the basal lipid levels were increased. Additionally, these mice displayed significantly reduced atherosclerotic plaque sizes with increased plaque stability. Importantly, inducible PLTP deficiency significantly ameliorated atherosclerosis by reducing the size of established plaques and the number of macrophages in the plaques without causing lipid accumulation in the liver. Conclusions Induced PLTP deficiency in adult mice reduces plasma total cholesterol and triglycerides, prevents atherosclerosis progression, and promotes atherosclerosis regression. Thus, PLTP inhibition is a promising therapeutic approach for atherosclerosis.

Background Cryptosporidium baileyi is an economically important zoonotic pathogen that causes serious respiratory symptoms in chickens for which no effective control measures are currently available. An accumulating body of evidence indicates the potential and usefulness of metabolomics to further our understanding of the interaction between pathogens and hosts, and to search for new diagnostic or pharmacological biomarkers of complex microorganisms. The aim of this study was to identify the impact of C. baileyi infection on the serum metabolism of chickens and to assess several metabolites as potential diagnostic biomarkers for C. baileyi infection. Methods Ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) and subsequent multivariate statistical analysis were applied to investigate metabolomics profiles in the serum samples of chickens infected with C. baileyi, and to identify potential metabolites that can be used to distinguish chickens infected with C. baileyi from non-infected birds. Results Multivariate statistical analysis identified 138 differential serum metabolites between mock- and C. baileyi-infected chickens at 5 days post-infection (dpi), including 115 upregulated and 23 downregulated compounds. These metabolites were significantly enriched into six pathways, of which two pathways associated with energy and lipid metabolism, namely glycerophospholipid metabolism and sphingolipid metabolism, respectively, were the most enriched. Interestingly, some important immune-related pathways were also significantly enriched, including the intestinal immune network for IgA production, autophagy and cellular senescence. Nine potential C. baileyi-responsive metabolites were identified, including choline, sirolimus, all-trans retinoic acid, PC(14:0/22:1(13Z)), PC(15:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PE(16:1(9Z)/24:1(15Z)), phosphocholine, SM(d18:0/16:1(9Z)(OH)) and sphinganine. Conclusions This is the first report on serum metabolic profiling of chickens with early-stage C. baileyi infection. The results provide novel insights into the pathophysiological mechanisms of C. baileyi in chickens. Graphic abstract

Five new compounds (xuejieins A–E), including three new phenolic glycosides (1, 2, and 5) and two new flavonoids (10 and 11), together with six known compounds were isolated from the resins of Dracaena cochinchinensis (Chinese dragon's blood). The structures of the new compounds were confirmed by extensive spectroscopic methods and electronic circular dichroism (ECD) data analysis. Especially, the absolute configurations of the sugar moieties in compounds 1, 2, and 5 were clarified by GC analysis after acid hydrolysis. All isolated compounds have been tested for antifungal and wound healing promoting activities, The results showed that compound 9 shows significant antifungal activities against Botrytis cinerea, Magnaporthe grisea, Penicillium digitatum, and Sclerotinia sclerotiorum. In addition, compound 4 could significantly stimulate human keratinocytes (HaCAT) proliferation, mobility, and human umbilical vein vascular endothelial cells (HUVECs) tube formation at 40 μM.

Anaplastic thyroid cancer (ATC) is a rare but highly lethal disease. So far, there is no available established treatment which can prolong its survival. In this regard, effective therapies are urgently needed. Vitamin C widely serves as an anti-cancer agent. However, the potential effects of vitamin C against thyroid tumorigenesis remained unclear. The present study demonstrated that vitamin C could significantly inhibit ATC cells growth through ferroptosis activation, evidenced by the GPX4 inactivation, ROS accumulation and iron-dependent lipid peroxidation. Our results demonstrated that vitamin C treatment induced ferritinophagy and subsequent degradation of ferritin, leading to the release of free iron. Excessive iron further triggered ROS generation via Fenton reaction. The positive feedback mediated by ROS and iron sustained lipid peroxidation and further resulted in ferroptosis of ATC cells. The better understanding of the anti-cancer mechanisms of vitamin C provides a potential strategy for ATC therapy.

Sphingomyelin (SM) is one major phospholipids on lipoproteins. It is enriched on apolipoprotein B-containing particles, including very low-density lipoprotein (VLDL) and its catabolites, low-density lipoprotein (LDL). SM is synthesized by sphingomyelin synthase 1 and 2 (SMS1 and SMS2) which utilizes ceramide and phosphatidylcholine, as two substrates, to produce SM and diacylglyceride. SMS1 and SMS2 activities are co-expressed in all tested tissues, including the liver where VLDL is produced. Thus, neither Sms1 gene knockout (KO) nor Sms2 KO approach is sufficient to evaluate the effect of SMS on VLDL metabolism. We prepared liver-specific Sms1 KO/ global Sms2 KO mice to evaluate the effect of hepatocyte SM biosynthesis in lipoprotein metabolism. We found that hepatocyte total SMS depletion significantly reduces cellular sphingomyelin levels. Also, we found that the deficiency induces cellular glycosphingolipid levels which is specifically related with SMS1 but not SMS2 deficiency. To our surprise, hepatocyte total SMS deficiency has marginal effect on hepatocyte ceramide, diacylglyceride, and phosphatidylcholine levels. Importantly, total SMS deficiency decreases plasma triglyceride but not apoB levels and reduces larger VLDL concentration. The reduction of triglyceride levels also was observed when the animals were on a high fat diet. Our results show that hepatocyte total SMS blocking can reduce VLDL-triglyceride production and plasma triglyceride levels. This phenomenon could be related with a reduction of atherogenicity.

Background: Even though treatment outcomes for hepatocellular carcinoma patients have significantly improved, prognostic clinical evaluation remains a substantial challenge due to the heterogeneity and complexity of cancer. Accumulating evidence has revealed that the tumor immune microenvironment is critical for progression and prognosis of hepatocellular carcinoma. A powerful predictive model could assist physicians to better monitor patient treatment outcomes and improve overall survival rates. Therefore, we introduced tumor immune-related genes into a model that could be used for patient risk classification. Results: First, the Single-sample gene set enrichment analysis (ssGSEA) and Weighted gene co-expression networks construction (WGCNA) methods were applied to identify highly associated immunity genes. Following this, a multi-immune-related gene-based signature determined by The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to determine risk stratification. In addition, this predictive model was evaluated according to its performance as a prognostic model in the training and testing datasets. Furthermore, tumor mutation burden and biological enrichment analysis were applied to reveal the potential mechanisms through which the gene signature functions. Conclusion: In conclusion, our four-gene signature model may be clinically applied in hepatocellular carcinoma patients at high risk of mortality for personalized therapy.

Silk fibroin (SF) can be used to construct various stiff material interfaces to support bone formation. An essential preparatory step is to partially transform SF molecules from random coils to β-sheets to render the material water insoluble. However, the influence of the SF conformation on osteogenic cell behavior at the material interface remains unknown. Herein, three stiff SF substrates were prepared by varying the β-sheet content (high, medium, and low). The substrates had a comparable chemical composition, surface topography, and wettability. When adsorbed fibronectin was used as a model cellular adhesive protein, the stability of the adsorbed protein-material interface, in terms of the surface stability of the SF substrates and the accompanying fibronectin detachment resistance, increased with the increasing β-sheet content of the SF substrates. Furthermore, (i) larger areas of cytoskeleton-associated focal adhesions, (ii) higher orders of cytoskeletal organization and (iii) more elongated cell spreading were observed for bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on SF substrates with high vs. low β-sheet contents, along with enhanced nuclear translocation and activation of YAP/TAZ and RUNX2. Consequently, osteogenic differentiation of BMSCs was stimulated on high β-sheet substrates. These results indicated that the β-sheet content influences osteogenic differentiation of BMSCs on SF materials in vitro by modulating the stability of the adsorbed protein-material interface, which proceeds via protein-focal adhesion-cytoskeleton links and subsequent intracellular mechanotransduction. Our findings emphasize the role of the stability of the adsorbed protein-material interface in cellular mechanotransduction and the perception of stiff SF substrates with different β-sheet contents, which should not be overlooked when engineering stiff biomaterials.

Panax notoginseng (Burkill) F.H.Chen (Araliaceae), of which the dry root and rhizome are precious traditional Chinese medicine, suffers severely from diseases during planting. Essential oils (EOs) with antimicrobial activity are a possibility for the development of green pesticides. We extracted EOs from Pogostemon cablin (Blanco) Benth. and Eupatorium fortunei Turcz., respectively and tested their inhibitory rates on fungi isolated from diseased P. notoginseng by the Oxford cup method. The compounds of the EO were identified by GC/MS and the minimum inhibitory concentrations (MICs) of the EOs and their main components were evaluated by the 96-well plate method. We also mixed P. cablin EO, E. fortunei EO and hymexazol in pairs to explore whether their combinations produce stronger antifungal effects than individual components. Finally, we evaluated the effects of the EOs against Fusarium oxysporum in vivo. P. cablin EO and E. fortunei EO exhibited different antifungal activities against fungi, with the inhibitory rates of 21.02 %-100 % and 54.84 %-100 % and MICs of 0.07-0.88 mg/mL and 0.20-1.17 mg/mL, respectively. Pogostone (24.96 %) and thymol (15.64 %) were the major compounds of P. cablin EO and E. fortunei EO, respectively, and they exhibited stronger antifungal activities than EOs, with MICs of 0.008-0.078 mg/mL and 0.12-0.31 mg/mL, respectively. Moreover, hymexazol was mixed with E. fortunei EO, and the inhibitory effect against Cylindrocarpon destructans was enhanced with a synergistic effect. The disease incidence and disease index of EO treatments decreased significantly in vivo. Based on our study, P. cablin EO and E. fortunei EO have great potential to be developed into green fungicides for use in agriculture to control diseases of P. notoginseng.

Five new terpenoids including one new abietane diterpenoid (1), one new aromadendrane diterpenoid (6), two new norsesquiterpenoids (8 and 9), and a new cembrane-derived diterpenoid (12), together with seven known compounds were isolated from Populus euphratica resins. The structures of these new compounds, including their absolute configurations, were characterized by spectroscopic and computational methods. All the compounds except 8 were test for their neuroprotective activities. The result revealed that compounds 1, 7, and 10-12 display neuroprotective activities in glutamate-induced SH-SY5Y cells in a concentration-dependent manner.

NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-β signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-β signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-β signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-β signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-β signaling related diseases.

Background Eimeria necatrix, the most highly pathogenic coccidian in chicken small intestines, can cause high morbidity and mortality in susceptible birds and devastating economic losses in poultry production, but the underlying molecular mechanisms in interaction between chicken and E. necatrix are not entirely revealed. Accumulating evidence shows that the long-non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are key regulators in various infectious diseases. However, the expression profiles and roles of these two non-coding RNAs (ncRNAs) during E. necatrix infection are still unclear. Methods The expression profiles of mRNAs, lncRNAs and circRNAs in mid-segments of chicken small intestines at 108 h post-infection (pi) with E. necatrix were analyzed by using the RNA-seq technique. Results After strict filtering of raw data, we putatively identified 49,183 mRNAs, 818 lncRNAs and 4153 circRNAs. The obtained lncRNAs were classified into four types, including 228 (27.87%) intergenic, 67 (8.19%) intronic, 166 (20.29%) anti-sense and 357 (43.64%) sense-overlapping lncRNAs; of these, 571 were found to be novel. Five types were also predicted for putative circRNAs, including 180 exonic, 54 intronic, 113 antisense, 109 intergenic and 3697 sense-overlapping circRNAs. Eimeria necatrix infection significantly altered the expression of 1543 mRNAs (707 upregulated and 836 downregulated), 95 lncRNAs (49 upregulated and 46 downregulated) and 13 circRNAs (9 upregulated and 4 downregulated). Target predictions revealed that 38 aberrantly expressed lncRNAs would cis-regulate 73 mRNAs, and 1453 mRNAs could be trans-regulated by 87 differentially regulated lncRNAs. Additionally, 109 potential sponging miRNAs were also identified for 9 circRNAs. GO and KEGG enrichment analysis of target mRNAs for lncRNAs, and sponging miRNA targets and source genes for circRNAs identified associations of both lncRNAs and circRNAs with host immune defense and pathogenesis during E. necatrix infection. Conclusions To the best of our knowledge, the present study provides the first genome-wide analysis of mRNAs, lncRNAs and circRNAs in chicken small intestines infected with E. necatrix. The obtained data will offer novel clues for exploring the interaction mechanisms between chickens and Eimeria spp.

PLTP plays an important role in lipoprotein metabolism and cardiovascular disease development in humans; however, the mechanisms are still not completely understood. In mouse models, PLTP deficiency reduces cardiovascular disease, while its overexpression induces it. Therefore, we used mouse models to investigate the involved mechanisms. In this chapter, the recent main progresses in the field of PLTP research are summarized, and our focus is on the relationship between PLTP and lipoprotein metabolism, as well as PLTP and cardiovascular diseases.

(+)- and (−)-Spirocochlealactones A–C (1–3), three pairs of new spiro meroterpenoidal dimeric enantiomers together with one known compound ganodilactone (4), were isolated from the fruiting bodies of Ganoderma cochlear. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD calculations. All the isolated compounds were tested for their COX-2 inhibitory and cytotoxic activities toward human cancer lines (A549, K562, and Huh-7). The results show that all the compounds could inhibit COX-2 with IC50 values in the range of 1.29 to 3.63 μM. In addition, (+)-spirocochlealactone A and (+)-ganodilactone were found to be moderate activities against human cancer cell line A549 with the IC50 values of 7.14 and 9.47 μM, respectively.

Five new meroterpenoids, zizhines P-S and U (1&minus, 4,7), together with two known meroterpenoids (5 and 6) were isolated from Ganoderma sinensis. Their structures including absolute configurations were assigned by using spectroscopic, computational, and chemical methods. Racemics zizhines P and Q were purified by HPLC on chiral phase. Biological evaluation found that 4, 5 and 6 are cytotoxic toward human cancer cells (A549, BGC-823, Kyse30) with IC50 values in the range of 63.43&ndash, 80.83 &mu, M towards A549, 59.2 &plusmn, 2.73 &mu, M and 64.25 &plusmn, 0.37 &mu, M towards BGC-823, 76.28 &plusmn, 1.93 &mu, M and 85.42 &plusmn, 2.82 &mu, M towards Kyse30.

Ganoderma mushrooms possess antioxidant, anticancer, and immunomodulatory properties. In this study, eleven new meroterpenoids, ganotheaecolumols A-K (1–6, 10,11, 13, 14, and 17), together with nine known ones (7–9, 12, 15, 16, and 18–20) were isolated from the fruiting bodies of G. theaecolum. Their structures were elucidated by spectroscopic and computational methods. All the new compounds and iso-ganotheaecolumol I (12) were tested for their inhibitory activities against COX-2 and JAK3 kinases, and cytotoxic effects. It was found that most meroterpenoids could inhibit COX-2 and JAK3 with compounds 3, 4, 12, 13, and 17 having IC50 values of 1.05 ± 0.10, 1.38 ± 0.11, 2.61 ± 0.79, 3.47 ± 0.58, and 4.84 ± 0.60 μM towards COX-2. Whereas, none of the test compounds exhibited cytotoxic effects against human cancer cells (K562, A549, and Huh-7).

Enterocytozoon bieneusi has been considered as the most frequently diagnosed microsporidian species in humans and various animal species, accounting for more than 90% of the cases of human microsporidiosis. Spores of this pathogen excreted from both symptomatic and asymptomatic hosts into environment also would be an important source of waterborne outbreak of microsporidiosis. Due to limited effective drugs available but with too much side effects to mammals (eg. toxic), accurate characterization of E. bieneusi in both humans and animals is essential to implement effective control strategies to this pathogen. In China, E. bieneusi infection was presented in humans and some animals with high prevalence. Analysis of genetic variations of the internal transcribed spacer (ITS) sequences found 361 genotypes in China, and some novel genotypes were identified in some specific hosts. Additionally, associations between infections and some risk factors were also observed. In the present article, we reviewed the current status of prevalence, genotypes, multilocus genotypes (MLGs) in humans, various animals and waters in China. These findings will provide basic information for developing effective control strategies against E. bieneusi infection in China as well as other countries.

A series of new terminal cyclohexane-type meroterpenoids, ganotheaecoloids A-N (1-6, 8-13, 15, and 16), along with three known ones (7, 14, and 17), were isolated from the dried fruiting bodies of Ganoderma theaecolum. Their chemical structures were identified by using spectroscopic data and computational methods. Biological activity of all the new meroterpenoids against COX-2 was evaluated in vitro, only ganotheaecoloid J (11) was found to have COX-2 inhibitory activity with IC50 value of 9.96μM.

The dried roots of Rehmannia glutinosa Libosch. (Scrophulariaceae) are of both medicinal and nutritional importance. Our previous study has found that the 80% ethanol extract of R. glutinosa (RGEE) produced antidepressant-like activities in mouse behavioral despair depression models. However, its mechanisms are still unclear. The present study aimed to observe the antidepressant-like mechanisms of RGEE on a rat chronic unpredictable mild stress (CUMS) model by involving monoaminergic neurotransmitters and brain-derived neurotrophic factor (BDNF). CUMS-stressed rats were orally given RGEE daily (150, 300, and 600 mg/kg) or fluoxetine hydrochloride (FH) for 3 weeks after starting the CUMS procedure. Sucrose preference test was carried out to observe depression-like behavior, and serum and brain tissues were used for neurochemical and fluorescent quantitative reverse transcription PCR analysis. Results demonstrated that CUMS induced depression-like behavior, whereas RGEE and FH administration inhibited this symptom. Furthermore, CUMS caused excessively elevated levels of serum corticosterone (CORT), an index of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, in a manner attenuated by RGEE and FH administration. RGEE administration also further elevated monoamine neurotransmitters and BDNF levels, up-regulated the mRNA expression of BDNF and tropomyosin-related kinase B (TrkB) in hippocampus of rats suffering CUMS. Together, our findings suggest that RGEE can improve CUMS-evoked depression-like behavior, and indicate its mechanisms may partially be associated with restoring HPA axis dysfunctions, enhancing monoamineergic nervous systems, and up-regulating BDNF and TrkB expression.

The new sesquiterpene dimers commiphoroids A-D (1-4) were isolated from Resina Commiphora, and their structures were assigned by spectroscopic methods and X-ray diffraction analysis. Compounds 1 and 2 are stereoisomers of putative [2 + 4]-cycloaddition reactions, and 3 is a trinorsesquiterpene dimer containing a 6/6/5/6/6/6 hexacyclic framework, while 4 possesses a 8-oxabicyclo[3.2.1]oct-6-ene skeletal core. Plausible biosynthetic pathways for 1-4 are proposed. Biochemical studies show that compound 1 promotes ca. 60% expression of keratinocyte-specific markers in adipose-derived stem cells at 10 μM.