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Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B’/B and C’/C. POST1 promotes the generation of the functional S1P-C’/C from S1P-B’/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/β-subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis. Electronic supplementary material The online version of this article (10.1007/s13238-020-00753-3) contains supplementary material, which is available to authorized users.

Diabetic nephropathy (DN) is one of the most important complications&nbsp, of&nbsp, diabetes，&nbsp, and the leading cause of end-stage renal disease (ESRD). While Chromium picolinate (CrPic) supplementation has been found to be effective in treating diabetes, its effects on diabetic-induced nephropathy have not been studied. Therefore, in this study, CrPic (1 mg kg &minus, 1 d &minus, 1) was administered to a DN rat model by oral gavage for eight weeks to investigate its effects. The results show that CrPic supplementation caused a decrease in levels of blood glucose, serum insulin, blood urea nitrogen (BUN), serum creatinine, and urinary albumin in DN rats. It also reversed renal pathological changes, including renal glomerular sclerosis and interstitial fibrosis. In addition, the oxidative defense system in the kidneys of DN rats was found to be improved, the biological activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) increased, and the content of malondialdehyde (MDA) lowered. Immunohistochemical results reveal that the expression levels of renal transforming growth factor-&beta, 1 (TGF-&beta, 1), Smad 2, and Smad 3 decreased significantly in the kidneys of rats in the CrPic-treated group. CrPic administration was thus found to ameliorate diabetic nephropathy in SD rats via an antioxidative stress mechanism, as well the ability to inhibit TGF-&beta, 1/Smad2/3 expression. This study suggests that CrPic could be a potential renal-protective nutrient against diabetic nephropathy.

Two new pyran-2-one derivatives, crotonpyrones A (1) and B (2), were isolated from the roots of Croton crassifolius. Compounds 1 and 2 represent the first examples of the natural occurrence of the new pyran-2-one derivatives in the family Euphorbiaceae. Their structures were elucidated by extensive spectroscopic analysis (HRESIMS, 1D and 2D NMR), and the structure of compound 1 was further confirmed by single-crystal X-ray diffraction analyses. Compounds 1 and 2 showed good cytotoxicity against human cancer cell lines of HeLa and NCI-446. Compound 2 also exhibited antibacterial activity against Staphylococcus aureus.

Background By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. Methods From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. Results 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). Conclusions This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam. Trial registration NTC01165372

Euphorikanin A (1), an unprecedented diterpenoid lactone which possesses a novel 5/6/7/3-fused tetracyclic ring skeleton, was isolated from the roots of Euphorbia kansui. The chemical structure and absolute stereochemistry were elucidated on the basis of extensive spectroscopic methods and single-crystal X-ray diffraction analysis. Compound 1 exhibited moderate cytotoxicity against two human tumor cell lines HeLa and NCI-446. A proposed biosynthetic pathway of compound 1 is also described.

A chemical investigation of Croton crassifolius afforded a novel norclerodane diterpenoid (1) with an unprecedented six-membered oxygen ring between C-1 and C-12, together with three known compounds. The structure of the new compound was elucidated based on spectroscopic (IR, 1D, and 2D NMR) and HR-ESI-MS techniques. This report describes the first example of a natural norclerodane with a 4 H-chromene ring system.

= 11.2, H-12)], which represented the structure moieties C-1–C-5 and C-7–C-12 of a lathyrane diterpenoid, respective-ly. The HMBC correlations enable assembly of units A andB with the quaternary carbons and other functionalities. TheHMBC correlations of H-5 with C-3, C-6, C-7, and C-17,correlations of H-12 with C-11, C-13, C-14, and C-20, andcorrelations of H

Crocrassins A (1) and B (2), two novel sesquiterpenoids with a unique skeleton, were isolated from a Chinese medicinal plant Croton crassifolius. Their structures were assigned on the basis of detailed spectroscopic analyses (especially HRESIMS and 2D NMR), and their absolute configuration was established via single-crystal X-ray diffraction studies as well as chemical transformation.

A sensitive and specific optical immunoassay (OIA) has been developed for snake venom detection. The assay is based on the principle of detection of physical changes in thickness of molecular thin film resulting from specific binding events on an optical silicon chip (SILAS-I, ThermoBioStar, Colorado, USA). The reflection of white light through the thin film results in destructive interference of a particular wavelength of the light from gold to purple-blue depending on the thickness of the thin film formed or the amount of venom in the test sample. A prototype test kit for the simultaneous identification of species and semi-quantitative detection of venoms from four medically important snakes of South Vietnam (Trimeresurus albolabris, Calloselasma rhodostoma, Naja kaouthia and Ophiophagus hannah) has been developed. The kit can detect venom analytes in blood, plasma, urine, wound exudates, blister fluid or tissue homogenates. The efficacy of the test kit in snakebite diagnosis has been demonstrated in experimental envenomations and sample analytes taken from snakebite victims in South Vietnam. This rapid snake venom detection kit based on OIA technique is potentially applicable in the clinics as well as in the field.

A highly sensitive avidin-biotin optical immunoassay (AB-OIA) has been developed for the detection of beta-bungarotoxin (beta-BuTx), a neurotoxin from the venom of Bungarus multicinctus, in whole blood, plasma, and urine. Affinity purified rabbit IgG anti-beta-BuTx antibody was immobilized on an optically active silicon surface (SILIAS wafer). The test sample was incubated and the antigen-antibody reaction was monitored by the addition of a biotinylated monoclonal antibody (mAb 15) specific to the toxin, avidin-horseradish peroxidase (HRP) and tetramethylbenzidine substrate. The silicon assay surface technology enables us to directly visualize a physical change in the optical thickness of the antibody thin film. The change in thickness is due to the specific capture of the toxin on the surface and when the substrate is added, the binding event is amplified, which then alters the reflected light path and a change in colour is visualized. The assay could detect beta-BuTx levels as low as 16 pg/ml in sample buffer and 100 pg/ml in whole blood or plasma. The AB-OIA is simple, requires only 40 microl of biological fluid and can be performed without specialized equipment. The efficacy of the test for detection of beta-BuTx in blood or plasma obtained from mice during experimental envenomation with B. multicinctus venom was demonstrated. The AB-OIA was also used to quantitate the postmortem level of beta-BuTx in various organs such as brain, liver, and kidney, as well as the tissue at the site of injection. Development of a simple, rapid snake toxin detection kit based on AB-OIA technique potentially applicable in the clinics as well as in the field is discussed.

isolation, structural elucidation and cytotoxicity of the new halimane diterpenoid crassifoliusin A (I)

A new eremophilane norsesquiterpenoid (1), together with a known eremophilane sesquiterpenoid (2), was isolated from the leaves of Ligularia virgaurea. The structure of 1 was elucidated by a combination of spectroscopic analysis (IR, 1D NMR, 2D NMR, and HR-ESI-MS), and its absolute configuration was determined by a single-crystal X-ray diffraction experiment (with copper radiation). The known compound 2 was identified by comparison of its physical and spectral data with those reported in the literature. Compound 1 was assayed for its cytotoxic activities against human cervical carcinoma cell (HeLa) and human small cell lung cancer cell (NCI-446) lines.

The new lathyrane diterpenoid (I) shows moderate activity against the cancer cell line K562.

The title compound, C17H20O5, an eremophilane sesquiternoid, was isolated from the roots of Ligularia lapathifolia. The mol­ecule contains four fused rings of which the six-membered ring A adopts a half-chair conformation, the six-membered ring B adopts a chair conformation, the five-membered ring C is almost planar (r.m.s. deviation = 0.015 A) and the five-membered ring D adopts an envelope conformation with the quaternary C atom as the flap. The methyl and the eth­oxy groups adopt a syn conformation and the A/B ring junction is cis-fused. No directional inter­molecular inter­actions could be identified in the crystal.

Experiments have been conducted to investigate the sheetflow sediment transport of uniform sand under asymmetric oscillatory flows in combination with relatively strong opposite currents. Two kinds of nearshore waves were performed, namely, velocity asymmetric waves and acceleration asymmetric waves. Image analysis technique is utilized to study major influences of wave shapes and current through observing the instantaneous sheetflow layer thickness. Maximum sheetflow layer thickness was formulated and incorporated to an enhanced Watanabe and Sato’s formulation. The new conceptual model is examined its validity for a wide range of experimental conditions

Liposomes containing either pilocarpine hydrochloride or pilocarpine free base were prepared by the sonication method. This manufacturing process yielded after removal of non-encapsulated solute, small multilamellar vesicles (MLV) as was confirmed by electron microscopy examinations. For an identical liposomal composition, the encapsulation capacity and the drug content of the liposomes were drastically higher for pilocarpine hydrochloride than for pilocarpine free base. Investigation of the preparative parameters revealed that increasing the initial amount of drug decreased the drug content and the encapsulation efficiency of the liposomes formed. Since fixed amounts of lipids were used, the volume sequestration rate decrease was attributed to a moderate viscosity increase of the dispersion medium. Increase of phospholipid concentration at a constant ratio of cholesterol and dicetylphosphate to phosphatidylcholine reduced the aqueous volume entrapped per mg of lipid and subsequently the pilocarpine content in the liposomes. Negatively charged liposomes gave larger rates of pilocarpine hydrochloride and aqueous volume encapsulation than neutral liposomes but, on the contrary, positively charged liposomes gave the lowest rates of pilocarpine hydrochloride and aqueous volume encapsulation. Thus, for drug carrying the same net charge as the phospholipids an increase in the surface charge density of the liposome was not only ineffective, but actually resulted in a lower drug encapsulation due to electrostatic repulsion. Preliminary in vivo results on rabbit eyes suggested that the liposomal vehicle was probably unable to improve sufficiently the corneal penetration of pilocarpine to reach satisfactory therapeutic levels when administered at lower concentrations than commonly used.

Different effects of chronic treatment with bromocriptine (BRO) on D-1 and D-2 receptors in the rat were studied through behavioral observation and DA receptor binding assays. Chronic BRO led to enhancement of stereotypy to apomorphine (APO), at the same time it increased the density of D-1 receptor binding by 43 % and decreased that of D-2 receptor binding by 21 %. Our data suggest that BRO has different effects on D-1 and D-2 receptors and the behavioral hypersensitivity caused by BRO may be relevant to the proliferation of D-1 receptor.