Guidongnins I-J: Two New 6,7-seco-7,20-Olide-ent-kaurene Diterpenes with Unusual Structures from Isodon rubescens.

Two undescribed ent-kaurene diterpenes, named guidongnins I (1) and J (2), were isolated from the medicinal plant Isodon rubescens. Compound 1 was determined to contain an unprecedented 23 carbons in the skeleton by bearing an extra isopropyl group at C-17 out of the diterpenoid parent structure, and compound 2 was the first example of 6,7-seco-7,20-olide-ent-kaurenes with two fused-tetrahydrofuran rings formed between C-6 and C-19/C-20 through oxygen bridges. Their structures, including their absolute configurations, were determined using the analyses of the spectroscopic and X-ray diffraction data. Guidongnins I (1) and J (2) were assessed for their anti-cancer activities against the growth of various cancer cell lines, and 2 displayed cytotoxic potency against HepG2 at IC50 27.14 ± 3.43 µM.

Prognostic value of initial routine laboratory blood tests in patients with aneurysmal subarachnoid hemorrhage requiring mechanical ventilation: a retrospective cohort study.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) necessitating mechanical ventilation (MV) presents a serious challenge for intensivists. Laboratory blood tests reflect individual physiological and biochemical states, and provide a useful tool for identifying patients with critical condition and stratifying risk levels of death. This study aimed to determine the prognostic role of initial routine laboratory blood tests in these patients. Methods: This retrospective cohort study included 190 aSAH patients requiring MV in the neurosurgical intensive care unit from December 2019 to March 2022. Follow-up evaluation was performed in May 2022 via routine outpatient appointment or telephone interview. The primary outcomes were death occurring within 7 days after discharge (short-term mortality) or reported at time of follow-up (long-term mortality). Clinico-demographic and radiological characteristics, initial routine laboratory blood tests (e.g., metabolic panels and arterial blood gas analysis), and treatment were analyzed and compared in relation to mortality. Multivariable logistic and Cox regression analyses, with adjustment of other clinical predictors, were performed to determine independent laboratory test predictors for short- and long-term mortality, respectively. Results: The patients had a median age of 62 years, with a median World Federation of Neurosurgical Societies grade (WFNS) score of 5 and a median modified Fisher grade (mFisher) score of 4. The short- and long-term mortality of this cohort were 60.5% and 65.3%, respectively. Compared with survivors, non-survivors had more severe disease upon admission based on neurological status and imaging features and a shorter disease course, and were more likely to receive conservative treatment. Initial ionized calcium was found to be independently associate with both short-term [adjusted odds ratio (OR): 0.92; 95% confidence interval (CI): 0.86 to 0.99; P=0.020] and long-term mortality [adjusted hazard ratio (HR): 0.95; 95% CI: 0.92 to 0.99; P=0.010], after adjusting for potential confounders. Moreover, the admission glucose level was found to be associated only with short-term mortality (adjusted OR: 1.19; 95% CI: 1.06 to 1.34; P=0.004). Conclusions: Laboratory screening may provide a useful tool for the management of aSAH patients requiring MV in stratifying risk levels for mortality and for better clinical decision-making. Further study is needed to validate the effects of calcium supplementation and glucose-lowering therapy on the outcomes in this disease.

3,4-Seco-Isopimarane Diterpenes from the Twigs and Leaves of Isodon Flavidus.

Three isopimarane diterpenes [fladins B (1), C (2), and D (3)] were isolated from the twigs and leaves of Chinese folk medicine, Isodon flavidus. The chemical structures were determined by the analysis of the comprehensive spectroscopic data, and the absolute configuration was confirmed by X-ray crystallographic analysis. The structures of 1-3 were formed from isopimaranes through the rearrangement of ring A by the bond break at C-3 and C-4 to form a new δ-lactone ring system between C-3 and C-9. This structure type represents the first discovery of a natural isopimarane diterpene with an unusual lactone moiety at C-9 and C-10. In the crystal of 1, molecules are linked to each other by intermolecular O-H···O bonds, forming chains along the b axis. Compounds 1-3 were evaluated for their bioactivities against different diseases. None of these compounds displayed cytotoxic activities against HCT116 and A549 cancer cell lines, antifungal activities against Trichophyton rubrum and T. mentagrophytes, or antiviral activities against HIV entry at 20 µg/mL (62.9-66.7) µM. Compounds 1 and 3 did not show antiviral activities against Ebola entry at 20 µg/mL either; only 2 was found to show an 81% inhibitory effect against Ebola entry activity at 20 µg/mL (66.7 µM). The bioactivity evidence suggested that this type of compound could be a valuable antiviral lead for further structure modification to improve the antiviral potential.

Precision photothermal therapy and photoacoustic imaging by in situ activatable thermoplasmonics.

Phototherapy holds great promise for disease treatment; however, traditional "always-on" photoagents have been restricted to clinical translation due to their nonspecific response and side effects on normal tissues. Here, we show a tumor microenvironment activated photothermal and photoacoustic agent as an activatable prodrug and probe that allows precise cancer diagnosis and treatment. Such an in situ revitalized therapeutic and contrast agent is achieved via controllable plasmonic heating for thermoplasmonic activation. This enables monitoring of signal molecule dynamics, real-time photothermal and photoacoustic imaging of tumors and lymph node metastasis, and targeted photothermal therapy without unwanted phototoxicity to normal tissues. Our study provides a practical solution to the non-specificity problem in phototherapy and offers precision cancer therapeutic and theranostic strategies. This work may advance the development of ultrasensitive disease diagnosis and precision medicine.

Cascaded Amplifier Nanoreactor for Efficient Photodynamic Therapy.

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) to treat established diseases and has attracted growing attention in the field of cancer therapy. However, in a tumor microenvironment (TME), the inherent hypoxia and high level of antioxidants severely hamper the efficacy of ROS generation. Here, we describe a cascaded amplifier nanoreactor based on self-assembled nanofusiforms for persistent oxygenation to amplify ROS levels. The nanofusiform assembly is capable of photothermal and photodynamic treatment and regulation of redox oxidation stress by antioxidant depletion to prevent ROS tolerance. The Pt nanozyme decoration of the nanofusiform enables efficient oxygen supplements via Pt nanozyme-catalyzed decomposition of H2O2 overexpressed in TME and generation of O2. Furthermore, the temperature elevation resulted from the photothermal effect of the nanofusiform increases the catalase-like catalytic activity of the Pt nanozyme for boosted oxygen generation. Thus, such a triple cascade strategy using nanozyme-based nanofusiforms amplifies the ROS level by continuous oxygenation, enhancing the efficacy of PDT in vitro and in vivo. Meanwhile, an in vivo multi-modal imaging including near-infrared fluorescence imaging, photothermal imaging, and magnetic resonance imaging achieves precise tumor diagnosis. The rationally designed nanofusiform acts as an efficient ROS amplifier through multidimension strengthening of continuous oxygenation, providing a potential smart nanodrug for cancer therapy.

Puerarin suppresses the hepatic gluconeogenesis via activation of PI3K/Akt signaling pathway in diabetic rats and HepG2 cells.

Pueraria, a Chinese herbal medicine, plays an important role in many classic prescriptions for the treatment of diabetes. Puerarin is the main component of pueraria. The current in vivo and in vitro research mainly focus on exploring the potential mechanism of puerarin in inhibiting hepatic gluconeogenesis. The type 2 diabetic rats were established by a combination of small dosage of streptozotocin (STZ) injection with high-fat diet. After the administration of puerarin 4 weeks, the parameters of the glucose and lipid metabolism were determined. HepG2 cells were treated by palmitic acid (PA) to induce the insulin resistance in vitro model. After the treatment of puerarin, the glucose consumption and cell viability were examined. Then, the protein expression of PI3K, Akt, pAkt, pFOXO1, FOXO1, PEPCK and G6pase in liver tissue and HepG2 cells were evaluated by western blot. RT-PCR was used to measure the content of PEPCK, G6pase mRNA in liver tissue. The results showed that puerarin administration significantly decrease the level of FBG, HbA1C and triglycerides in diabetic rats. Mechanistic research showed that puerarin activating PI3K/Akt is puerarin-mediated beneficial effects and can be reversed by inhibitor of PI3K or Akt. In conclusion, puerarin inhibits hepatic gluconeogenesis by activating PI3K/Akt signaling pathway.

Plasmonic and Photothermal Immunoassay via Enzyme-Triggered Crystal Growth on Gold Nanostars.

Immunoassay is commonly used for the detection of disease biomarkers, but advanced instruments and professional operating are often needed with current techniques. The facile readout strategy for immunoassay is mainly limited to the gold nanoparticles-based colorimetric detection. Here, we show that photothermal nanoparticles can be applied for biosensing and immunoassay with temperature as readout. We develop a plasmonic and photothermal immunoassay that allows straightforward readout by color and temperature based on crystal growth, without advanced equipment. It is demonstrated that alkaline phosphatase-triggered silver deposition on the surface of gold nanostars causes a large blue shift in the localized surface plasmon resonance of the nanosensor, accompanied by photothermal conversion efficiency changes. This approach also allows dual-readout of immunoassays with high sensitivity and great accuracy for the detection of prostate-specific antigen in complex samples. Our strategy provides a promising way for point-of-care testing and may broaden the applicability of programmable nanomaterials for diagnostics.

Standard versus Abdominal Lifting and Compression CPR.

Background. This study compared outcomes of abdominal lifting and compression cardiopulmonary resuscitation (ALP-CPR) with standard CPR (STD-CPR). Materials and Methods. Patients with cardiac arrest seen from April to December 2014 were randomized to receive standard CPR or ALP-CPR performed with a novel abdominal lifting/compression device. The primary outcome was return of spontaneous circulation (ROSC). Results. Patients were randomized to receive ALP-CPR (n = 40) and STD-CPR (n = 43), and the groups had similar baseline characteristics. After CPR, 9 (22.5%) and 7 (16.3%) patients in the ALP-CPR and STD-CPR groups, respectively, obtained ROSC. At 60 minutes after ROSC, 7 (77.8%) and 2 (28.6%) patients, respectively, in the ALP-CPR and STD-CPR groups survived (P = 0.049). Patients in the ALP-CPR group had a significantly higher heart rate and lower mean arterial pressure (MAP) than those in the STD-CPR group (heart rate: 106.8 versus 79.0, P < 0.001; MAP: 60.0 versus 67.3 mm Hg, P = 0.003). The posttreatment PCO2 was significantly lower in ALP-CPR group than in STD-CPR group (52.33 versus 58.81, P = 0.009). PO2 was significantly increased after ALP-CPR (45.15 to 60.68, P < 0.001), but it was not changed after STD-CPR. PO2 after CPR was significantly higher in the ALP-CPR group (60.68 versus 44.47, P < 0.001). There were no differences between genders and for patients who are > 65 or ≤ 65 years of age. Conclusions. The abdominal lifting and compression cardiopulmonary resuscitation device used in this study is associated with a higher survival rate after ROSC than standard CPR.

Discovery of antifungal constituents from the Miao medicinal plant Isodon flavidus.

ETHNOPHARMACOLOGICAL RELEVANCE: Leigong Mountain is an area in the Southwest of China where there is a high incidence rate of athlete's foot, but the Miao people, a Chinese minority who reside in this mountainous area have suffered less from this disease due to their use of the herbal medicine Isodon flavidus (Hand.-Mazz.) H. Hara. AIM OF THE STUDY: The present study is to identify the active chemical constituents responsible for antifungal effects of the folk medicine plant. MATERIALS AND METHODS: The natural compounds were separated from the methanol extract of the twigs and leaves of I. flavidus by phytochemical study using chromatographic methods, and their chemical structures were determined by analysis of the spectroscopic data including 1D and 2D NMR spectra. The absolute configuration of fladin A (1) was further confirmed by X-ray crystallographic analysis. The compounds were evaluated for their antifungal activity against the athlete's foot fungus Trichophyton rubrum. They were further evaluated for their antimicrobial and anti-biofilm activity against the dental pathogens Streptococcus mutans, Porphyromonas gingivalis and Candida albicans. RESULTS: Phytochemical and biological studies of I. flavidus led to the discovery of two antifungal compounds, fladin A (1) and lophanic acid (2). Fladin A (1) is a novel diterpene with an unprecedented cyclic ether group formed between C-4 and C-9. Lophanic acid (2) displayed inhibition activity against the athlete's foot fungus Trichophyton rubrum with an MIC value of 7.8µg/mL, and fladin A (1) also showed inhibition activity against the fungus with a MIC value of 62.5µg/mL. CONCLUSIONS: Our identification of two antifungal compounds provided strong evidence for the Miao people to use I. flavidus as a medicinal plant for treatment of athlete's foot disease. The very different chemical structures of the active compounds from those in the market presents them as potential antifungal lead compounds for follow-up study.

[Bushen Tiaojing Recipe Regulated Expressions of BMPR I[/ALK6-Smads in Mouse Oocytes Cul- ture in vitro].

Objective To observe the effects of Bushen Tiaojing Recipe (BTR) on the counts of survival preantral follicles and the bone morphogenetic protein receptor II (BMPR II )/activin receptor- like kinase 6-drosophila mothers against decapentaplegic proteins (ALK6-Smads) signal pathway in oocytes cultured in vitro, and to study its mechanism for improving the quality of oocytes. Methods Prean- tral follicles were mechanically isolated from 65 female 12-day old healthy Kunming mice, which were inoculated by normal rats' serum (as the control group) , high, medium, low dose BTR containing serums (as Shen-supplementing groups) , high dose BTR containing serum + K02288 (as the inhibitor group) , respectively. All were cultured by common method in vitro. On the 6th day the counts of survival preantral follicles were compared between each Shen-supplementing group and the control group respectively. mR- NA expressions of BMPR II, ALK6, Smad1 , Smad5, and Smad8 were detected by Real-time fluorescence quantitative PCR. The protein expressions of indices mentioned above and phospho-Smadl/5/8 (p- Smadl/5/8) were detected by cellular immunofluorescence test. Results Compared with the control group, the quantity of survival preantral follicles increased in the high dose BTR containing serum group; mRNA expressions of BMPR II, ALK6, Smad5, and Smad8 were elevated, protein expressions of indi- ces mentioned above and p-Smadl/5/8 were increased in the 3 Shen-supplementing groups (P <0. 05) ; mRNA and protein expressions of Smad1 were increased in high and medium dose BTR containing serum groups (P<0.05). Compared with the high dose BTR containing serum group, protein expressions of Smad1/5/8 were reduced in the inhibitor group (P <0.05). Conclusion BTR could elevate the quantity of survival preantral follicles cultured in vitroand improve the quality of oocytes, which might be possibly as- sociated to regulating the BMPR II/ALK6-Smads signal pathway in oocytes.