Biomarkers based on multiplatform comprehensive analysis: A systematic analysis of Geng-Nian-Shu in perimenopausal syndrome.

Although Geng-Nian-Shu has been shown to be clinically effective in perimenopausal syndrome, its active components and mechanism have not yet been elucidated. To demonstrate the mechanism-based biomarkers of Geng-Nian-Shu in treating perimenopausal syndrome, a total of 135 chemical constituents including 52 prototype blood constituents were identified via high-performance liquid chromatography-quadrupole-time of flight/mass spectrometry. Then, network pharmacology showed significant enrichment for the PhosphoInositide-3 Kinase/Akt pathway, suggesting that it may be the main regulatory pathway for the Geng-Nian-Shu treatment of the perimenopausal syndrome. Subsequently, multivariate analysis was performed between the Geng-Nian-Shu sham-treated and Geng-Nian-Shu ovariectomy-treated groups and further screened out 18 prototype blood constituents by correlation analysis with plasma estrogen levels to identify potential biomarkers associated with Geng-Nian-Shu treat the ovariectomy-induced perimenopausal syndrome. Finally, the results of pharmacological experimental verification and Pearson correlation analysis indicated that catalpol, ligustilide, paeoniflorin, and gallic acid were selected as biomarkers of Geng-Nian-Shu which were strongly and positively correlated with PhosphoInositide-3 Kinase/Akt signaling pathway. In this study, based on high-performance liquid chromatography-quadrupole-time of flight/mass spectrometry combined with pharmacodynamics, network pharmacology, pharmacology, and other disciplines, we explored the effects and mechanisms of Geng-Nian-Shu in the treatment of perimenopausal syndrome at multiple levels. Using multiplatform technology to investigate the role of Geng-Nian-Shu represents a new strategy for the selection and verification of biomarkers of Geng-Nian-Shu and provides a basis for further development and utilization of Geng-Nian-Shu.

Mesoporous Silica-Encapsulated Gold Nanorods for Drug Delivery/Release and Two-Photon Excitation Fluorescence Imaging to Guide Synergistic Phototherapy and Chemotherapy.

Photothermal therapy is a promising light-based medical treatment that relies on light absorption agents converting light irradiation into localized heat to destroy cancer cells or other diseased tissues. It is critical to enhance the therapeutic effects of cancer cell ablation for their practical applications. This study reports a high-performance combinational therapy for ablating cancer cells, including both photothermal therapy and chemotherapy to improve therapeutic efficiency. The prepared AuNR@mSiO2 loading molecular Doxorubicin (Dox) assemblies were highlighted by merits of facile acquisition, great stability, easy endocytosis, and rapid drug release in addition to improved anticancer capability upon irradiation with a femtosecond pulsed near-infrared (NIR) laser, where AuNR@mSiO2 nanoparticles afforded a high photothermal conversion efficiency of 31.7%. Two-photon excitation fluorescence imaging was introduced into confocal laser scanning microscope multichannel imaging to track the drug location and cell position in real time for monitoring the process of drug delivery in killing human cervical cancer HeLa cells and then to realize imaging-guiding cancer treatment. These nanoparticles exhibit widespread potential in photoresponsive utilizations including photothermal therapy, chemotherapy, one- and two-photon excited fluorescence imaging, and 3D fluorescence imaging and cancer treatment.

The efficacy and safety of Zengxiao Jiandu decoction combined with definitive concurrent chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a randomized, double-blind, placebo-controlled clinical trial.

Background: Traditional Chinese medicine (TCM) makes a synergistic and attenuative effect when combined with chemoradiotherapy. However, strong evidence-based studies are lacking. The study sought to investigate whether Zengxiao Jiandu decoction as an adjunctive therapy is superior to definitive concurrent chemoradiotherapy (DCCRT) alone in unresectable, locally advanced (LA), stage III non-small cell lung cancer (NSCLC). Methods: Patients with unresectable LA-NSCLC were randomly assigned to receive DCCRT either combined with Zengxiao Jiandu decoction (TCM arm) or placebo therapy (Control arm), by computer-generated random assignment lists using a central randomization system. The patients were routinely followed-up every 3 months for the first 2 years after the therapy, and every 6 months for the subsequent 3 years, or earlier if clinically indicated. The primary endpoint was grade ≥3 chemoradiotherapy-related toxicities, while secondary endpoints included the completion rate of chemoradiotherapy, the clinical objective response rate (ORR), and survival. The placebo achieved full consistency in color, aroma, taste and appearance with the Zengxiao Jiandu decoction. Results: From February 2019 to December 2020, 163 patients were randomly allocated to TCM arm (n=82) or Control arm (n=81). Fifty-nine (72.0%) patients in TCM arm finished chemoradiotherapy per protocol and 79 (96.3%) received protocol-specified Zengxiao Jiandu decoction. Forty-two patients in Control arm finished chemoradiotherapy per protocol. The incidence of grade ≥3 chemoradiotherapy-related toxicities was higher in Control arm than TCM arm (44.4% vs. 31.7%, P=0.094). Grade ≥3 radiation pneumonitis occurred more frequently in Control arm than TCM arm (13.6% vs. 3.7%, P=0.024). The completion rate of the protocol-specified chemotherapy was significantly higher in TCM arm than Control arm (79.3% vs. 64.2%, P=0.033), but the completion rates of the definitive-dose radiotherapy were similar. There were no significant differences in ORR between the 2 arms. The progression-free survival (PFS) of TCM arm was significantly better than Control arm (median PFS, 12.0 vs. 9.0 months, P=0.035). However, Zengxiao Jiandu decoction was not found to produce any significant benefit in overall survival. Conclusions: The Zengxiao Jiandu decoction adjunctive therapy, as compared to DCCRT alone, reduced grade ≥3 radiation pneumonitis, improved the completion rate of DCCRT, and prolonged PFS for unresectable LA-NSCLC. Trial Registration: Chinese Clinical Trial Registry ChiCTR2000031667.

Targeted Chinese Medicine Delivery by A New Family of Biodegradable Pseudo-Protein Nanoparticles for Treating Triple-Negative Breast Cancer: In Vitro and In Vivo Study.

Triple negative breast cancer (TNBC) has the worst overall survival among all breast cancer subtypes; 80% of TNBC harbors TP53 mutation. Gambogic acid (GA) is an herbal compound isolated from the dry brownish gamboge resin of Garcinia hanburyi. A new family of biodegradable polymer, the folate (FA)-conjugated arginine-based poly(ester urea urethane)s nanoparticles (FA-Arg-PEUU NP), was developed as nano-carrier for GA. Its anti-TNBC effects and the underlying mechanism of action were examined. The average diameters of FA-Arg-PEUU NP and GA-loaded FA-Arg-PEUU NP (NP-GA) in water are around 165 and 220nm, respectively. Rhodamine-tagged FA-Arg-PEUU NP shows that the conjugation of FA onto Arg-PEUU NPs facilitates the internalization of FA-Arg-PEUU-NP into TNBC. Compared to free-GA at the same GA concentrations, NP-GA exhibits higher cytotoxicity in both TP53-mutated and non-TP53 expressed TNBC cells by increasing intrinsic and extrinsic apoptosis. In HCC1806-bearing xenograft mouse model, the targeted delivery of GA by the FA-Arg-PEUU-NP nano-carriers to the tumor sites results in a more potent anti-TNBC effect and lower toxicity towards normal tissues and organs when compared to free GA. Furthermore, NP-GA also reduces the tumor-associated macrophage (TAM) M1/M2 ratio, suggesting that the use of Arg-based nanoparticles as carriers for GA not only makes the surface of the nanoparticles positively charged, but also confers on to the nanoparticles an ability to modulate TAM polarization. Our data clearly demonstrate that NP-GA exhibits potent anti-TNBC effects with reduced off-target toxicity, which represents novel alternative targeted therapeutics for TNBC treatment.

Overexpression of StGA2ox1 Gene Increases the Tolerance to Abiotic Stress in Transgenic Potato (Solanum tuberosum L.) Plants.

It has been known that GA2ox is one kind of key enzyme gene in the gibberellin synthesis pathway, which plays important regulatory roles throughout plant whole growth and development. In this article, one of the GA2ox family genes, designated StGA2ox1, was isolated from potato (Solanum tuberosum L.). The full length of cDNA is 1005 bp, and the cDNA corresponds to a protein of 334 amino acids; this protein was classified in a group with NtGA2ox3 based on multiple sequence alignments and phylogenetic characterization. A plant expression vector pCAEZ1383-StGA2ox1 was established. qRT-PCR showed that the expression of RD28, DREB1, WRKY1, and SnRK2 genes in StGA2ox1 transgenic plant is higher than that in non-transformed control under dehydration, low temperature conditions, and abscisic acid treatments. Overexpression of StGA2ox1 cDNA in transgenic potato plants exhibited an improved salt, drought, exogenous hormone, and low temperature stress tolerance in comparison to the non-transformed plant. The enhanced stress tolerance may be associated with the subsequent accumulation of proline osmoprotectant in addition to a better control of chlorophyll, carotenoids, and water loss. These data suggest that the StGA2ox1 is involved in the regulation of plant growth and tolerance in potato by regulating the synthesis of gibberellin.

The Protective Effect of Total Flavones from Rhododendron simsii Planch. on Myocardial Ischemia/Reperfusion Injury and Its Underlying Mechanism.

OBJECTIVES: Total flavones from Rhododendron simsii Planch. (TFR) are the effective part extracted from the flowers of Rhododendron simsii Planch. and have obvious protective effects against cerebral ischemic or myocardial injuries in rabbits and rats. However, their mechanism of cardioprotection is still unrevealed. Therefore, the present study was designed to investigate the effect of TFR on myocardial I/R injury and the underlying mechanism. METHODS: TFR groups were treated by gavage once a day for 3 days at a dose of 20, 40, and 80 mg/kg, respectively, and then the model of myocardial I/R injury was established. Myocardial infarction, ST-segment elevation, and the expression of UTR, ROCK1, ROCK2, and p-MLC protein in rat myocardium were determined at 90 min after reperfusion. UTR siRNA in vivo transfection and competition binding assay method were used to study the relationship between the protective effect of TFR and UTR. RESULTS: The expression of UTR protein markedly decreased in myocardium of UTR siRNA transfection group rats. TFR could significantly reduce the infarct size and inhibit the increase of RhoA activity and ROCK1, ROCK2, and p-MLC protein expressions both in WT and UTR knockdown rats. The reducing rate of TFR in myocardial infarction area, RhoA activity, and ROCK1, ROCK2, and p-MLC protein expressions in UTR knockdown rats decreased markedly compared with that in WT rats. In addition, TFR had no obvious effect on the increase of ΣST in UTR knockdown rats in comparison with that in model group. In particular, TFR could significantly inhibit the combination of [125I]-hu-II and UTR, and IC50 was 0.854 mg/l. CONCLUSIONS: The results indicate that the protective effect of TFR on I/R injury may be correlated with its blocking UTR and the subsequent inhibition of RhoA/ROCK signaling pathway.

Metal Nanoparticles for Diagnosis and Therapy of Bacterial Infection.

Infectious diseases caused by pathogenic bacteria, especially multidrug-resistant bacteria, and their global spreading have become serious public health concerns. Early diagnosis and effective therapy can efficiently prevent deterioration and further spreading of the infections. There is an urgent need for sensitive, selective, and facile diagnosis as well as therapeutically potent treatment. The emergence of nanotechnology has provided more options for diagnosis and treatments of bacterial infections. Metal nanoparticles and metal oxide nanoparticles have drawn intense attention owing to their unique optical, magnetic, and electrical properties. These versatile metal-based nanoparticles have great potential for selective detection of bacteria and/or therapy. This review gives an overview of recent efforts on developing various metal-based nanoparticles for bacterial detection and infection therapy. It begins with an introduction of fundamental concepts and mechanisms in designing diagnostic and therapeutic strategies. Representative achievements are selected to illustrate the proof-of-concept in vitro and in vivo applications. A brief discussion of challenges and perspective outlook in this field is provided at the end of this review.

Relative contribution of Na+/K+ homeostasis, photochemical efficiency and antioxidant defense system to differential salt tolerance in cotton (Gossypium hirsutum L.) cultivars.

In this study, the role of specific components of different coping strategies to salt load were identified. A pot experiment was conducted with four cotton (Gossypium hirsutum L.) cultivars (differing in salt-sensitivity) under salinity stress. Based on observed responses in growth performance and physiological characteristics, CZ91 was the most tolerant of the four cultivars, followed by cultivars CCRI44 and CCRI49, with Z571 being much more sensitive to salt stress. To perform this tolerant response, they implement different adaptative mechanisms to cope with salt-stress. The superior salt tolerance of CZ91 was conferred by at least three complementary physiological mechanisms: its ability to regulate K+ and Na+ transport more effectively, its higher photochemical efficiency and better antioxidant defense capacity. However, only one or a few specific components of these defense systems play crucial roles in moderately salt tolerant CCRI44 and CCRI49. Lower ROS load in CCRI44 may be attributed to simultaneous induction of antioxidant defenses by maintaining an unusually high level of SOD, and higher activities of CAT, APX, and POD during salt stress. CCRI49 could reduce the excess generation of ROS not only by maintaining a higher selective absorption of K+ over Na+ in roots across the membranes through SOS1, AKT1, and HAK5, but also by displaying higher excess-energy dissipation (e.g., higher ETR, PR and qN) during salt stress. Overall, our data provide a mechanistic explanation for differential salt stress tolerance among these cultivars and shed light on the different strategies employed by cotton cultivars to minimize the ill effects of stress.

In vitro, ex vivo and in vivo anti-hypertensive activity of Chrysophyllum cainito L. extract.

Chrysophyllum cainito L., a traditional herbal medicine, could have the potential for management of hypertension due to presence of polyphenolic compounds. The extracts and fractions of the pulp of plant were evaluated for in vitro (inhibition of angiotensin I converting enzyme/ACE assay), ex vivo (isolated aorta relaxation assay) and in vivo (salt induced hypertensive rat assay). The alcoholic and aqueous extract (ALE and AQE respectively) of fruit of plant C. cainito was having 14.8 and 9.2% yield respectively. The fractionation with ethyl alcohol (EAF) and butanol (BTF) yielded 2.52 & 2.17% respectively from ALE and 0.46 & 0.31% respectively from AQE with respect to fruit pulp dry weight. More phenolic content was found in ALE (3.75±0.15 mg gallic acid equivalent or GAE g(-1) of dry power of fruit pulp) compared to AQE and maximum in ethyl acetate fraction of ALE (ALE-EAF) (2.32±0.21 mg GAE g(-1) of dry power of fruit pulp) among all fractions. ACE inhibition activity was found to be maximum in ALE-EAF 62.5±7.34%. While ex vivo study using isolated tissue of aorta showed again showed maximum activity (62.82±6.19 and 46.47±8.32% relaxation with 50 µg mL(-1) and 10 µg mL(-1) GAE concentration respectively). ALE-EAF reduced the elevated arterial pressure of salt induced hypertensive rat significantly to the level of normotensive animal group. Results of ALE-EAF have shown its potential as a source for novel constituent for the treatment hypertension and should further be studied for isolation of specific constituent for more effectiveness.

[Effects of rosuvastatin on monocrotaline-induced pulmonary artery hypertension in rats].

OBJECTIVE: To investigate the effects of rosuvastatin on monocrotaline (MCT)-induced pulmonary artery hypertension in rats. METHODS: Pulmonary arterial hypertension was induced by a single subcutaneous injection of monocrotaline (50 mg/kg) in rats. In the prevention protocol, 32 male Sprague-Dawley rats were randomly divided into four groups (n = 8 each): low-dose rosuvastatin prevention group (2 mg×kg(-1)×d(-1)), high-dose rosuvastatin prevention group (10 mg×kg(-1)×d(-1)), pulmonary arterial hypertension group, normal control group. Beginning on the MCT injection day, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by gavage. In the treatment protocol, 52 male Sprague-Dawley rats were randomly divided into four groups (n = 13 each): low-dose rosuvastatin treatment group (2 mg×kg(-1)×d(-1)), high-dose rosuvastatin treatment group (10 mg×kg(-1)×d(-1)), pulmonary arterial hypertension group, normal control group. Four weeks after MCT injection, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by gavage. At the end of study, survival rates, mean pulmonary arterial pressure (mPAP), wall thickness of small pulmonary artery and right ventricular hypertrophy among groups were compared. The expression levels of proliferating cell nuclear antigen (PCNA) and endothelial nitricoxide synthase (eNOS) protein in small pulmonary artery, the expression levels of Rho kinase 1(ROCK-1) and eNOS mRNA in lung tissue were also detected. RESULTS: All rats in the prevention protocol survived. Rosuvastatin treatment improved survival in the treatment protocol (58%, 75% vs.30%, P < 0.05). Rosuvastatin therapy in both preventive or treatment protocols significantly lowered mPAP [prevention protocol: (27.53 ± 3.43), (25.72 ± 1.76) vs. (36.05 ± 2.45) mm Hg (1 mm Hg = 0.133 kPa), P < 0.01; treatment protocol: (30.39 ± 3.17), (27.59 ± 1.99) vs. (40.68 ± 1.39) mm Hg, P < 0.01], reduced thickening of small pulmonary artery wall (P < 0.01) and right ventricular hypertrophy (P < 0.01). Rosuvastatin also inhibited PCNA expression of SMC (P < 0.01), restored eNOS expression of EC (P < 0.05) and inhibited ROCK-1 mRNA expressions in lung tissue (P < 0.05). CONCLUSIONS: Rosuvastatin therapy reduced mPAP in monocrotaline-induced pulmonary arterial hypertension rat model and this effect is linked with inhibition of ROCK-1 expression, inhibition of smooth muscle cell proliferation and restoration of endothelial cell functions.