Nowadays, colorectal cancer is the fourth most common type of tumor all over the world. When diagnosed, ∼50%-60% of tumors have metastasized, thus resulting in a grim prognosis. Chemotherapy is regarded as standard treatment for patients with colorectal cancer, however, limitations of chemotherapy cannot be ignored, such as low selectivity, insufficient concentrations in tumor tissues, and systemic toxicity. Recently, six targeted drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer (mCRC), including bevacizumab, aflibercept, regorafenib, cetuximab, and panitumumab. The development of these drugs marked significant advancement in the field of mCRC therapy. The addition of biologic agents to chemotherapy has prolonged the median overall survival. Now, many investigational drugs are under clinical trials, of which programmed death (PD)-1/L1 has drawn much attention. In this review, new biologic agents under clinical trials such as MEK/MET/RAS/RAF/PD-1 inhibitors with potentials for mCRC treatment are concluded by describing targeted drugs approved by FDA, to offer new insights into global trends and future development.

Phenylethanoid glycosides are a group of phenolic compounds with diverse biological activities such as hypotensive, diuretic, and hypoglycemic effects. In this study, a target profiling analysis approach using ultra-performance liquid chromatography coupled with tandem quadrupole mass spectrometry (MS) was established on the basis of parent ion scanning for m/z 161, the characteristic product ion for phenylethanoid glycosides. It was successfully employed to discriminate the chemical composition of phenylethanoid glycosides between Plantaginis Herba and Plantaginis Semen, two medicinal parts of Plantago plants, which are widely used as herbal medicine in China. Totally, 34 phenylethanoid glycosides were characterized and tentatively identified by their retention times, MS, and tandem quadrupole MS (MS/MS) data. Combined with chemometrics analysis of principal component analysis and orthogonal projection to latent structural discriminate analysis, eight of them, especially acteoside and plantamajoside, were picked out and contributed to the chemical distinction between Plantaginis Herba and Plantaginis Semen, which might be responsible for the differences in diuretic and hypotensive effects between the two medicinal parts. This new approach for target profiling provides not only a novel idea for specific analysis of active chemical constituents in the same type, but also a promising and reference method for quality evaluation of traditional Chinese medicines.

Ethanolic extract of the seeds of Plantago asiatica L. showed significant inhibitory activity of angiotensin-converting enzyme (ACE) determined by monitoring the transformation from a substrate hippuryl-histidyl-leucine (HHL) to the product hippuric acid (HA) in vitro using an UPLC-MS method. The bioguided fractionation of the extract resulted in the isolation of four ACE inhibitory active phenylpropanoid glycosides acteoside, isoacteoside, plantainoside D, and plantamajoside with IC(50) values of 2.69 mM, 2.46 mM, 2.17 mM, and 2.47 mM, respectively. Their structures were elucidated through the analysis of NMR, UV, IR and MS data. Our study is the first demonstration that Plantago asiatica L. and its major constituents have ACE inhibitory activity in vitro. It is assumed that the identified compounds contribute to the angiotensin-converting enzyme-inhibitory activity of the extract.

The prolonged life expectancy accelerates the development of implantable bioelectronic devices. However, conventional batteries with limited lifetime, rigid architecture, and inferior energy density greatly restrict their applications in patient’s body. Herein, a novel flexible symmetric Na-ion microbattery based on the heteronanomat electrode and the biocompatible electrolyte has been developed. The film electrodes with sphere-in-network architecture are synthesized by simultaneously electrospinning and electrospraying followed by carbonization. The combined technologies allow a uniform incorporation of active materials/C spheres into the carbon nanofiber matrix, which results in the heteronanomat electrodes with robust structure, fast electron/ion transport, and compact mass loading. The flexible microbatteries are fabricated based on the interdigitated microelectrodes and the biocompatible electrolytes, which provides a new implantable power source for bioelectronics. As a proof-of-concept study, the symmetric sodium-ion microbatteries are constructed from the heteronanomat bifunctional electrodes (based on Na2VTi­(PO4)3) and the biocompatible electrolyte. The high reversibility, fast kinetics, and high energy density of the symmetric system in the biocompatible electrolytes reveal their superior performance in bioenvironments. Moreover, the high capacity retention (over 98%) and the high stability of microbattery implanted in a living SD rat for a month further demonstrate its high reliability for long-term in vivo diagnosis. Therefore, this work not only presents a new sphere-in-net heteronanomat structure for fabricating high-performance electrode but also gives significant contributions to develop high-energy-density and high safety biocompatible power sources of implantable bioelectronics.

Senile plaque accumulation and neurofibrillary tangles are primary characteristics of Alzheimer's disease. We aimed to assess the protective functions of naringenin against β-amyloid protein fragment 25-35 (Aβ)-caused nerve damage in differentiated PC12 cells, and study the potential mechanisms. We evaluated cell viability and apoptosis using the 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test and flow cytometry, respectively. Moreover, we measured protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), and caspase-3 activity via western blotting and RT-PCR. We found that naringenin protected cell against Aβ-caused nerve damage by increasing cell viability, promoting Akt and GSK3β activation, and inhibiting cell apoptosis and caspase-3 activity. However, treatment with the estrogen receptor (ER) antagonist ICI182, 780 or phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 suppressed the effects of naringenin. Our results suggested that naringenin could effectively suppress Aβ-caused nerve damage in PC12 cells by regulating the ER and PI3K/Akt pathways.

Angiotensin-converting enzyme (ACE) plays an important role in the renin-angiotensin system and ACE activity is usually assayed in vitro by monitoring the transformation from a substrate to the product catalyzed by ACE. A rapid and sensitive analysis method or ACE activity by quantifying simultaneously the substrate hippuryl-histidyl-leucine and its product hippuric acid using an ultra-performance liquid chromatography coupled with electrospray ionization-mass spectrometry (UPLC-MS) was first developed and applied to assay the inhibitory activities against ACE of several natural phenolic compounds. The established UPLC-MS method showed obvious advantages over the conventional HPLC analysis in shortened running time (3.5 min), lower limit of detection (5 pg) and limit of quantification (18 pg), and high selectivity aided by MS detection in selected ion monitoring (SIM) mode. Among the six natural products screened, five compounds, caffeic acid, caffeoyl acetate, ferulic acid, chlorogenic acid and resveratrol indicated potent in vitro ACE inhibitory activity with IC(50) values of 2.527 +/- 0.032, 3.129 +/- 0.016, 10.898 +/- 0.430, 15.076 +/- 1.211 and 6.359 +/- 0.086 mm, respectively. A structure-activity relationship estimation suggested that the number and the situation of the hydroxyls on the benzene rings and the acrylic acid groups may play the most predominant role in their ACE inhibitory activity.

Chemodynamic therapy (CDT) based intracellular chemical reactions to produce highly cytotoxic reactive oxygen species has received wide attention. However, low efficiency of single CDT in weakly acidic pH and glutathione (GSH) overexpressed tumor cells has limited its clinical application. For this study were prepared two-dimensional metal–organic framework (MOF) to improve CDT efficiency based on the combined action of bimetallic CDT, consumption of overexpressed glutathione (GSH) in cells, folic acid (FA) induced tumor targeting and triphenylphosphine (TPP) induced mitochondrial targeting. With the use of Cu­(II) as the central ion and tetrakis­(4-carboxyphenyl)­porphyrin (TCPP) as the ligand, two-dimensional Cu-MOF nanosheets were prepared, which were surface modified by manganese dioxide based on the in situ redox reaction between poly­(allylamine hydrochloride) (PAH) and KMnO4 to obtain Cu-MOF@MnO2. Then FA and TPP were coupled with the nanosheets to form the title nanoplatform. Comprehensive physiochemical research has suggested that Cu­(II) and MnO2 constituents in the nanoplatform could consume intracellular GSH and hydrogen peroxide to generate hydroxyl radicals through a Fenton-like reaction; meanwhile Cu­(II) could undergo a Russell reaction to produce cytotoxic singlet oxygen. Detailed in vitro and in vivo biological experiments have revealed a good biosafety profile and a high tumor suppression effect. Therefore, the present research has realized multiple and efficient CDT effects with the aid of the sequential targeting of FA/TPP, also providing a strategy for the development of CDT drugs based on polymetallic organic frameworks.

As a traditional Chinese medicine, Drynariae rhizoma (Kunze ex Mett.) J. Sm. has been used to treat osteoporosis and bone resorption for 2500 years. Based on the previous study and literature references, flavonoids were proved to be the most abundant and main active compounds of Drynariae rhizoma for osteoporosis treatment. In order to make good and rational use of Drynariae rhizoma in future, a rapid, sensitive, and selective ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed to investigate the pharmacokinetics of eight main flavonoids in rat plasma after oral administration of the Drynariae rhizoma extract, including neoeriocitrin, luteolin-7-O-β-D-glucoside, astragalin, naringin, eriodictyol, luteolin, naringenin, and kaempferol. Plasma samples' pretreatment involved a solid-phase extraction column. The separation was performed on an ACQUITY UPLCTM BEH C18 column with a gradient mobile-phase system of acetonitrile and 1% acetic acid in water. The detection was performed using a triple quadrupole tandem mass spectrometer equipped with an electrospray ionization interface (ESI) by multiple reaction monitoring (MRM) in the positive ion mode. All calibration curves exhibited good linearity (r 2 > 0.9990) over the measured ranges. The intraday and interday precisions (RSD) were within 13.87%, and the accuracy (RE) ranged from −14.57% to −0.25% at three quality control levels. Extraction recovery, matrix effect, and stability were satisfactory. The pharmacokinetic characteristics of the eight flavonoids of interest were clearly elucidated.