No abstract

Panax ginseng and Panax notoginseng, two well-known medical plants with economic value, have a long history of use for managing various diseases in Asian countries. Accumulating clinical and experimental evidence suggests that notoginsenosides and ginsenosides, which are the major bioactive components of the plants, have a variety of beneficial effects on several types of disease, including metabolic, vascular, and central nervous system disease. Considerable attention has been focused on ginsenoside Rb1 derived from their common ownership as an anti-diabetic agent that can attenuate insulin resistance and various complications. Particularly, in vitro and in vivo models have suggested that ginsenoside Rb1 exerts various pharmacological effects on metabolic disorders, including attenuation of glycemia, hypertension, and hyperlipidemia, which depend on the modulation of oxidative stress, inflammatory response, autophagy, and anti-apoptosis effects. Regulation of these pathophysiological mechanisms can improve blood glucose and insulin resistance and protect against macrovascular/microvascular related complications. This review summarizes the pharmacological effects and mechanisms of action of ginsenoside Rb1 in the management of diabetes or diabetic complications. Moreover, a multi-target effect and mechanism analysis of its antidiabetic actions were performed to provide a theoretical basis for further pharmacological studies and new drug development for clinical treatment of type 2 diabetes. In conclusion, ginsenoside Rb1 exerts significant anti-obesity, anti-hyperglycemic, and anti-diabetic effects by regulating the effects of glycolipid metabolism and improving insulin and leptin sensitivities. All of these findings suggest ginsenoside Rb1 exerts protective effects on diabetes and diabetic complications by the regulation of mitochondrial energy metabolism, improving insulin resistance and alleviating the occurrence complications, which should be further explored. Hence, ginsenoside Rb1 may be developed as a potential anti-obesity, anti-hyperglycemic, and anti-diabetic agent with multi-target effects.

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Cerebral ischemia-reperfusion is a complicated pathological process. The injury and cascade reactions caused by cerebral ischemia and reperfusion are characterized by high mortality, high recurrence, and high disability. However, only a limited number of antithrombotic drugs, such as recombinant tissue plasminogen activator (r-TPA), aspirin, and heparin, are currently available for ischemic stroke, and its safety concerns is inevitable which associated with reperfusion injury and hemorrhage. Therefore, it is necessary to further explore and examine some potential neuroprotective agents with treatment for cerebral ischemia and reperfusion injury to reduce safety concerns caused by antithrombotic drugs in ischemic stroke. Ginseng Rg1 (G-Rg1) is a saponin composed of natural active ingredients and derived from the roots or stems of Panax notoginseng and ginseng in traditional Chinese medicine. Its pharmacological effects exert remarkable neurotrophic and neuroprotective effects in the central nervous system. To explore and summarize the protective effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury, we conducted this review, in which we searched the PubMed database to obtain and organize studies concerning the pharmacological effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury. This study provides a valuable reference and clues for the development of new agents to combat ischemic stroke. Our summarized review and analysis show that the pharmacological effects of and mechanisms underlying ginsenoside Rg1 activity against cerebral ischemia and reperfusion injury mainly involve 4 sets of mechanisms: anti-oxidant activity and associated apoptosis via the Akt, Nrf2/HO-1, PPARγ/HO-1, extracellular regulated protein kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) pathways (or mitochondrial apoptosis pathway) and the caspase-3/ROCK1/MLC pathway; anti-inflammatory and immune stimulatory-related activities that involve apoptosis or necrosis via MAPK pathways (the JNK1/2 + ERK1/2 and PPARγ/HO-1 pathways), endoplasmic reticulum stress (ERS), high mobility group protein1 (HMGB1)-induced TLR2/4/9 and receptor for advanced glycation end products (RAGE) pathways, and the activation of NF-κB; neurological cell cycle, proliferation, differentiation, and regeneration via the MAPK pathways (JNK1/2 + ERK1/2, PI3K-Akt/mTOR, PKB/Akt and HIF-1α/VEGF pathways); and energy metabolism and the regulation of cellular ATP levels, the blood-brain barrier and other effects via N-methyl-D-aspartic acid (NMDA) receptors, ERS, and AMP/AMPK-GLUT pathways. Collectively, these mechanisms result in significant neuroprotective effects against cerebral ischemic injury. These findings will be valuable in that they should further promote the development of candidate drugs and provide more information to support the application of previous findings in stroke clinical trials.

As one of the leading causes of drug failure in clinical trials, drug-induced liver injury (DILI) seriously impeded the development of new drugs. Assessing the DILI risk of drug candidates in advance has been considered as an effective strategy to decrease the rate of attrition in drug discovery. Recently, there have been continuous attempts in the prediction of DILI. However, it indeed remains a huge challenge to predict DILI successfully. There is an urgent need to develop a quantitative structure–activity relationship (QSAR) model for predicting DILI with satisfactory performance. In this work, we reported a high-quality QSAR model for predicting the DILI risk of xenobiotics by incorporating the use of eight effective classifiers and molecular descriptors provided by Marvin. In model development, a large-scale and diverse dataset consisting of 1254 compounds for DILI was built through a comprehensive literature retrieval. The optimal model was attained by an ensemble method, averaging the probabilities from eight classifiers, with accuracy (ACC) of 0.783, sensitivity (SE) of 0.818, specificity (SP) of 0.748, and area under the receiver operating characteristic curve (AUC) of 0.859. For further validation, three external test sets and a large negative dataset were utilized. Consequently, both the internal and external validation indicated that our model outperformed prior studies significantly. Data provided by the current study will also be a valuable source for modeling/data mining in the future.

Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolyzed, enhancing by approximately 10-fold the CNS levels of the antibody with respect to the administration of naked rituximab. When the nanocapsules are functionalized with CXCL13, the ligand for the chemokine receptor CXCR5 frequently found on B-cell lymphoma, a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone-marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases. Treatments for cancer metastases, especially those of the central nervous system (CNS), are less successful than those for primary tumors 1. Approximately 15%−40% of all cancers develop a CNS metastasis 2,3 , which most commonly arises from lung cancer, melanoma, breast cancer, and colorectal cancer. Therapeutic monoclonal antibodies (mAbs) have revolutionized the treatment of cancer; however, their efficacy is limited in patients with CNS metastases due to insufficient mAb CNS delivery-typically 0.1% of the levels in plasma 4. By bypassing the blood-brain barrier (BBB) through intrathecal or intraventricular administration, mAb therapy has shown some effectiveness against CNS tumor metastases 4-10. However, direct CNS administration is invasive, with potential for neurotoxicity, and is limited by rapid efflux of antibodies from the CNS within hours 5,10,11. Therefore, novel approaches for mAbs delivery are preferable to maintain systemic therapeutic effect in the CNS with improved efficiency.

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Hyperlipidemia is considered to be one of the greatest risk factors contributing to the prevalence and severity of cardiovascular diseases. In this work, we investigated the anti-hyperlipidemic effect and potential mechanism of action of the Pandanus tectorius fruit extract in hamsters fed a high fat-diet (HFD). The n-butanol fraction of the P. tectorius fruit ethanol extract (PTF-b) was rich in caffeoylquinic acids (CQAs). Administration of PTF-b for 4 weeks effectively decreased retroperitoneal fat and the serum levels of total cholesterol (TC), triglycerides (TG) and low density lipoprotein–cholesterol (LDL-c) and hepatic TC and TG. The lipid signals (fatty acids, and cholesterol) in the liver as determined by nuclear magnetic resonance (NMR) were correspondingly reduced. Realtime quantitative PCR showed that the mRNA levels of PPARα and PPARα-regulated genes such as ACO, CPT1, LPL and HSL were largely enhanced by PTF-b. The transcription of LDLR, CYP7A1, and PPARγ was also upregulated. Treatment with PTF-b significantly stimulated the activation of AMP-activated protein kinase (AMPK) as well as the activity of serum and hepatic lipoprotein lipase (LPL). Together, these results suggest that administration of the PTF-b enriched in CQAs moderates hyperlipidemia and improves the liver lipid profile. These effects may be caused, at least in part, by increasing the expression of PPARα and its downstream genes and by upregulation of LPL and AMPK activities.