Stress-induced cellular defense machinery has a critical role in mediating cancer drug resistance, and targeting stress-related signaling has become a novel strategy to improve chemosensitivity. Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid with potent anticancer bioactivities in multiple malignancies, whereas its underlying mechanisms remain unclear. Here in, we found that BA has synergistic effects with taxol to induce breast cancer cells G2/M checkpoint arrest and apoptosis induction, but had little cytotoxicity effects on normal mammary epithelial cells. Drug affinity responsive target stability (DARTS) strategy further identified glucose-regulated protein 78 (GRP78) as the direct interacting target of BA. BA administration significantly elevated GRP78-mediated endoplasmic reticulum (ER) stress and resulted in the activation of protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2a/CCAAT/enhancer-binding protein homologous protein apoptotic pathway. GRP78 silencing or ER stress inhibitor salubrinal administration was revealed to abolish the anticancer effects of BA, indicating the critical role of GRP78 in mediating the bioactivity of BA. Molecular docking and coimmunoprecipitation assay further demonstrated that BA might competitively bind with ATPase domain of GRP78 to interrupt its interaction with ER stress sensor PERK, thereby initiating the downstream apoptosis cascade. In vivo breast cancer xenografts finally validated the chemosensitizing effects of BA and its biofunction in activating GRP78 to trigger ER stress-mediated apoptosis. Taken together, our study not only uncovers GRP78 as a novel target underlying the chemosensitizing effects of BA, but also highlights GRP78-based targeting strategy as a promising approach to improve breast cancer prognosis.

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Abstract. Ligustrazine, also known as 2,3,5,6-tetramethylpyrazine (TMP), one of the major active compounds of Ligusticum wallichii Franchat., has been shown to reduce neuroinflammation and protect neurons during cerebral ischemia/reperfusion injury. However, whether it reduces blood-brain barrier (BBB) permeability during ischemic stroke is unclear. The aim of the present study was to investigate the role that TMP plays in protecting the BBB integrity in ischemia/reperfusion injury and to investigate the relevant mechanisms involved. Rats received an intraperitoneal injection of 20 mg/kg TMP 15 min before the onset of ischemia, which was induced by middle cerebral artery occlusion. Infarct volume, neurological score, brain edema, BBB permeability and tight junction protein impairment were observed. The results showed that TMP reduced the neurological score and levels of brain infarction and edema. In addition, TMP significantly decreased BBB permeability and prevented the impairment of occludin and claudin-5, two tight junction protein components of the BBB, in rat brains with ischemia/reperfusion injury. In addition, the expression and activity of matrix metalloproteinases, enzymes responsible for the degradation of the extracellular matrix and tight junctions, were reduced in the rat brains by TMP treatment. These results combined suggest that TMP reduces BBB permeability as well as neuronal damage in focal cerebral ischemia/reperfusion injury in rats.

The Colorado potato beetle (Leptinotarsa decemlineata (Say)) in the north Xinjiang Uygur autonomous region has evolved resistance to various types of insecticides. Chlorantraniliprole is a novel anthranilic diamide insecticide that binds and activates ryanodine receptors. It exhibited excellent efficacy against L. decemlineata in several field trails in Europe. In the present paper, the susceptibility of L. decemlineata fourth-instar larvae derived from six field populations and L. decemlineata adults derived from three field populations to chlorantraniliprole was determined by a topical application. The fourth-instar larvae were substantially more susceptible to chlorantraniliprole than adults, although the range of susceptibility was far greater among the fourth-instar larvae. Regarding stomach toxicities, adult beetles were less susceptible to chlorantraniliprole than larvae. Chlorantraniliprole was most toxic to second-instar larvae, followed by third- and fourth-instar larvae. These data suggested that the appropriate timing for chlorantraniliprole spraying is the early larval stage. Moreover, the synergistic activities of chlorantraniliprole in combination with triphenyl phosphate, diethyl maleate, or piperonyl butoxide against fourth-instar larvae from two field populations and adults from one field population were tested. Piperonyl butoxide had synergistic effects with chlorantraniliprole against fourth-instar larvae but not against adult beetles. Conversely, triphenyl phosphate and diethyl maleate exerted little synergistic effects. It appears that there is a potential risk of resistance against chlorantraniliprole resulting from cytochrome P450 monooxygenase activity.

Atherosclerosis (AS), the most common underlying pathology for coronary artery disease, is a chronic inflammatory, proliferative disease in large- and medium-sized arteries. The vascular endothelium is important for maintaining vascular health. Endothelial dysfunction is a critical early event leading to AS, which is a major risk factor for stroke and myocardial infarction. Accumulating evidence has suggested the critical roles of histone deacetylases (HDACs) in regulating vascular cell homeostasis and AS. The purpose of this review is to present an updated view on the roles of HDACs (Class I, Class II, Class IV) and HDAC inhibitors in vascular dysfunction and AS. We also elaborate on the novel therapeutic targets and agents in atherosclerotic cardiovascular diseases.

Background: Premature ventricular complex (PVC) with narrow QRS duration originating from proximal left anterior fascicle (LAF) is challenging for ablation. This study was performed to evaluate the safety and feasibility of ablation from right coronary cusp (RCC) for proximal LAF-PVC and to investigate this PVC’s characteristics. Methods: Mapping at RCC and left ventricle and ECG analysis were performed in 20 patients with LAF-PVC. Results: The earliest activation site (EAS), with Purkinje potential during both PVC and sinus rhythm, was localized at proximal LAF in 8 patients (proximal group) and at nonproximal LAF in 12 patients (nonproximal group). The Purkinje potential preceding PVC-QRS at the EAS in proximal group (32.6±2.5 ms) was significantly earlier than that in nonproximal group (28.3±4.5 ms, P =0.025). Similar difference in the Purkinje potentials preceding sinus rhythm QRS at the EAS was also observed between proximal and nonproximal groups (35.1±4.7 versus 25.2±5.0 ms, P <0.001). In proximal group, the distance between the EAS to left His bundle and to RCC was shorter than that of nonproximal group (12.3±2.8 versus 19.7±5.0 mm, P =0.002, and 3.9±0.8 versus 15.7±7.8 mm, P <0.001, respectively). No difference in the distance from RCC to proximal LAF was identified between the 2 groups. PVCs were successfully eliminated from RCC for all proximal groups but at left ventricular EAS for nonproximal groups. The radiofrequency application times, ablation time, and procedure time of nonproximal group were longer than that of proximal group. Electrocardiographic analysis showed that, when compared with nonproximal group, the PVCs of proximal group had narrower QRS duration; smaller S wave in leads I, V 5 , and V 6 ; lower R wave in leads I, aVR, aVL, V 1 , V 2 , and V 4 ; and smaller q wave in leads III and aVF. The QRS duration difference (PVC-QRS and sinus rhythm QRS) <15 ms predicted the proximal LAF origin with high sensitivity and specificity. Conclusions: PVCs originating from proximal LAF, with unique electrocardiographic characteristics, could be eliminated safely from RCC.

Venom and ovarian proteins in braconid and ichneumonid wasps play an important role in the successful parasitism of their host, especially for immune suppression immediately after oviposition. In this study, we compared the effect of venom and ovarian proteins collected from the female wasps of Macrocentrus cingulum, a polyembryonic parasitoid of the larvae of Ostrinia funacalis, on the encapsulation capacity of Sephadex A‐25 beads at 4 h and 24 h post‐injection both in vivo and in vitro. The results showed that the ovarian proteins significantly interfered with the encapsulation capacity of hemocytes in a dose‐dependent manner. Spreading and viability of hemocytes in O. furnacalis was not disrupted by venom and ovarian proteins at various concentrations injected. It seems likely that the ovarian proteins from M. cingulum play a role in suppressing the encapsulation capacity of host hemocytes.

Recent researches have shown that autophagy is associated with the pathogenesis of neurodegenerative disorders, but there is no paper to investigate the effects of autophagy modulation on Parkinson's disease depression (PDD). In addition, glycyrrhizic acid (GA), the major bioactive ingredient of Radix glycyrrhizae, can induce autophagy and ease rotenone-induced Parkinson's disease (PD). However, there is also no paper to study the action and molecular mechanisms of GA on PDD. In this research, we built the injury model of SH-SY5Y cells through 6-hydroxydopamine (6-OHDA) and corticosterone (CORT). Then, our results showed that GA markedly increased the viability and decreased the apoptosis in SH-SY5Y cells after pre-treating with 6-OHDA and CORT. Moreover, GA notably decreased the expressions of α-Syn and p-S1292-LRRK2 proteins, and significantly increased the levels of CREB and BDNF proteins. Previous papers have suggested that CORT contributed to dopaminergic neurodegeneration via the glucocorticoid (GC)/glucocorticoid receptor (GR) interaction, and our results showed that GA reduced GC level and hypothalamic-pituitary-adrenal (HPA) activity in SH-SY5Y cells by regulating GR signaling pathway. Furthermore, mechanism investigations also showed that GA had the ability to up-regulate the conversion of LC3B II/I and the expression of Beclin-1, and induce autophagy in SH-SY5Y cells, which were reversed by the autophagy inhibitor 3-methyladenine (3-MA). Collectively, these findings proved that GA exerted efficient activity against neurotoxicity in SH-SY5Y cells induced by 6-OHDA and CORT via activation of autophagy, which should be developed as an efficient candidate for treating PDD in the future.