Recent advances in mechanisms of KRASG12C inhibitors anti-tumor resistance and relevant overcoming strategies / 药学学报

KRAS is one of the most frequently mutated human oncogenes. In spite of mounting efforts on the development of direct or indirect inhibition targeting KRAS, little has been achieved because of insurmountable difficulties, titling KRAS "undruggable". Recently, subtype-specific inhibitors have shown great hope. Some KRASG12C inhibitors have entered clinical trials, including adagrasib and sotorasib, and have shown preliminary clinical effectiveness. Experiences from the inhibitors targeting the downstream factors of RAS pathways show that the anticancer activity of these drugs will be limited due to the development of drug resistance. Preclinical studies of KRASG12C inhibitors have revealed that the application of these agents might be hampered by the drug resistance issue. The current review aims to describe the current status of KRASG12C inhibitors, and discuss the mechanisms underlying KRASG12C inhibitor resistance, so as to provide the clues for the combat of drug resistance.

Research on antitumor effects of small molecule inhibitors of deubiquitinases: new progress and new ideas / 药学学报

The abnormality of ubiquitin proteasome pathway is an important factor leading to the imbalance of protein homeostasis. In this process, the deubiquitinase responsible for removing the ubiquitin chain of protein substrate is very important. Its abnormal activity or expression can cause the functional changes of key oncogenic/tumor suppressor proteins, which directly or indirectly lead to the occurrence, development and malignant evolution of tumors. Based on this, the discovery and research of small molecule inhibitors targeting deubiquitinases have become a hot field of anti-tumor candidate drugs. This review will focus on the regulatory effect and mechanism of ubiquitin proteasome pathway, especially deubiquitinase on tumor, introduce the application of deubiquitinase small molecule inhibitors in tumor treatment, and discuss the research status and latest progress of small molecule inhibitors, so as to provide ideas for the research of new anti-tumor strategies based on deubiquitinase.

Glycyrrhizic acid: a potential drug against COVID-19 / 药学学报

Pneumonia caused by SARS-CoV-2 has seriously threatened human life and health worldwide and caused a large number of deaths. Viral infection and acute inflammation are important causes of death, so it is particularly important to combine antiviral therapy with anti-inflammatory therapy. Glycyrrhizic acid, the main component of the glycyrrhizic root extract, has a wide range of pharmacological effects as well as high efficiency and low toxicity, its preparation has been widely used in the treatment of chronic hepatitis and other diseases. Glycyrrhizic acid can regulate the expression and release of a variety of cytokines and play a significant anti-inflammatory effect. At the same time, glycyrrhizic acid also showed significant inhibition towards a variety types of viruses. Therefore, the potential application of glycyrrhizic acid as COVID-19 treatment should be explored.

Application of Sequential Changes of Dural Thickness and Biomechanical Parameters in Postmortem Interval Estimation / 法医学杂志

Objective To study the relations of the dural thickness and the biomechanical parameters with postmortem interval （PMI） of human cadavers, and to explore the feasibility of the two indexes used for PMI estimation. Methods Dural samples were collected at different postmortem intervals of 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 48 h, 60 h, 72 h, 84 h and 96 h, then fabricated into 4.0 cm×1.0 cm A and B test specimens. The thickness of the A test specimen was measured, and the biomechanical parameters, such as ultimate load, maximum force deformation, tensile strength, elastic modulus and fracture force, were measured. The regression equations of thickness, biomechanical parameters and PMI were fitted respectively, and the difference between the predicted value and actual measured value of PMI was verified by the verification group. The B test specimen was fixed with 10% neutral formaldehyde solution, then tissue sections were prepared to observe its morphological changes. Results From 6 h to 96 h after death, the dural thickness decreased gradually, the collagen fibers gradually changed from clear arrangement to mutual fusion, and the number of nuclei decreased gradually. The dural thickness, ultimate load, tensile strength, elastic modulus and fracture force decreased sequentially, among which the dural thickness, ultimate load, elastic modulus and fracture force had a correlation with PMI （P<0.05）. In the return test, the difference between the predicted value and actual measured value of PMI in the verification group had no statistical significance （P>0.05）. Conclusion The dural thickness, ultimate load, elastic modulus and fracture force change sequentially from 6 h to 96 h after death. The regression equation established by the relationship between the changes and PMI can be used for PMI estimation.

Roles of miRNA and lncRNA in triple-negative breast cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Triple-negative breast cancer (TNBC) is currently the most malignant subtype of breast cancer without effective targeted therapies, which makes its pathogenesis an important target for research. A growing number of studies have shown that non-coding RNA (ncRNA), including microRNA (miRNA) and long non-coding RNA (lncRNA), plays a significant role in tumorigenesis. This review summarizes the roles of miRNA and lncRNA in the progression, diagnosis, and neoadjuvant chemotherapy of TNBC. Aberrantly expressed miRNA and lncRNA are listed according to their roles. Further, it describes the multiple mechanisms that lncRNA shows for regulating gene expression in the nucleus and cytoplasm, and more importantly, describes lncRNA-regulated TNBC progression through complete combining with miRNA at the post-transcriptional level. Focusing on miRNA and lncRNA associated with TNBC can provide new insights for early diagnosis and treatment-they can be targeted in the future as a novel anticancer target of TNBC.

Multi-Epitope Fusion Protein Eg mefAg-1 as a Serodiagnostic Candidate for Cystic Echinococcosis in Sheep

Cystic echinococcosis (CE) in sheep is a hazardous zoonotic parasitic disease that is caused by Echinococcus granulosus (Eg). At present, serological test is an important diagnostic method for Eg infection in domestic animals. Here, a fusion protein Eg mefAg-1 harboring 8 dominant B-cell epitopes of Eg such as antigen B, tetraspanin 1, tetraspanin 6, reticulon and Eg95 was produced in E. coli and evaluated for CE in sheep by indirect ELISA. Eg mefAg-1 showed in ELISA a high sensitivity (93.41%) and specificity (99.31%), with a coincidence rate of 97.02%. Overall, it is suggested that the Eg mefAg-1 could be a potential antigen candidate for CE serodiagnosis in sheep.

Effects of activation or blockade of 5-HT1A receptors in the medial septum-diagonal band of Broca complex on cognitive functions in hemiparkinsonian rats / 西安交通大学学报(医学版)

Objective To explore the role and mechanisms of 5-HT1Areceptors in the medial septum-diagonal band of Broca complex (MS-DB) in hemiparkinsonian rats. Methods Combined behavioral and electrophysiological studies were performed to assess the role of MS-DB 5-HT1Areceptors in working memory and hippocampal theta rhythm in rats with 6-hydroxydopamine (6-OHDA)lesions in the medial forebrain bundle (MFB).Results ① MFB lesions in the rats decreased choice accuracy in the T-maze rewarded alternation test. Intra-MS-DB injection of 5-HT1Areceptor agonist 8-OH-DPAT further decreased choice accuracy,while intra-MS-DB injection of 5-HT1Areceptor antagonist WAY-100635 increased choice accuracy in the lesioned rats.② MFB lesions in the rats decreased peak theta rhythm frequency. Intra-MS-DB injection of 8-OH-DPAT suppressed hippocampal theta rhythm and decreased normalized theta power,while intra-MS-DB injection of WAY-100635 induced theta rhythm and increased normalized theta power.Conclusion Blockade of MS-DB 5-HT1Areceptors can recover cognitive dysfunction in Parkinson's disease, which may be attributed to the enhancement of hippocampal theta rhythm.

Sirtuins in malignant progression of tumor / 药学学报

As a post-translational modification, protein acetylation plays an important role in the regulation of apoptosis, mitochondriopoiesis, lipid metabolism and cellular stress response. The imbalance of acetylation and deacetylation has been blamed for the tumorigenesis and malignant progression, which is gradually considered as a promising therapeutic target. Mammalian sirtuins, a NAD+ dependent class Ⅲ HDACs, are closely related to the development of aging, tumor, diabetes, obesity and neurodegenerative diseases. To provide a theoretical basis for the development of new anti-tumor drugs and the treatment of malignant tumors, this paper is prepared to focus on the irreplaceable role of sirtuins in tumor evolution:maintaining genomic stability, regulating energy metabolism, and facilitating tumor cells stemness. The modulator and pathways of sirtuins family and the research progress of agonists and inhibitors are also reviewed. The functions of SIRT2 in resistance, proliferation and metastasis have been highlighted.

The roles of deubiquitinating enzymes in cancer therapy / 药学学报

Ubiquitination and deubiquitination play important roles in the regulation of protein stability and function. Deubiquitinating enzymes (DUBs) are involved in the regulation of survival, migration and proliferation of cancer cells, by participating in a variety of signaling pathways. Most of the DUBs promote the malignant transformation and progression, while the others may function as tumor-suppressors. Given the central roles of DUBs in tumorigenesis and malignant progression, some of these enzymes have been regarded as promising anti-cancer targets. This paper reviews the recent advances in tumor-related DUBs and inhibitors.

Study on the regulation of autophagy against anticancer drugs' toxicity / 药学学报

Autophagy is a crucial biological process in eukaryotes, which is involved in cell growth, survival and energy metabolism. It has been confirmed that autophagy mediates toxicity of anticancer drugs, especially in heart, liver and neuron. It is important to understand the function and mechanism of autophagy in anticancer drugs-induced toxicity. Given that autophagy is a double-edged sword in the maintenance of the function of heart, liver and neuron, the autophagy-mediated toxicity are very complicated in the body. We provide a review on the concept of autophagy and current status about autophagy-mediated toxicity of anticancer drugs. The knowledge is crucial in the basic study of anticancer drugs-induced toxicity, and provides some strategies for the development of alleviating the toxicity of anticancer drugs.

Study on the regulation of autophagy against anticancer drugs' toxicity / 药学学报

Autophagy is a crucial biological process in eukaryotes, which is involved in cell growth, survival and energy metabolism. It has been confirmed that autophagy mediates toxicity of anticancer drugs, especially in heart, liver and neuron. It is important to understand the function and mechanism of autophagy in anticancer drugs-induced toxicity. Given that autophagy is a double-edged sword in the maintenance of the function of heart, liver and neuron, the autophagy-mediated toxicity are very complicated in the body. We provide a review on the concept of autophagy and current status about autophagy-mediated toxicity of anticancer drugs. The knowledge is crucial in the basic study of anticancer drugs-induced toxicity, and provides some strategies for the development of alleviating the toxicity of anticancer drugs.

Prevalence of Hydatid Cysts in Livestock Animals in Xinjiang, China

Hydatid worms, hosted by humans and animals, impose serious human health risk and cause significant livestock production loss. To better understand the disease infection status in Xinjiang, China, we investigated the disease epidemics in 4 livestock animals, i.e., cattle, sheep (both sheep and goat), camels, and horses, slaughtered at the abattoirs in Urumqi, Yining, Tacheng, and Altay areas. The results showed that the animals were infected at different rates, in the order of sheep (9.8%), cattle (8.4%), camels (6.8%), and horses (4.3%). The infection rates were found to be different between the abattoirs in various regions even for the same animals. For sheep, the rates increased significantly as the animals grew older. It was 1.9% before 1 year of age and increased to 8.2% in the age of 1-2 years, and further increased to 12.3% when the animals were 3-4 years old, and reached 17.2% when they were 5-6 year old. Sheep older than 6 years had an infection rate of 19.5%. This study demonstrates that the 4 livestock animals in the pastoral areas in Xinjiang were infected by the parasites to various extend. This study is the first systematic investigation of the hydatid worms in various livestock animals in Xinjiang, China, which provides epidemiological information about the infection of hydatid worms in livestock, and is valuable in developing strategies for prevention and control of the hydatid disease.

Signal transduction pathway mediated by thrombopoietin in the inflammation model of microglia / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To explore the signal transduction pathway mediated by thrombopoietin (TPO) in the inflammation model of microglia induced by lipopolysaccharide (LPS).</p><p><b>METHODS</b>The inflammation model of microglia BV2 cells was prepared by LPS of 0.5 and 1.0 μg/mL stimulation. The expression of TPO and ERK mRNA in BV2 cells was detected by real time quantitative PCR. Western blot was used to evaluate the expression of TPO and ERK protein in BV2 cells. TPO and IL-6 contents in the culture supernatant fluid were measured using ELISA.</p><p><b>RESULTS</b>LPS stimulation increased significantly the mRNA and protein expression of TPO and ERK in BV2 cells, especially at the concentration of 1.0 μg/mL for 12 hrs stimulation. There was a significant positive correlation between the mRNA and protein expression of TPO and ERK.</p><p><b>CONCLUSIONS</b>Signal transduction pathway of ERK1/2 participates in the activation of TPO in inflammatory injury of BV2 cells.</p>

Intensive glycemic control and macrovascular events in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>There is no agreement as to whether intensive glucose control in type 2 diabetes can reduce the incidence of macrovascular events in these patients. We performed a meta-analysis comparing intensive glucose control or conventional glucose control in randomized controlled trials.</p><p><b>METHODS</b>Databases including MEDLINE, EMBASE, and Cochrane controlled trials register, the Cochrane Library, and Science Citation Index were searched to find relevant trials. Outcome measures were the incidence of major macrovascular events.</p><p><b>RESULTS</b>Six trials involving 28 065 patients were included. Analysis suggested that there was an obviously decreased incidence of major macrovascular events in patients having intensive glucose treatment vs. controls (RR 0.92; 95%CI 0.87, 0.98; P = 0.005). However, intensive glycemia control strategies in type 2 diabetes showed no significant impact on the incidence of death from any cause compared with conventional glycemia control strategies, intensive 14.7%, controls 12.0% (RR 0.95; 95%CI 0.80, 1.12; P = 0.55), as well as on the incidence of cardiovascular death, intensive 3.7%, controls 3.6% (RR 1.10, 95%CI 0.79, 1.53; P = 0.57).</p><p><b>CONCLUSIONS</b>Control of glycemia to normal (or near normal levels) in type 2 diabetes appears to be effective in reducing the incidence of major macrovascular events, but there were no significant differences of either the mortality from any cause or from cardiovascular death between the two glycemia-control strategies.</p>

Expression of matrix metalloproteinase-2 and insulin-like growth factor-1 in gastric carcinoma and their clinicopathological significance / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the expression of matrix metalloproteinase-2 (MMP-2) and insulin-like growth factor-1 (IGF-1) in gastric carcinoma and their clinicopathological significance.</p><p><b>METHODS</b>Expressions of MMP-2 and IGF-1 were examined by using immunohistochemical SP staining and cross-compared with clinicopathological features of gastric carcinoma.</p><p><b>RESULTS</b>High expression of MMP-2 and IGF-1 were observed in 70.4% (307/436) and 49.5% (216/436) of gastric carcinoma tissues respectively, significantly higher than those in non-tumor gastric mucosa (3.3% and 5.4%, respectively; all P < 0.05). The high expression rate of MMP-2 and IGF-1 were significantly associated with the patient age, tumor size, tumor location, Lauren classification, TNM staging, depth of tumor infiltration, presence of vessel invasion, lymph node and distant metastasis (all P < 0.05). In addition, the expression of MMP-2 was positively linked with the expression level of IGF-1 (P < 0.05). Univariate analysis showed that high expression of MMP-2, was significantly associated with poor prognosis of tumor of TNM stage I and II (all P < 0.05), high expression of IGF-1 was significantly correlated with poor prognosis of patients with TNM stage I, II and III tumor (all P < 0.05). Cox multivariate analysis indicated that the high expressions of MMP-2 and IGF-1 could be independent prognostic indices for gastric carcinoma.</p><p><b>CONCLUSIONS</b>High expression of MMP-2 and IGF-1 proteins are significantly correlated with the invasion and metastasis of gastric carcinoma, it is helpful to simultaneously detect the expressions of MMP-2 and IGF-1 proteins in predicting prognosis of patients with gastric carcinoma.</p>

Firing activity of locus coeruleus noradrenergic neurons increases in a rodent model of Parkinsonism / 神经科学通报·英文版

<p><b>OBJECTIVE</b>To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD).</p><p><b>METHODS</b>2 and 4 weeks after unilateral lesion of the nigrostriatal pathway in the rat by local injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra pars compacta (SNc), the firing activity of noradrenergic neurons in LC was recorded by extracellular single unit recording.</p><p><b>RESULTS</b>The firing rate of LC noradrenergic neurons increased significantly 2 and 4 weeks after 6-OHDA lesions compared to normal rats, respectively (P < 0.05). The percentage of irregularly firing neurons was obviously higher than that of normal rats during the fourth week after SNc lesion (P < 0.05).</p><p><b>CONCLUSION</b>LC noradrenergic neurons are overactive and more irregular in 6-OHDA-lesioned rats. These changes suggest an implication of the LC in the pathophysiological mechanism of PD.</p>

The selective 5-HT(1A) receptor antagonist WAY-100635 increases neuronal activity of the basolateral nucleus of the amygdala in 6-hydroxydopamine-lesioned rats / 生理学报

In the present study, extracellular recording was used to examine the neuronal activity of the basolateral nucleus (BL) of the amygdala and the effects of systemic administration of the selective 5-HT(1A) receptor antagonist WAY-100635 on the neuronal activity in the normal rats and rats with 6-hydroxydopamine (6-OHDA)-produced lesions in the substantia nigra pars compacta (SNc). The results showed that the firing rates of BL projection neurons and interneurons were (0.39±0.04) Hz and (0.83±0.16) Hz in the normal rats, and (0.32±0.04) Hz and (0.53±0.12) Hz in 6-OHDA-lesioned rats. There was no significant difference in the firing rates of BL projection neurons and interneurons between the normal and 6-OHDA-lesioned rats. In the normal rats, all BL projection neurons fired in burst; 94% of BL interneurons fired in burst and 6% fired irregularly. In 6-OHDA-lesioned rats, 85% of BL projection neurons displayed a burst firing pattern and 15% fired irregularly; 86% of BL interneurons had a burst firing pattern and 14% fired irregularly. The distribution of firing patterns of projection neurons and interneurons in the BL in 6-OHDA-lesioned rats did not differ from that in the normal rats. Systemic administration of WAY-100635 at 0.1 mg/kg body weight did not change the mean firing rates of projection neurons and interneurons in the BL in both normal and 6-OHDA-lesioned rats. However, a higher dose of WAY-100635 at 0.5 mg/kg body weight significantly decreased the mean firing rate of BL projection neurons from (0.43±0.07) to (0.15±0.02) Hz in the normal rats (P<0.01), but significantly increased the activity of BL projection neurons in 6-OHDA-lesioned rats from (0.37±0.08) to (0.69±0.18) Hz (P<0.004). The mean firing rates of BL interneurons in the normal and 6-OHDA-lesioned rats did not change after administration of a higher dose of WAY-100635 at 0.5 mg/kg body weight. These results demonstrate that the activity of BL neurons after substantia nigra dopaminergic lesion in the SNc is regulated by activation of intrinsic and extrinsic inputs, and that 5-HT(1A) receptors significantly contribute to the regulation of the activity of BL projection neurons in both normal and 6-OHDA-lesioned rats. Furthermore, WAY-100635 induced an increase in the mean firing rate of projection neurons in the BL in 6-OHDA-lesioned rats, suggesting that 5-HT(1A) receptor is likely to play a role in generating affective symptoms in Parkinson's disease.

The selective 5-HT1A receptor antagonist WAY-100635 inhibits neuronal activity of the ventromedial prefrontal cortex in a rodent model of Parkinson's disease / 神经科学通报·英文版

<p><b>OBJECTIVE</b>The ventral part of the medial prefrontal cortex (mPFC) plays an important role in initiation and control of voluntary movement, mood and cognition. However, after the degeneration of the nigrostriatal pathway, the neuronal activity of the ventral mPFC and the role of serotonin(1A) (5-hydroxytryptamine, 5-HT(1A)) receptors in the firing of the neurons are still unknown. The present study is to investigate the change of neuronal activity in the ventral mPFC and the effect of systemic administration of the selective 5-HT(1A) receptor antagonist WAY-100635 on the activity of the neurons in normal and 6-hydroxydopamine (6-OHDA)-lesioned rats.</p><p><b>METHODS</b>Single unit responses were recorded extracellularly with glass microelectrodes from ventral mPFC neurons in normal rats and 6-OHDA unilaterally lesioned rats in vivo.</p><p><b>RESULTS</b>6-OHDA lesion of the substantia nigra pars compacta (SNc) significantly increased the firing rate with no change in the firing pattern of neurons of the ventral mPFC in rats. Systemic administration of WAY-100635 (0.1 mg/kg, i.v.) did not change the mean firing rate and firing pattern of ventral mPFC neurons in normal rats. In contrast, WAY-100635 significantly decreased the mean firing rate of the neurons in rats with 6-OHDA lesion of the SNc.</p><p><b>CONCLUSION</b>These data suggest that the degeneration of the nigrostriatal pathway results in an increase of neuronal activity of ventral mPFC and dysfunction of 5-HT(1A) receptor.</p>

Changes in the firing activity of serotonergic neurons in the dorsal raphe nucleus in a rat model of Parkinson's disease / 生理学报

In the present study, changes in the neuronal activity of serotonergic neurons in the dorsal raphe nucleus (DRN) and the effect of the selective 5-HT(1A) receptor antagonist WAY-100635 in a rat model of Parkinson's disease (PD) were investigated by using extracellular single unit recording. Rat model of PD was produced by microinjection of 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta on the right side of the brain. The results showed that the mean spontaneous firing rate of DRN serotonergic neurons in the control and 6-OHDA-lesioned rats were (1.76+/-0.11) spikes/s (n=24) and (2.43+/-0.17) spikes/s (n=21), respectively. The firing rate of serotonergic neurons in 6-OHDA-lesioned rats was significantly higher than that in the control rats (P<0.001). In the control rats, 92% (22/24) of the neurons fired regularly and 8% (2/24) fired in bursts. In rats with 6-OHDA lesions, 9% (2/21) of neurons fired regularly, 43% (9/21) exhibited irregular pattern and 48% (10/21) fired in bursts. The percentage of DRN serotonergic neurons firing in bursts was obviously higher in 6-OHDA-lesioned rats than that in the control rats (P<0.001). Local injection of WAY-100635 (3 microg in 200 nL) into the DRN significantly increased the firing rate of serotonergic neurons with no change in firing pattern in the control rats (n=19, P<0.002), but did not change the firing rate and firing pattern of serotonergic neurons in 6-OHDA-lesioned rats (n=17, P>0.05). These results suggest the dysfunction of 5-HT(1A) receptor in 6-OHDA-lesioned rats and the involvement of the DRN in the pathophysiological mechanism of PD.

Effects of Maidang Rutong granule on l-dopa-induced galactozemia in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To study galactagogue effect of Maidang Rutong granule on the lactation rats.</p><p><b>METHOD</b>The experiments were designed to observe the efficiency of Maidang Rutong granule on lactescence, serum prolactin, and morphology of mammary gland with rat galactozemia model established by injecting l-dopa.</p><p><b>RESULT</b>Maidang Rutong granule showed significant enhancement for lactescence and the offspring's body weight. It could antagonize the decrease of serum prolactin and the atrophy of mammary gland induced by l-dopa.</p><p><b>CONCLUSION</b>Maidang Rutong granule exhibited significant galactagogue effect on the l-dopa-induced galactozemia in rats.</p>