In recent years, rituximab has been gradually used in the treatment of idiopathic membranous nephropathy (IMN). Compared with traditional treatments, the safety and effectiveness of rituximab in the treatment of IMN have been confirmed, which induces remission in 60%-80% of patients. For the remaining 20%-40% patients, several mechanisms can explain rituximab resistance: decreased rituximab bioavailability; internalized by targeted B cells; the generation of anti-rituximab antibody; chronic and irreversible damage to the glomerular filtration barrier; autoreactive B-cell clones in secondary lymphoid organs that cannot be effectively eliminated. The treatment of patients with rituximab-refractory IMN remains controversial and challenging. The recognition of IMN as an antibody-mediated autoimmune disease has rationalized the use of immunosuppressive drugs such as B cell-targeted therapies, plasma cell-targeted therapies, and complement inhibitors. This review mainly summarizes recent advances in the understanding of the physiological mechanisms of rituximab resistance, and in the management of rituximab-refractory IMN, aiming to aid in the clinical management of IMN.

Humans ; Asthma/drug therapy* ; Biological Therapy

Astrocytes are important nerve cells in the central nervous system （CNS）， which mainly play a key role in nutrition and support. Astrocytes and neurons undergo close energy coupling and substance coupling， which are closely related and interact with each other. In recent years， many studies have shown that the astrocyte-neuron coupling imbalance plays a central role in the occurrence and progression of Alzheimer's disease （AD） and serves as an important therapeutic target receiving increasing attention. According to traditional Chinese medicine （TCM） theory， the main pathogenesis of AD is kidney deficiency and marrow inadequacy， and in clinical medication， kidney-tonifying and marrow-filling TCM prescriptions are often employed with satisfactory results achieved. As reported， many kidney-tonifying and marrow-filling prescriptions exhibit regulatory and protective effects on the imbalance of astrocyte-neuron coupling， suggesting that the effect of kidney-tonifying and marrow-filling prescriptions in treating AD may have some internal relationship with its regulation of the imbalance of astrocyte-neuron coupling. This article reviewed the underlying internal relationship between the imbalance of astrocyte-neuron coupling and the pathogenesis of kidney deficiency and marrow inadequacy in AD and the research progress in the intervention mechanism of TCM for tonifying the kidney and filling the marrow.

ObjectiveTo explore the mechanism of Dihuang Yinzi in improving astrocyte injury and glycolysis in Alzheimer's disease （AD） mice via regulating the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， thereby improving the cognitive function of AD mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + Dihuang Yinzi （0.25 g·kg^-1） group， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + Dihuang Yinzi （0.25 g·kg^-1） group， with 20 mice in each group. The mice in the control + Dihuang Yinzi group and the model + Dihuang Yinzi group were administered with Dihuang Yinzi by gavage， and those in the control group and the model group received an equal volume of sterilized normal saline， once a day for 150 days. Morris water maze test was performed to test the ability of navigation and space exploration of mice. The protein expression of p-PI3K， PI3K， p-Akt， Akt， phosphofructokinase-1 （PFK-1）， and aldehyde dehydrogenase 3 family member B2 （ALDH3B2） in mouse brain tissues was measured by Western blot. An immunofluorescence assay was performed to detect astrocyte morphology and the expression level of ALDH3B2. ResultAs compared with the control group， the model group showed prolonged escape latency during the 2^nd to 5^th days of the location-based navigation （P<0.05， P<0.01）， reduced number of times crossing the target area of the platform， shortened residence time in the target quadrant （P<0.05， P<0.01）， prolonged residence time in the opposite quadrant （P<0.05）， increased surface area of the cell body and total length of cell protrusions of astrocytes （P<0.05， P<0.01）， and down-regulated protein expression of p-PI3K， p-Akt， ALDH3B2， and PFK-1 （P<0.01）， while the above experimental indexes were not significantly different in the control + Dihuang Yinzi group. Compared with the model group， the model + Dihuang Yinzi group showed shortened escape latency of APP/PS1 mice during the 2^nd to 5^th days of the location-based navigation （P<0.05， P<0.01）， increased number of times crossing the platform， prolonged target quadrant residence time （P<0.05， P<0.01）， shortened residence time in the opposite quadrant （P<0.05）， reduced surface area of the cell body and total length of cell protrusions of astrocytes （P<0.05）， and up-regulated protein expression of p-PI3K， p-Akt， ALDH3B2， and PFK-1 （P<0.01）. ConclusionDihuang Yinzi can improve the learning and memory ability of AD mice by activating the PI3K/Akt signaling pathway and up-regulating the protein expression of PFK-1 and ALDH3B2 to protect against astrocyte injury in brain tissues and improve glycolysis.

ObjectiveTo explore the mechanism of Dihuang Yinzi （DHYZ）in improving astrocyte injury in the brain and regulating energy metabolism and autophagy disorder in Alzheimer's disease （AD） model mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + DHYZ group （2.5 g·kg^-1）， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + DHYZ group （2.5 g·kg^-1）， with 20 mice in each group. The mice in the control group and the model group were administered with an equal volume of sterilized normal saline by gavage， once a day for 150 days. Novel object recognition test and step-down test were performed to evaluate the learning and memory ability of mice. The expression of glial fibrillary acidic protein （GFAP） in astrocytes was detected by immunofluorescence and Western blot. High-performance liquid chromatography （HPLC） was used to detect adenosine triphosphate （ATP）， adenosine diphosphate （ADP）， and adenosine monophosphate （AMP） in brain tissues of mice， and the data obtained were used to calculate energy charge （EC） levels. The phosphorylation levels of liver kinase B1 （LKB1）， adenosine 5′-monophosphate （AMP）-activated protein kinase （AMPK）， UNC-51-like kinase 1 （ULK1）， and mammalian target of rapamycin （mTOR） and the expression levels of autophagy-related proteins Beclin-1， microtuble-associated protein 1 light chain 3 （LC3）-Ⅱ/LC3-Ⅰ， and p62 in mouse brain were measured by Western blot. ResultCompared with the control group， the model group showed decreased novel object recognition index， shortened retention latency， increased error times in the step-down test， up-regulated protein expression of GFAP， decreased content of ATP， ADP， and EC in brain tissues， elevated AMP ， increased levels of p-AMPK， p-LKB1， and p-mTOR， and protein expression of p62 ， and down-regulated p-ULK1 level and protein expression of Beclin-1 and LC3-Ⅱ/LC3-Ⅰ（P<0.01）， while the above experimental indexes were not significantly different in the control + DHYZ group. Compared with the model group， the model + DHYZ group showed increased novel object recognition index（P<0.05）， prolonged retention latency（P<0.01）， decreased error times（P<0.01） in the step-down test， reduced protein expression of GFAP（P<0.05）， increased content of ATP， ADP， and EC in brain tissues （P<0.05， P<0.01）， decreased AMP content（P<0.05）， reduced p-AMPK， p-LKB1， and p-mTOR levels and protein expression of p62， and up-regulated p-ULK1 level and protein expression of Beclin-1 and LC3-Ⅱ/LC3-Ⅰ（P<0.01）. ConclusionBy protecting astrocytes， DHYZ can improve energy metabolism and autophagy disorder in AD mice to improve the learning and memory ability of model mice.

ObjectiveTo investigate the mechanism of Dihuang Yinzi in improving astrocyte injury and protecting synaptic structure and function in the brain of Alzheimer's disease （AD） mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + Dihuang Yinzi （0.25 g·kg^-1） group， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + Dihuang Yinzi （0.25 g·kg^-1） group， with 20 mice in each group. The mice in the control + Dihuang Yinzi group and the model + Dihuang Yinzi group were administered with Dihuang Yinzi by gavage， and those in the control group and the model group received an equal volume of sterilized normal saline， once a day for 150 days. The learning and memory ability of mice was tested by the light-dark box test and Y-maze spontaneous alternation test. The content of glutamate （Glu） and glutamine （Gln） was measured by liquid chromatography-tandem mass spectrometry （LC-MS）. Long-term potentiation （LTP） assay was used to detect synaptic plasticity in brain tissues. The protein expression levels of excitatory amino acid transporter 2 （EAAT2）， postsynaptic density protein95 （PSD95）， and synaptophysin （SYN） in brain tissues were measured by Western blot. Immunofluorescence was used to assess the localization and expression of EAAT2. Colorimetry was performed to detect Na⁺-K⁺ ATPase activity in mouse brain tissues. ResultAs compared with the control group， the model group showed shortened residence latency （P<0.01）， increased number of errors （P<0.01） in the light-dark box test， reduced spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， down-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， blunted activity of Na⁺-K⁺ ATPase （P<0.01）， up-regulated Glu level （P<0.01）， down-regulated Gln level （P<0.01）， and reduced relative population spike （PS） amplitude and the slope of excitatory postsynaptic potential （EPSP） （P<0.05， P<0.01）， while the above experimental indexes were not significantly different in the control + Dihuang Yinzi group. Compared with the model group， the model + Dihuang Yinzi group displayed prolonged residence latency （P<0.05）， decreased number of errors （P<0.01） in the light-dark box test， increased spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， up-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， potentiated activity of Na⁺-K⁺ ATPase （P<0.01）， reduced Glu level （P<0.01）， up-regulated Gln level （P<0.01）， and increased PS amplitude and EPSP slope （P<0.01）. ConclusionDihuang Yinzi can improve cognitive dysfunction in AD mice by protecting astrocytes， increasing Glu uptake to reduce its abnormal accumulation， and protecting synaptic structure and function.

Objective:To investigate the predictive value of systemic immune inflammation index (SII) for the overall survival of patients with pancreatic cancer by propensity score matching analysis.Methods:The clinical data of 457 patients with pancreatic cancer admitted to the Affiliated Hospital of Qingdao University from August 2000 to December 2019 were retrospectively analyzed. The age, gender, presence of jaundice, pancreatitis and diabetes, serum CA19-9, total bilirubin level, neutrophil count, platelet count, lymphocyte count in blood, presence of radical surgery, tumor TNM stage, tumor location and the like were recorded. The cut-off value of SII was determined by Youden index. The patients were divided into high and low SII groups accroding to the cut-off value. The propensity score matching was applied to reduce the selection bias of patients. Patients were 1∶2 matched and the caliper value was 0.1. The difference on overall survival between the two groups was compared. The prognostic factors were analyzed by univariate and multivariate Cox regression analysis. Kaplan-Meier was used to draw the overall survival curve to calculate the cumulative survival rate, and the differences between the curves were analyzed by Log-Rank test.Results:The cut-off value of SII was 765. There were statistically significant differences between the high SII group ( n=125) and the low SII group ( n=332) on the presence or absence of pancreatitis, the level of total bilirubin in blood, radical surgery, and TNM stage before the propensity score matching (all P value <0.05). After propensity score matching, there was no statistically significant difference between the high SII group ( n=113) and the low SII group ( n=182) on all the clinical parameters mentioned above except for CA19-9, indicating that the two groups were comparable. Univariate analysis showed that the level of CA19-9, SII, radical surgery and different TNM stage were all related to the overall survival of pancreatic cancer patients. Multivariate analysis showed that high CA19-9 level, high SII, no radical surgery, and worse TNM stage were independent risk factors for short overall survival, and high SII ( HR=1.882, 95% CI 1.446-2.450, P<0.001) was significantly associated with poor prognosis. The overall survival of patients with high SII was obviously shorter than the low SII group ( P<0.001), and the average survival time of patients with high and low SII were 8.86 and 11.38 months, respectively. Conclusions:SII is of great value in evaluating the overall survival of pancreatic cancer patients. Higher SII is associated with shorter overall survival.

Objective To synthesis,nine N-[3-(2-furanyl)-acryloyl]-N'-substituted benzyl piperazine derivatives were synthesized and evaluated for their primary biological activities.Methods First, the furylacrylic acid was synthesized, Then the target compounds could be obtained by direct furylacrylic acid with the different substituted benzyl piperazine derivatives.In the biological active experiments, taking the different concentrations, comparing with the blank test, the inhibitory effect of the target compounds on VSMC proliferation was investigated by MTT.Results The successful synthesis of nine new compounds.The method was mild and get high yields.The structures of these compounds were confirmed by IR 1 H-NMR, MS, and elemental analysis.The results of preliminary activity test showed that the synthesized products exhibited inhibitory activity at different concentrations , and the highest inhibitory rate was 15μg/mL.Pharmacological results showed that the compounds 3e, 3f and 3 g showed the moderate inhibitory activities against vascular smooth muscle cells proliferation were higher than other compounds , and were worth further studying.Conclusion The synthesized compounds have inhibitory activities and could very well lead to the development of novel types of treat atherosclerosis drug .

Obejective To explore the effect of combined use of dexmedetomidine and ultra-low dose naloxone on postoperative hyperalgesia induced by remifentanil. Method 80 ASA gradeⅠ-Ⅱ female patients who were scheduled to perform endoscopic sinus surgery (ESS) were randomly divided into four groups: purely remifentanil group (group R) and remifentanil plus different dosage dexmedetomidine and ultra-low dose naloxone group (group RDN1 ~ RDN3). Then the postoperative VAS on 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h together with the firstpostoperative pain time , PCA press numbers , fentanyl usage and adverse reaction rate were recorded and evaluated. Results Average VAS of group R are higher than other groups in all 7 time points at the adjusted significant level of 0.0083, and group R > group RDN1 > group RDN2 > group RDN3, while differences between group RDN2 and RDN3 in all time points are not statistical significant.There is no difference between group RDN1 and group RDN2 inthe first postoperative pain time and the PCA press time at 1h after operation. Difference between group RDN2 and group RDN3 in the PCA press time at 24 h after operation was not significant, and the fentanyl usage of RDN groups are significantly less than group R. Conclusions Combined use of dexmedetomidine and ultra-low dose naloxone induced by remifentanil can improving patients′postoperative hyperalgesia , effect increase with the dose of dexmedetomidine increas , and the increasement is more sensitive in acute pain.

Objective To analyse tratment strategies and to evaluate the relation between different therapies and survival rate of patients of with asynchronous liver metastases after pancreatic cancer surgery (PCLM).Methods From January 2006 to January 2012,48 patients with PCLM were included in this study,and their medical records were retrospectively analyzed.Results Among the 48 patients,27 cases of liver metastases were found within six months after surgery,and the survival rate for 1,3 and 5 years was 22.2％,3.7％ and 0％,respectively,with the median survival of 6 months,and 21 cases of liver metastases were found after six months,and the survival rate for 1,3 and 5 years was 85.7％,30.6％ and 9.2％,with the median survival of 15 months,and the difference between the two groups was statistically significant (P ＜ 0.01).After pancreatic cancer surgery and adjuvant gemcitabine chemotherapy,the probability of liver metastases was 33.3％ (8/24) within six months,the median disease-free survival time was 8 months and the disease-free survival rate for 1,3 and 5 years was 20.8％,4.3％ and 0％.For patients without adjuvant gemcitabine chemotherapy,the probability of liver metastases was 79.2％ (19/24),the median disease-free survival time was 3 months and the disease-free survival rate for 1,3 and 5 years was 4.2％,0％ and 0％,and the difference between the two groups was statistically significant (P ＜ 0.01).The overall survival for patients undergoing resection of liver metastases combined with gemcitabine treatment was better than the other groups (P ＜ 0.01).And the overall survival for patients undergoing transhepatic arterial embolization (TACE) combined with gemcitabine treatment was better than TACE group,gemcitabine group or the observation group (P ＜0.05).There were no difference in overall survival between TACE group,gemcitabine group and observation group.Conclusions Pancreatic cancer patients who develop liver metastasis within six months after surgery have poor prognosis,but postoperative chemotherapy can delay the development of liver metastasis.For patients with resectable lesion,resection of asynchronous liver metastasis is the treatment of choice,and TACE combined with gemcitabine has better efficacy than that of single treatment.