Recent progress of nanoparticle-enabled modulation of macrophages for cancer immunotherapy / 药学学报

Macrophages play an important role in maintaining homeostasis of the body, and they are also one of the most abundant immune cells in the tumor microenvironment (TME). These macrophages are often called tumor-associated macrophages (TAMs), which play an important role in the development of tumor and are an important target for tumor therapy. Studies have shown that tumor growth and metastasis can be inhibited by regulating the function of macrophages, but the therapeutic efficacy was often hampered by the poor performance of the drugs such as lack of targeting, poor solubility, low bioavailability, and severe side effects. After introduction of the background of macrophage and tumor therapy, this review focuses on the research progress of nano-drug delivery systems in the modulation of the function of macrophages to enhance tumor immunotherapy. Nano-drug delivery systems are diverse in structures and functions, and can regulate macrophage functions through a variety of mechanisms. Four important aspects of macrophage modulation, which included TAMs depletion, repolarization of TAMs, promoted phagocytosis of TAMs, and combinational modulation of TAMs were summarized. Each strategy together with typical examples was reviewed and future directions in this field were also prospected.

SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas / 生物医学与环境科学（英文）

Objective@#SET8 is a member of the SET domain-containing family and the only known lysine methyltransferase (KMT) that monomethylates lysine 20 of histone H4 (H4K20me1). SET8 has been implicated in many essential cellular processes, including cell cycle regulation, DNA replication, DNA damage response, and carcinogenesis. There is no conclusive evidence, however, regarding the effect of SET8 on radiotherapy. In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tumors and the underlying mechanism.@*Methods@#First, we explored the radiotherapy benefit of the SET8 expression signature by analyzing clinical data. Then, we measured a series of biological endpoints, including the xenograft tumor growth in mice and apoptosis, frequency of micronuclei, and foci of 53BP1 and γ-H2AX in cells to detect the SET8 effects on radiosensitivity. RNA sequencing and subsequent experiments were exploited to verify the mechanism underlying the SET8 effects on radiotherapy.@*Results@#Low expression of SET8 predicted a better benefit to radiotherapy in lung adenocarcinoma (LUAD) and invasive breast carcinoma (BRCA) patients. Furthermore, genetic deletion of SET8 significantly enhanced radiation treatment efficacy in a murine tumor model, and A549 and MCF7 cells; SET8 overexpression decreased the radiosensitivity. SET8 inhibition induced more apoptosis, the frequency of micronuclei, and blocked the kinetics process of DNA damage repair as 53BP1 and γ-H2AX foci remained in cells. Moreover, RNF8 was positively correlated with the SET8 impact on DNA damage repair.@*Conclusion@#Our results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing DNA damage repair, thus suggesting that SET8 potentiated radiotherapy of carcinomas. As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings, combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.

Traditional use of Paris polyphylla and its active components / 中国中药杂志

This paper reviewed the traditional use of Paris polyphylla and its active components, aiming to provide reference for the development and utilization of this plant. It was found that P. polyphylla has been used as a medicinal plant by eight ethnic minorities. A total of 62 experiential effective recipes, including 29 simple recipes and 33 compound recipes, were analyzed for their indications, traditional processing methods, medicinal compatibilities, and administration doses. The top three in the eight ethnic minorities sorted by the quantity of folk recipes were the Yi nationality(18), Naxi nationality(13) and Bai nationality(12). P. polyphylla has been widely employed for the treatment of nine categories of diseases, especially the dermatologic diseases, trauma, and toxicosis currently. The collating of material basis for its traditional functions revealed 26 active components, among which 19 were steroidal saponins capable of resisting cancer, furuncles, carbuncles, abscesses, bacteria, inflammation and stopping bleeding. This study preliminarily proved the efficacy of P. polyphylla in treating cancer and respiratory system, digestive system, and genitourinary system diseases, which has provided clues for related basic research of P. polyphylla and development of new preparations.

Bronchogenic Cyst of Stomach:Report of One Case / 中国医学科学院学报

Bronchogenic cysts are rare congenital cysts caused by anomalism of foregut in the embryonic stage.They locate most frequently in the mediastinum and are rarely seen in stomach.Here we report a case of gastric bronchogenic cysts that was diagnosed and treated in Peking Union Medical College Hospital from April 2 to 9,2018.

Three-dimensional Culture of Human Airway Epithelium in Matrigel for Evaluation of Human Rhinovirus C and Bocavirus Infections / 生物医学与环境科学（英文）

OBJECTIVE@#Newly identified human rhinovirus C (HRV-C) and human bocavirus (HBoV) cannot propagate in vitro in traditional cell culture models; thus obtaining knowledge about these viruses and developing related vaccines are difficult. Therefore, it is necessary to develop a novel platform for the propagation of these types of viruses.@*METHODS@#A platform for culturing human airway epithelia in a three-dimensional (3D) pattern using Matrigel as scaffold was developed. The features of 3D culture were identified by immunochemical staining and transmission electron microscopy. Nucleic acid levels of HRV-C and HBoV in 3D cells at designated time points were quantitated by real-time polymerase chain reaction (PCR). Levels of cytokines, whose secretion was induced by the viruses, were measured by ELISA.@*RESULTS@#Properties of bronchial-like tissues, such as the expression of biomarkers CK5, ZO-1, and PCK, and the development of cilium-like protuberances indicative of the human respiration tract, were observed in 3D-cultured human airway epithelial (HAE) cultures, but not in monolayer-cultured cells. Nucleic acid levels of HRV-C and HBoV and levels of virus-induced cytokines were also measured using the 3D culture system.@*CONCLUSION@#Our data provide a preliminary indication that the 3D culture model of primary epithelia using a Matrigel scaffold in vitro can be used to propagate HRV-C and HBoV.

Novel sesquiterpenoids isolated from Chimonanthus praecox and their antibacterial activities / 中国天然药物

In the present study, four new sesquiterpenoids, chimonols A-D (compounds 1-4), together with four known compounds (5-8) were isolated from the EtOAc extract of Chimonanthus praecox Link. The structures of these new compounds were elucidated on the basis of spectroscopic techniques (UV, IR, MS, and 1D and 2D NMR), and their absolute configurations were established by comparing experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1-8 were evaluated for antimicrobial activities and the minimum inhibitory concentrations (MICs) were determined by the broth microdilution method in 96-well culture plates. Compounds 1, 2, and 7 exhibited weak antibacterial effects for S. aureus (ATCC 6538), E. coli (ATCC 11775), and P. aeruginosa (ATCC 10145) with MIC values being 158-249 µg·mL. Compounds 3-7 showed activities against C. glabrata (ATCC 2001) and S. aureus (ATCC 43300) with MIC values being 128-197 µg·mL. Compounds 1-4 showed activity against S. aureus (ATCC 25923) with MIC values being 162-254 µg·mL. The present study provided a basis for future evaluation of these compounds as antibacterial agents.

Novel sesquiterpenoids isolated from Chimonanthus praecox and their antibacterial activities / 中国天然药物

In the present study, four new sesquiterpenoids, chimonols A-D (compounds 1-4), together with four known compounds (5-8) were isolated from the EtOAc extract of Chimonanthus praecox Link. The structures of these new compounds were elucidated on the basis of spectroscopic techniques (UV, IR, MS, and 1D and 2D NMR), and their absolute configurations were established by comparing experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1-8 were evaluated for antimicrobial activities and the minimum inhibitory concentrations (MICs) were determined by the broth microdilution method in 96-well culture plates. Compounds 1, 2, and 7 exhibited weak antibacterial effects for S. aureus (ATCC 6538), E. coli (ATCC 11775), and P. aeruginosa (ATCC 10145) with MIC values being 158-249 µg·mL. Compounds 3-7 showed activities against C. glabrata (ATCC 2001) and S. aureus (ATCC 43300) with MIC values being 128-197 µg·mL. Compounds 1-4 showed activity against S. aureus (ATCC 25923) with MIC values being 162-254 µg·mL. The present study provided a basis for future evaluation of these compounds as antibacterial agents.

MMP Inhibitor Ilomastat Improves Survival of Mice Exposed to γ-Irradiation / 生物医学与环境科学（英文）

There is still a need for better protection against or mitigation of the effects of ionizing radiation following conventional radiotherapy or accidental exposure. The objective of our current study was to investigate the possible roles of matrix metalloproteinase inhibitor, ilomastat, in the protection of mice from total body radiation (TBI), and the underlying protective mechanisms. Ilomastat treatment increased the survival of mice after TBI. Ilomastat pretreatment promoted recovery of hematological and immunological cells in mice after 6 Gy γ-ray TBI. Our findings suggest the potential of ilomastat to protect against or mitigate the effects of radiation.

Effects of bisbenzylisoquinoline alkaloid tetrandrine derivative HL-27 on biological properties of BLM helicase / 中国药理学通报

Aim To investigate the effects of bisbenzyl-isoquinoline alkaloid tetrandrine derivative HL-27 on the biological properties of the BLM642-1290 helicase. Methods Fluorescence polarization technique was used to investigate the effects of bisbenzylisoquinoline alkaloid tetrandrine derivative HL-27 on the DNA bind-ing activity and unwinding activity of the BLM642-1290 helicase. Malachite green-phosphate ammonium molyb-date colorimetry was used to investigate the effects of HL-27 on the ATPase activity of the BLM642-1290 heli-case. Ultraviolet spectral scanning was used to investi-gate the effects of HL-27 on the conformation of the BLM642-1290 helicase. Results When the concentra-tion of HL-27 reached 33.34 μmol·L-1, the inhibi-tion ratio of dsDNA and ssDNA binding activity of the BLM642-1290 helicase was 41.35% and 59.54% , re-spectively. When the concentration of HL-27 reached 50 μmol·L-1, the inhibition ratio of DNA unwinding activity of the BLM642-1290 helicase was 78.68% . When the concentration of HL-27 reached 100 μmol· L-1, the inhibition ratio of ATPase activity of the BLM642-1290 helicase was 43.8% . Conclusion The DNA binding activity, ATPase activity and unwinding activity of the BLM642-1290 helicase can be inhibited by bisbenzylisoquinoline alkaloid tetrandrine derivative HL-27.

Comparison of Regional Cerebral Oxygen Saturation During Cardiac Surgery in Children With Ventricular Septal Defect and Tetralogy of Fallot / 中国循环杂志

Objectives: To compare regional cerebral tissue oxygen saturation (rScO2) changes during cardiac surgery in children with ventricular septal defect (VSD) and tetralogy of Fallot (TOF). Methods: A total of 60 children aged 3~36 months were enrolled (28 in VSD group 32 in TOF group). rScO2was monitored by Fore-Sight near-infrared spectroscopy device. rScO2, pulse oxygen saturation (SpO2), systolic pressure, diastolic pressure, heart rate, stroke volume index, cardiac index, systemic vascular reststance index the maximal slope of systolic upstroke (dp/dt max) were obtained at following time points: after anesthesia induction (t0), pericardium opening (t1), 5 min after cardiopulmonary bypass (CPB) initiation (t2), 5 min before separation from CPB (t3), separation from CPB (t4), post-modified ultrafiltration (t5), end of surgery (t6). Results: (1) The lowest rScO2value was observed at separation from CPB (t4), and which was significantly lower than that at t0(P<0.05) for both groups; rScO2, stoke volume index, cardiac index, and dp/dt max at t5were significantly higher than at t4(all P<0.001) for both groups. (2) rScO2and SpO2were significantly higher at t5and t6than at t0(both P<0.05) in TOF group. rScO2at t0-t2was significantly lower in TOF group than in VSD group (both P<0.05). rScO2increased more significantly after modified ultrafiltration and rScO2was positively correlated with SpO2at t0and t1(r=0.35, P<0.05 and r=0.64,P<0.01) in TOF group. (3) In the total cohort, rScO2was positively correlated with age, weight at t0, t1, t3, t4, t5, t6(all P<0.01). After modified ultrafiltration, the increase in cardiac index was positively correlated with increase in rScO2(r=0.41, P<0.05), and the amount of cardiac index and rScO2increases were negatively correlated with age (r=-0.30;r=-0.34, both P<0.05). Conclusions: rScO2is closely related with age and weight. Cerebral oxygen delivery before biventricular surgical correction is lower in TOF group than in VSD group, and the cerebral oxygenation improves significantly after surgical repair. Modified ultrafiltration could significantly improve systemic hemodynamics and rScO2, and TOF children and younger children benefit more from modified ultrafiltration. Pre- and post-separation from CPB period is vulnerable to cerebral desaturation, it is therefore of importance to maintain the cerebral oxygen delivery-consumption balance at these periods for children with TOF and VSD undergoing surgical repair.

Application and analysis of endoscopic surgery in treating carpal tunnel syndrome / 中国内镜杂志

Objective To investigate the clinical effect of endoscopic treatment of carpal tunnel syndrome (CTS) with subsynovial hyperplasia. Methods 37 cases (total 41 wrists) of CTS with subsynovial hyperplasia who accepted endoscopic treatment in our hospital were retrospectively analysised, all the transverse ligament of wrist were cutted off under endoscope and the hyperplastic subsynovial membrane arounding the superficial flexor tendon of finger. The changes of clinical symptoms and signs before and after operation were compared. Results According to Kelly classification, the overall excellent and good rate was 95.12%. After operation, the feel of numb and pain during night disappeared in all patients, the positive rate of Tinel and Phalen sign was both reduced to 2.44% (P < 0.05), and the mean value of two-point discrimination was reduced to (3.5 ± 0.9) mm. No serious complication occurred during treatment. Conclusion For the patients of CTS with subsynovial hyperplasia, to cut the transverse ligament tendon under endoscope and remove the subsynovial around the flexor tendon at the same time is a new and feasible surgical procedure with notable curative effect, which deserves clinical popularization.

Influence of nocturnal orthokeratology lens on sleep quality in myopic patients / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To observe the influence of wearing nocturnal orthokeratology lens on sleep quality in myopic patients.?METHODS: Totally 30 myopic patients ( 58 eyes ) wearing nocturnal orthokeratology lens, who received medical treatment at the Department of Ophthalmology of Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, were included in study ( treated group ) . And 30 myopic patients wearing spectacles at the same time were randomly selected as the control group. Sleep quality of two groups were assessed with Pittsburgh sleep quality index ( PSQI ) before and after wearing the lens in the first and the third months, and compared.?RESULTS:Equivalent diopter of the 30 patients wearing nocturnal orthokeratology lens was -2. 78D±0. 90D before treated with orthokeratology lens, -0. 30D ± 0. 31D after 1mo of treatment, and -0. 28D ± 0. 30D after 3mo of treatment. There was significant difference between the equivalent diopter got before treated with orthokeratology lens and that got after 1mo of treatment (P<0.05), and between the equivalent diopter got before treated with orthokeratology lens and that got after 3mo of treatment (P<0. 05). The total scores of PSQI of 30 myopic patients got before wearing nocturnal orthokeratology lens and after 1 or 3mo of that were respectively 2. 13±1. 36, 2. 47±1. 98, and 1. 74±1. 39. There only was significant difference in scores of subjective sleep quality got after 3mo of treatment between treated group and control group (P<0. 05), but no significant difference in scores of total PSQI, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction( P>0. 05).?CONCLUSION:Wearing nocturnal orthokeratology lens has no significant effect on the overall sleep quality index of myopic patients, but the subjective sleep quality decreased in the early stage of wearing the lens.

Relationship between radiographic parameters and clinical outcomes of elderly patients with distal radius fractures / 中国骨伤

<p><b>OBJECTIVE</b>To analyze the relationship between radiographic parameters and clinical outcomes of patients with distal radius fractures in elderly patients following conservative treatment, and find the important radiographic parameters with distal radius fractures in elderly patients.</p><p><b>METHODS</b>From May 2012 to May 2015, a retrospective analysis was performed of 45 elderly patients with distal radius fractures treated by conservative treatment, which including 17 males and 28 females with an average age of 64.49 years old from 60 to 89 years old. The imaging parameters were measured and the clinical efficacy was evaluated. The imaging parameters on the standard wrist joint X-ray picture were measured including metacarpal angle, the radius height, the ulna variation, the ulnar angle, and so on. The clinical effect of wrist joint was evaluated by Dienst score standard. Multiple factor linear regression was used to analyze the relationship between the image parameters and the clinical efficacy.</p><p><b>RESULTS</b>All patients were followed up for 12 to 24 months with an average of 17.6 months. All fractures of the distal radius were healed. According to the Dienst evaluation, at the final follow-up the result was excellent in 27 cases, good in 10 cases, fair in 6 cases and poor in 2 cases. There was a significant correlation between the height of the radius, the angle of the palmar and the variation of the ulna and the function of the wrist joint in the imaging parameters. When the radius height more than 8.12 mm, the palmar angle more than -1.64 degree and the ulna variant less than 4.05 mm, the result of Dienst function was better.</p><p><b>CONCLUSIONS</b>The imaging parameters such as the radius height, the palmar angle and the ulna variation are related to the recovery of the clinical efficacy of the distal radius fractures in the elderly. The most important parameter is the radius height, which reminds the surgeon to pay special attention to the reduction of the radius fracture in the elderly.</p>

Compatibility Stability Investigation of Fat-soluble Vitamin (Ⅱ)/Water-soluble Vitamin for Injection with Common Electrolytes / 中国药房

OBJECTIVE:To investigate the compatibility stability of Fat-soluble vitamin (Ⅱ)/Water-soluble vitamin for in-jection with common electrolytes. METHODS:Referring to clinical common dose,Fat-soluble vitamin (Ⅱ) for injection/Wa-ter-soluble vitamin for injection collective packing [containing Fat-soluble vitamin(Ⅱ) for injection 2 ampoules and Water-soluble for injection 1 ampoule] were respectively mixed with Glucose injection,Potassium chloride injection,Concentrated sodium chlo-ride injection,Sodium bicarbonate injection,Potassium aspartate injection,Potassium aspartate and magnesium aspartate injection, Sodium glycerophosphate injection,Multi-trace elements injection (Ⅱ) to obtain mixture A-H. At room temperature (25 ℃),these mixtures were investigated in terms of appearance,pH value,osmotic pressure molar concentration and the number of insolu-ble particles at 0,1,2,3,4 h. The contents of bacterial endotoxin were tested at 0,4 h. RESULTS:Within 4 h after mixing, there was no significant change in appearance of those mixtures;pH value of mixture H changed greatly (RSD=5.13%,n=5), and that of mixture D and G increased significantly. The osmotic pressure molar concentration of those mixtures had no significantly change(RSD<2%,n=5)and lower than 600 mOsmol/kg. The bacterial endotoxin tests of those mixtures were negative. Two and four hours after mixing,the number of insoluble particles ≥10 μm in mixture B was increased significantly;2,3,4 h after mix-ing,the number of insoluble particles ≥10 μm in mixture E,F,H were increased significantly;0 ,1,2,3,4 h after mixing,the number of insoluble particles ≥10 μm in mixture G was increased significantly. There was statistical significance in the number of insoluble particle ≥10 μm in above mixtures compared to mixture A at the same time point(P<0.05),but it was in line with the standard of 2015 pharmacopeia. One,two,three and four hours after mixing,the number of insoluble particle ≥10 μm in mixture D was increased significantly,there was statistical significance compared to mixture A at the same time point(P<0.05);the num-ber of insoluble particle ≥10 μm in mixture D was beyond prescribed scope of pharmacopeia at 2,3,4 h after mixing. Within 4 h after mixing,both the number of insoluble particle ≥10 μm in mixture C and the number of insoluble particle ≥25 μm in edch mixture had no significant change,in accordance with pharmacopeia standard. CONCLUSIONS:Fat-soluble vitamin (Ⅱ)/Wa-ter-soluble vitamin for injection is not suitable for mixing with Multi-trace elements injection(Ⅱ),Sodium glycerophosphate injec-tion or Sodium bicarbonate injection due to great change of pH value and the number of insoluble particles.

Recent highlights of Chinese herbs in treatment of allergic disease: Acting via mitogen-activated protein kinase signal pathway / 中国结合医学杂志

The histamine receptor antagonists in the treatment of allergic disease have limitations. The treatments of Chinese herbs have some curative effects on allergic skin lesions. Present research indicates that the mitogen-activated protein kinase (MAPK) signaling pathway might be equally important in allergic reactions. It was found that the inhibition of MAPK signaling pathways might relieve allergy symptoms, and some herbs can inhibit the MAPK pathway, which yields anti-allergy effects. Chinese medicines (CMs) have immense potential in the development of treatments for allergic disease.

Comparison of Multislice Spiral CT Dual Phase and Somatosatatin Receptor Scintigraphy in the Diagnosis of Pancreas Neuroendocrine Tumors / 中国医学科学院学报

Objective To compare the sensitivity of multislice spiral CT dual phase and somatosatatin receptor scintigraphy (SRS) in the diagnosis of pancreas nuroendocrine tumors (pNET). Methods Totally 28 patients with pathologically confirmed pNET recieved both CT dual phase contrast and SRS and the results were compared. Results Of these 28 pNET patients,26 (92.8%) were accurately diagnosed by CT dual-phase scan and 20 (71.4%) by SRS (P＝0.031).In the functioning pNET cases,the diagnosis sensitivity of CT dual phase scan and SRS was 94.1% (16/17)and 58.8% (10/17)(P＝0.218). In the non-functioning pNET cases,the sensitivity was 90.9% (10/11) and 90.9% (10/11) (P＝0.740).Diagnostic sensitivity of CT dual phase scan and SRS for pNET without metastasis was 90.4% (19/21) and 57.1% (12/21) (P＝0.125).The sensitivity for pNET with metastasis was 100%(7/7)and 100% (7/7). Corresponding to the pathological grading,the diagnostic sensitivity of CT dual phase scanning and SRS was 84.6% (11/13) and 53.8% (7/13) for G1,100% (12/12) and 83.3% (10/12) for G2,and 100% (3/3) and 100% (3/3) for G3. The diagnostic sensitivity of CT dual phase scan and SRS for pNET with diameter less than or equal to 2.0 cm was 94.7% (18/19) and 52.6% (10/19) (P＝0.008). For pNET with diameter more than 2.0 cm,the sensitivity was 92.8% (13/14) and 100% (14/14). Conclusions Compared with SRS,dual phase CT scan is more sensitive in diagnosing pNET,especially for those in lower pathological stages. For lesions sized less than or equal to 2.0 cm,SRS should be combined with other imaging examinations to minimize false negative results.

Distinctive Drug-resistant Mutation Profiles and Interpretations of HIV-1 Proviral DNA Revealed by Deep Sequencing in Reverse Transcriptase / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To investigate distinctive features in drug-resistant mutations (DRMs) and interpretations for reverse transcriptase inhibitors (RTIs) between proviral DNA and paired viral RNA in HIV-1-infected patients.</p><p><b>METHODS</b>Forty-three HIV-1-infected individuals receiving first-line antiretroviral therapy were recruited to participate in a multicenter AIDS Cohort Study in Anhui and Henan Provinces in China in 2004. Drug resistance genotyping was performed by bulk sequencing and deep sequencing on the plasma and whole blood of 77 samples, respectively. Drug-resistance interpretation was compared between viral RNA and paired proviral DNA.</p><p><b>RESULTS</b>Compared with bulk sequencing, deep sequencing could detect more DRMs and samples with DRMs in both viral RNA and proviral DNA. The mutations M184I and M230I were more prevalent in proviral DNA than in viral RNA (Fisher's exact test, P<0.05). Considering 'majority resistant variants', 15 samples (19.48%) showed differences in drug resistance interpretation between viral RNA and proviral DNA, and 5 of these samples with different DRMs between proviral DNA and paired viral RNA showed a higher level of drug resistance to the first-line drugs. Considering 'minority resistant variants', 22 samples (28.57%) were associated with a higher level of drug resistance to the tested RTIs for proviral DNA when compared with paired viral RNA.</p><p><b>CONCLUSION</b>Compared with viral RNA, the distinctive information of DRMs and drug resistance interpretations for proviral DNA could be obtained by deep sequencing, which could provide more detailed and precise information for drug resistance monitoring and the rational design of optimal antiretroviral therapy regimens.</p>

Endoplasmic Reticulum Stress Induces the Early Appearance of Pro-apoptotic and Anti-apoptotic Proteins in Neurons of Five Familial Alzheimer's Disease Mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated.</p><p><b>METHODS</b>The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Morris water maze test was used to evaluate their cognitive performance. Immunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN1]) in the ERS-associated unfolded protein response (UPR) pathway.</p><p><b>RESULTS</b>Compared with age-matched WT mice, 5×FAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P < 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN1, were significantly increased when compared with those in age-matched WT mice (all P < 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes.</p><p><b>CONCLUSIONS</b>These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.</p>

Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model.</p><p><b>METHODS</b>The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence.</p><p><b>RESULTS</b>In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1-42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation.</p><p><b>CONCLUSIONS</b>oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.</p>

Matrix formulation of Hanbishu Cataplasma optimized by D-optimal mixture design and research on its in vitro evaluation / 中草药

Objective: To optimize the matrix formulation of Hanbishu Cataplasma (HC) and to investigate its realease and transdermal absorption properties in vitro. Methods: To optimize the cataplasma with liquid extract by D-optimal mixture design, using initial bonding strength, endurance bonding strength, and gel strength as evaluating indicators, and to validate the optimal formulation. Modified Franz diffusion cells were used to study the in vitro release and transdermal absorption of osthole in the HC. Results: The matrix formulation of HC was as follows: NP700 6.97 g, aluminum glycinate 0.30 g, tartaric acid 0.25 g, glycerin 35.00 g, PVP K90 3.87 g, water 43.61 g, and Hanbishu liquid extract 10 g. Cumulative release rate of osthole in HC was (63.30 ± 0.05)% in 24 h. The percutaneous penetration rate of osthole was 0.16 μg/(cm2∙h) and the 24 h permeated amount was (3.61 ± 0.32) μg/cm2. Conclusion: The optimal prescription of HC optimized by D-optimal mixture design has good adhesion and formability. In vitro release characteriistics of osthole in HC conform to the first dynamical equation, and the transdermal absorption behavior is a zero-order kinetics.