Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

Celastrol and wilforlide A are the main active triterpenoids of the traditional Chinese medicine Lei Gong Teng, which have anti-tumour, anti-inflammatory and immunosuppressive activities, and are the material basis for the clinical efficacy of Lei Gong Teng-related Chinese medicinal preparations. By analysing the biosynthetic pathway of active ingredients, optimizing genetic elements and utilizing "cell factory" to produce triterpenoids heterologously will be an effective way to obtain from Tripterygium wilfordii in the future in a "low-cost and high-efficient" manner. CYP712Ks are the first cytochrome P450s involved in the skeleton modification of friedelane-type and oleanane-type triterpenoids in T. wilfordii, and they can catalyse the generation of polpunonic acid from friedelin and 3-epi-katonic acid from β-amyrin by carboxylation at C-29 position. In this study, four multifunctional TwCYP712K1/2/3/5 were used to clarify the catalytic function and substrate selection preference using in vivo functional characterization in Saccharomyces cerevisiae. The spatial structure of the protein-substrate binding was clarified through homology modeling and molecular docking, and then the differential amino acids in the active pocket of the protein were mutated to clarify the crucial amino acids determining the catalytic function and the selection of substrate structure. A total of 63 mutant elements were constructed, and the amino acid sites affecting the carboxylation function of TwCYP712Ks were analyzed. In particular, the key amino acids affecting the substrate selectivity of TwCYP712K2 towards oleanane-type and friedelane-type triterpenoids were revealed and the TwCYP712K2^F127I and TwCYP712K2^A227T mutants would result in a reversal of the product ratio. In conclusion, four proteins of TwCYP712Ks were semi-rationally designed by homologous protein alignment and mutual mutation to elucidate multiple amino acid sites determining the catalytic function of the proteins, and a series of activity-enhancing or altering mutants were obtained, which provide abundant catalytic elements for the biosynthesis of active triterpenoids from T. wilfordii, and the mechanism of carboxylation in the C-29 position was initially elucidated.

From an aqueous extract of the Angelica sinensis root head (guitou), nine pairs of lignanoid enantiomers [(+)-/(-)-1-(+)-/(-)-9], including three pairs of new structures [(+)-/(-)-1-(+)-/(-)-3] and two pairs of chiral separated enantiomers for the first time [(+)-/(-)-4 and (+)-/(-)-5], were isolated and chirally separated by column chromatography over different types of resin, normal and reversed phase silica gels, together with HPLC techniques using reversed phase and chiral columns. Their structures were determined by spectroscopic data analysis, theoretic calculation of electronic circular dichroism (ECD) spectra, and single-crystal X-ray diffraction. The chiral separated new enantiomers named (+)-/(-)-angelignanins Q-T [(+)-/(-)-1-(+)-/(-)-4] and (+)-/(-)-daphneresinol [(+)-/(-)-5], respectively.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment, and there is a lack of effective drugs to treat AD clinically. Existing medications for the treatment of AD, such as Tacrine, Donepezil, Rivastigmine, and Aducanumab, only serve to delay symptoms and but not cure disease. To add insult to injury, these medications are associated with very serious adverse effects. Therefore, it is urgent to explore effective therapeutic drugs for AD. Recently, studies have shown that a variety of enzyme inhibitors, such as cholinesterase inhibitors, monoamine oxidase (MAO)inhibitors, secretase inhibitors, can ameliorate cholinergic system dysfunction, Aβ production and deposition, Tau protein hyperphosphorylation, oxidative stress damage, and the decline of synaptic plasticity, thereby improving AD symptoms and cognitive function. Some plant extracts from natural sources, such as Umbelliferone, Aaptamine, Medha Plus, have the ability to inhibit cholinesterase activity and act to improve learning and cognition. Isochromanone derivatives incorporating the donepezil pharmacophore bind to the catalytic active site (CAS) and peripheral anionic site (PAS) sites of acetylcholinesterase (AChE), which can inhibit AChE activity and ameliorate cholinergic system disorders. A compound called Rosmarinic acid which is found in the Lamiaceae can inhibit monoamine oxidase, increase monoamine levels in the brain, and reduce Aβ deposition. Compounds obtained by hybridization of coumarin derivatives and hydroxypyridinones can inhibit MAO-B activity and attenuate oxidative stress damage. Quinoline derivatives which inhibit the activation of AChE and MAO-B can reduce Aβ burden and promote learning and memory of mice. The compound derived from the combination of propargyl and tacrine retains the inhibitory capacity of tacrine towards cholinesterase, and also inhibits the activity of MAO by binding to the FAD cofactor of monoamine oxidase. A series of hybrids, obtained by an amide linker of chromone in combine with the benzylpiperidine moieties of donepezil, have a favorable safety profile of both cholinesterase and monoamine oxidase inhibitory activity. Single domain antibodies (such as AAV-VHH) targeted the inhibition of BACE1 can reduce Aβ production and deposition as well as the levels of inflammatory cells, which ultimately improve synaptic plasticity. 3-O-trans-p-coumaroyl maslinic acid from the extract of Ligustrum lucidum can specifically inhibit the activity of γ-secretase, thereby rescuing the long-term potentiation and enhancing synaptic plasticity in APP/PS1 mice. Inhibiting γ-secretase activity which leads to the decline of inflammatory factors (such as IFN-γ, IL-8) not only directly improves the pathology of AD, but also reduces Aβ production. Melatonin reduces the transcriptional expression of GSK-3β mRNA, thereby decreasing the levels of GSK-3β and reducing the phosphorylation induced by GSK-3β. Hydrogen sulfide can inhibitGSK-3β activity via sulfhydration of the Cys218 site of GSK-3β, resulting in the suppression of Tau protein hyperphosphorylation, which ameliorate the motor deficits and cognitive impairment in mice with AD. This article reviews enzyme inhibitors and conformational optimization of enzyme inhibitors targeting the regulation of cholinesterase, monoamine oxidase, secretase, and GSK-3β. We are hoping to provide a comprehensive overview of drug development in the enzyme inhibitors, which may be useful in treating AD.

Objective To analyse the clinical efficacy of low-frequency of midnight-noon ebb-flow acupuncture-opening method(also called Ziwu Liuzhu Acupuncture,referring to the needling method based on acupoints selection according to qi and blood movement following heavenly-stems and earthly-branches cycle)in treating low myopia in children.Methods A retrospective study was conducted to collect the clinical data of 84 cases(168 eyes)of children with low myopia who received treatment at the Outpatient Department of Guangdong Provincial Hospital of Chinese Medicine from January 2021 to December 2022.The children were divided into two groups according to the different treatment protocols:42 cases(84 eyes)treated with acupuncture combined with conventional optometry as the control group,and 42 cases(84 eyes)treated with low-frequency of midnight-noon ebb-flow acupuncture-opening method combined with conventional optometry as the observation group,and the treatment course of both groups was 24 weeks.The changes of refractive error and axial length before and after treatment were observed,and the clinical efficacy in the two groups of children were evaluated.Results(1)After treatment,there being statistically significant differences in the refractive error between the two groups of the children(P＜0.05),and the differential value of the refractive error of the children between the two groups before and after treatment was statistically significant(P＜0.05).(2)After treatment,there being statistically significant differences in the axial length of the children in both groups(P＜0.05).The differential value of axial lengths of the children between the two groups before and after treatment was statistically significant(P＜0.05).(3)The total effective rate of the observation group was 84.52%(71/84),and which of the control group was 63.10%(53/84),the efficacy of the observation group was significantly superior to that of the control group,and the difference was statistically significant(P＜0.05).Conclusion The low-frequency of midnight-noon ebb-flow acupuncture-opening method in treating low myopia in children can effectively postpone the degree of myopia,and decrease the growth of the axis,with exact therapeutic effect.

Objective To discuss the clinical application of coronary CT angiography(CCTA)-derived fractional flow reserve(CT-FFR)in evaluating the risk stratification of the coronary artery stenosis and atherosclerotic plaque quantitative parameters.Methods A total of 122 patients,who received CCTA examination at the Xuzhou Municipal Central Hospital of China,were enrolled in this study.The patients were divided into non-ischemia group(CT-FFR＞0.8,n=66)and ischemia group(CT-FFR0.8,n=56).The characteristics of atherosclerotic plaque were compared between the two groups.Logistic regression analysis was used to analyze the correlation between plaque characteristics and ischemic lesions.Results There were 218 vessels having a CT-FFR＞0.8 and 174 vessels having a CT-FFR ≤0.8.Statistically significant differences in the total plaque volume,calcified plaque volume,plaque length,and stenosis ratio＞50％existed between the two groups(all P＜0.05).Logistic regression analysis indicated that the total plaque volume,calcified plaque volume,plaque length,and stenosis ratio＞50％were the risk factors for myocardial ischemia.Conclusion CT-FFR can be used for the risk stratification of coronary stenosis and atherosclerotic plaque characteristics,which can evaluate the local myocardial blood supply condition from the anatomical stenosis and functional level so as to optimize the diagnosis and treatment measures.

Aim To investigate the intracellular up-take and target protein binding characteristics of two Bruton's tyrosine kinase inhibitors(BTKi)with differ-ent selectivities to provide further insights into the mechanisms of drug off-target-related bleeding risk.Methods Ibrutinib(non-selective BTKi)and za-nubrutinib(selective BTKi)were used as study drugs.After incubation of MEC-1 cells and human platelets with drugs,the cellular thermal shift assay(CETSA)was combined with Western blot to obtain the melting curve and isothermal curve to analyze the binding char-acteristics of the two drugs with the target protein BTK.After incubation of MEC-1 cells and human platelets with drugs,the concentrations of the two drugs were detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS)to analyze the intracellular uptake of the two drugs.Results CETSA analysis confirmed that zanubrutinib was more selective for the target protein BTK compared to ibrutinib.LC-MS/MS analysis showed that both drugs were uptaken intracel-lularly by MEC-1 cells and platelets in a concentration-dependent manner.Conclusions While BTKi targe-ting BTK to B lymphocytes exerts therapeutic effects,off-target effects on platelets due to differences in their intracellular uptake,and target-binding characteristics may be one of the reasons for the differences in bleed-ing risk across selective BTKi.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Microplastics pose a serious threat to the environment and human health,but the circulating distribution and transport processes of microplastics in organisms have not been fully assessed.Therefore,it is of great significance to construct a probe that can image trace microplastics and visually monitor their circulation and transport in vivo.Afterglow semiconducting polymers are attractive for applications in biological imaging as they do not contain heavy metal ions,are easy to biodegrade and allow high signal-to-noise ratio afterglow imaging without continuous excitation.In this study,with styrene as reaction monomer,polyvinylpyrrolidone as surfactant,and sodium persulfate as initiator,afterglow polystyrene microspheres for in vivo imaging of microplastics were prepared.During the polymerization process,poly[(9,9-di(2-ethylhexyl)-9H-fluo-rene-2,7-vinylene)-co-(1-methoxy-4-(2-ethylhexyloxy)-2,5-phenylenevinylene)](PF-MEHPPV)and photosensitizer silicon 2,3-naphthalocyanine bis(trihexylsilyloxide)(NCBS)were co-doped into polystyrene microspheres.The prepared afterglow polystyrene microspheres exhibited an afterglow duration of 96 h and a tissue penetration depth of 1.8 cm.It was found that co-doping of PF-MEHPPV and NCBS had little effect on the particle size and Zeta potential of the microspheres,and allowed to monitor the afterglow luminescence signal in vivo for 24 h.Imaging of mouse organs after anatomy showed that the afterglow signal was still observed in the stomach of mice 48 h after gavage.This study provided a new method for imaging and tracing microplastics in vivo.

Objective To develop a portable field infusion kit for first aid to meet the treatment requirements in field conditions.Methods The infusion kit had its frame made of third-generation carbon fiber material and was composed of a lid and a body.The lid was equipped with embedded handles on the outer surface,a medicine module consisting of 12 mesh bags on the inner surface and LED lights on the inner and outer front side walls.The kit body had three storage layers in its upper,middle and lower parts,of which the upper layer was for supplies of infusion and hemostatic dressing,the middle layer was for medical instruments and soft bags of liquid for first aid,and the lower layer was for medical waste and sharp instruments,and the bottom of the kit was provided with telescopic drawbars and invisible rollers.Results The first-aid infusion kit facilitated the storage and utilization of kinds of infusion supplies,and lowered time consumption and workloads for transport.Conclusion The first-aid infusion kit gains advantages in reasonable layout,comprehensive functions and convenient operation,and thus is worhty promoting for casualty treatment in field conditions.[Chinese Medical Equipment Journal,2024,45(7):115-117]