Objective A rat model of cerebral small vessel disease(CSVD)was established by unilateral injection of a single dose of sodium laurate into the internal carotid artery.The effectiveness of the model was assessed by behavior scoring and analysis of serum-related indicators,cerebral infarction volume,cerebral microvascular density,hemodynamics,brain histopathology and the expression of blood-brain barrier(BBB)-related proteins.Methods SPF-grade male SD rats were divided randomly into a control group and a model group(n=6 per group).The model group received a single injection of 100 μL of sodium laurate(2 g/L)via the internal carotid artery,while the control group underwent the same surgical procedure but received an equal volume of saline.Neurobehavioral assessments were conducted using the Longa score and postural reflex test.Serum homocysteine(HCY)levels were measured by enzyme-linked immunosorbent assay.Cerebral infarction volume was detected by magnetic resonance imaging and changes in cerebral vascular density were observed by cerebrovascular imaging.The resistance index(RI)and perfusion index(PI)were measured by ultrasonography.Histopathological changes in brain tissue were evaluated by hematoxylin and eosin(HE)staining.Expression of the cerebral microvascular marker CD31 and tight junction proteins ZO-1 and Occludin in brain cortex tissue were detected by immunohistochemical staining.Results The Longa score,postural reflex score(P＜0.05),and cerebral infarction volume were significantly increased(P＜0.05)while the cerebral vascular density was decreased in the model group compared with the control group.Serum HCY levels,carotid RI,and PI values were all significantly increased in the model group(P＜0.05).HE staining revealed solidified neuronal nuclei and enlarged perivascular spaces in the brain cortex in the model group.Immunohistochemical staining revealed that CD31,ZO-1,and Occludin expression were significantly reduced in the brain cortex in the model group compared with the control group(P＜0.05).Conclusions A rat model of CSVD can be established rapidly and effectively by a single unilateral injection of high-concentration sodium laurate via the internal carotid artery.This model is characterized by neurobehavioral abnormalities,cerebral infarction,insufficient cerebral blood supply,reduced vascular density,and disruption of the BBB,suggesting that it may serve as an effective rat model for the study of CSVD.

Objective A rat model of cerebral small vessel disease(CSVD)was established by unilateral injection of a single dose of sodium laurate into the internal carotid artery.The effectiveness of the model was assessed by behavior scoring and analysis of serum-related indicators,cerebral infarction volume,cerebral microvascular density,hemodynamics,brain histopathology and the expression of blood-brain barrier(BBB)-related proteins.Methods SPF-grade male SD rats were divided randomly into a control group and a model group(n=6 per group).The model group received a single injection of 100 μL of sodium laurate(2 g/L)via the internal carotid artery,while the control group underwent the same surgical procedure but received an equal volume of saline.Neurobehavioral assessments were conducted using the Longa score and postural reflex test.Serum homocysteine(HCY)levels were measured by enzyme-linked immunosorbent assay.Cerebral infarction volume was detected by magnetic resonance imaging and changes in cerebral vascular density were observed by cerebrovascular imaging.The resistance index(RI)and perfusion index(PI)were measured by ultrasonography.Histopathological changes in brain tissue were evaluated by hematoxylin and eosin(HE)staining.Expression of the cerebral microvascular marker CD31 and tight junction proteins ZO-1 and Occludin in brain cortex tissue were detected by immunohistochemical staining.Results The Longa score,postural reflex score(P＜0.05),and cerebral infarction volume were significantly increased(P＜0.05)while the cerebral vascular density was decreased in the model group compared with the control group.Serum HCY levels,carotid RI,and PI values were all significantly increased in the model group(P＜0.05).HE staining revealed solidified neuronal nuclei and enlarged perivascular spaces in the brain cortex in the model group.Immunohistochemical staining revealed that CD31,ZO-1,and Occludin expression were significantly reduced in the brain cortex in the model group compared with the control group(P＜0.05).Conclusions A rat model of CSVD can be established rapidly and effectively by a single unilateral injection of high-concentration sodium laurate via the internal carotid artery.This model is characterized by neurobehavioral abnormalities,cerebral infarction,insufficient cerebral blood supply,reduced vascular density,and disruption of the BBB,suggesting that it may serve as an effective rat model for the study of CSVD.

Non-alcoholic fatty liver disease is a common chronic liver disease in clinical practice. In recent years, with increasing social attention to the health of women and the elderly, the prevention and treatment of non-alcoholic fatty liver disease after menopause has increasingly become a research hotspot in metabolic diseases. This study explores the pathogenesis and treatment method of non-alcoholic fatty liver disease in postmenopausal women based on the theory of "deficient qi and stagnation" and combined with the physiological and pathological characteristics of postmenopausal women and the Western medicine understanding of non-alcoholic fatty liver disease. We believe that the pathogenesis of non-alcoholic fatty liver disease in postmenopausal women is rooted in the "deficient qi" caused by depletion of liver and kidney essence and blood. The imbalance between the physical and functional aspects of the liver due to this "deficient qi" is the primary factor, while the "stagnation" of phlegm and blood stasis is the manifestation. Furthermore, the "deficient qi" and "stagnation" reinforce each other, with the deficiency leading to stagnation and stagnation exacerbating the deficiency, thus accelerating the progression of the disease. The treatment approach should be one that combines nourishing deficiency and resolving stagnation, addressing both root cause and maifestations. Given the female characteristic of "the liver as the innate organ" and the post-menopausal physiological state of "gradual decline of kidney essence", it is important to focus on nourishing the liver and kidneys, nurturing the liver′s physical body while maintaining its function, and also promoting the circulation of qi, resolving phlegm, and invigorating blood circulation to remove blood stasis. This approach aims to reduce the accumulation of lipids in the liver, offering a new perspective and approach for the treatment of non-alcoholic fatty liver disease in post-menopausal women with traditional Chinese medicine.

Breast cancer is the most diagnosed cancer in women worldwide and the leading cause of most cancer-related deaths,posing a serious threat to women′s health worldwide.At present,although the prognosis of some patients with breast cancer has improved,the emergence of drug resistance and the metastasis and recurrence of breast cancer are still the main reasons for poor prognosis.CD36 is a multiligand transmembrane glycoprotein expressed on various cell types.In recent years,studies have confirmed that CD36 can reshape the lipid metabolism of cancer cells;promote the differentiation of tumor-related macrophages into M2 type and recruitment into tumor tissues;regulate the function of Treg cells,CD8+T cells,DCs,and other immune cells,and thus promote tumor development.In addition,CD36 is also associated with breast cancer stem cells,metastasis-initiating cells,and breast drug resistant cells.Therefore,CD36 could be an important potential therapeutic target for breast cancer.

Cognitive dysfunction,predominantly a consequence of neurodegenerative disorders,is a burgeoning health issue.Odor molecules have the unique ability to circumvent the blood-brain barrier through the olfactory pathway,exerting a direct influence on cognitive-related brain regions including the entorhinal cortex,hippocampus,and amygdala,without transiting through the thalamus.These olfactory molecules,mostly sourced from natural plant essential oils,are character-ized by significant volatility,minimal adverse reactions,and abundant availability.Hence,research into and applications of olfactory stimulation in improving cognitive dysfunction have raised widespread concerns.This article reviews the rela-tionship between the olfactory pathway and cognitive brain regions,and explores the mechanism by which natural plant es-sential oils alleviate cognitive dysfunction through olfactory stimulation in order to provide a reference for improving cogni-tive function via olfactory stimulation.

Objective To study the influence of rosemary essential oil inhalation on the memory of mice experiencing sleep deprivation and to delineate the possible mechanisms involved.Methods C57BL/6J mice were randomly divided into four experimental groups in this study:a control group(Con),a control group with rosemary essential oil inhalation(Con+REO),a sleep deprivation group(SD)and a sleep deprivation group with rosemary essential oil inhalation(SD+REO).A 72-hour sleep deprivation model was induced using the multiple platform water environment method,with the Con+REO and SD+REO groups exposed to rosemary essential oil inhalation.Cognitive function was evaluated through Y-maze and novel object recognition tests.The hippocampal tissue was analyzed for superoxide dismutase(SOD)activity and the concentrations of malondialdehyde(MDA)and glutathione(GSH).ELISA was used to determine the levels of norepinephrine(NE),dopamine(DA),and serotonin 5-hydroxytryptamine(5-HT)in the hippocampus.The expression levels of postsynaptic density 95(PSD95)and brain-derived neurotrophic factor(BDNF)in the hippocampus were determined using immunoblotting techniques.Results Compared with the Con and Con+REO groups,the SD group demonstrated a significant reduction in the spontaneous alternation percentage in the Y-maze as well as the novel object recognition index.Additionally,there was a pronounced decrease in hippocampal SOD activity and GSH content,a substantial elevation in MDA levels,and a decrease in the levels of DA,NE,and 5-HT.The expressions of PSD95 and BDNF proteins also decreased.In comparison with the SD group,the SD+REO group exhibited a significant increase in the spontaneous alternation percentage in the Y-maze and the novel object recognition index.There was also a marked increase in hippocampal SOD activity and GSH content,a reduction in MDA levels and elevated levels of NE and DA.Moreover,the expressions of PSD95 and BDNF proteins were upregulated.Conclusion The inhalation of rosemary essential oil enhances the memory of sleep-deprived mice,and the underlying mechanism may involve the mitigation of oxidative stress within the hippocampal tissue,the modulation of neurotransmitter levels,and the facilitation of synaptic plasticity.

Background::Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC.Methods::We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort ( n = 125), a validation cohort ( n = 82), and a control cohort ( n = 80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. Results::A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment.Conclusion::These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O6-methylguanine(O6-MG)-DNA-meth-yltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensi-tivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.

Objective:To investigate the role and mechanism of dopamine receptor D2(DRD2)in the immune microenvironment of breast cancer. Methods:The xenograft model of breast cancer is established using female C57BL/6J mice and murine breast cancer EO771 cells.Mice with transplanted tumor were treated by intraperitoneal injection of the specific antagonist of DRD2,thioridazine,while PBS was injected intraperitoneally in the control group.siDRD2 targeting DRD2 gene was intratumorally injected to tumor-bearing mice[negative control siRNA(siNC)was injected to the control group].The percentage of Ki-67 positive cells and CD4+T lymphocytes in tumor tissue was examined by immunohistochemical analysis.The proportion of CD45+CD4+T lymphocytes,CD45+CD4+IFNγ+Th1 cells and CD45+CD4+IL-1 7+Th17 cells was detected by flow cytometry. Results:Compared with the control group,the tumor volume(P＜0.05),tumor mass(P＜0.001)and the proportion of Ki-67 positive cells(P＜0.001)in tumor tissue were decreased in the thioridazine-treated group.The proportion of CD45+immune cells(P＜0.05)and CD4+T lymphocytes(P＜0.001)in thioridazine-treated group was higher than that in the control group.The proportion of Th1 cells(CD45+CD4+IFNγ+)increased(P＜0.001)in thioridazine-treated group.There was no significant changes in the proportion of Th1 7 cells(CD45+CD4+IL-1 7+)(P＞0.05).Compared with the control group(siNC),the tumor volume(P＜0.05),tumor mass(P＜0.001)and the proportion of Ki-67 positive cells(P＜0.001)were decreased in siDRD2 group.The proportion of tumor infiltrating CD4+T lymphocytes(P＜0.001)and Th1 cells(P＜0.001)in the siDRD2 group was higher than that in the siNC group,whereas the change in the proportion of Th1 7 cells was not statistically significant(P＞0.05). Conclusion:Down-regulation of DRD2 could promote the differentiation of Th1 cells and inhibit the proliferation of breast cancer cells in a mouse breast cancer model.

Objective To investigate the clinical features of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant infection and abnormal liver function in Guangdong Province, China. Methods The patients with SARS-CoV-2 Delta variant infection who belonged to the same chain of transmission in Guangdong Province (Guangzhou and Foshan) and were admitted to Guangzhou Eighth People's Hospital, Guangzhou Medical University from May 21 to June 18, 2021 were enrolled in this study, and the judgment criteria for liver function were alanine aminotransferase (male/female) > 50/40 U/L, aspartate aminotransferase > 40 U/L, total bilirubin > 26 μmol/L, gamma-glutamyl transpeptidase > 60 U/L, and alkaline phosphatase (ALK) > 125 U/L. Abnormality in any one item of the above criteria was defined as abnormal liver function, and such patients were included in analysis (the patients, aged < 18 years, who had a mild or moderate increase in ALP alone were not included in analysis). Clinical data were compared between the patients with normal liver function and those with abnormal liver function, and the etiology and prognosis of abnormal liver function were analyzed. The Mann-Whitney U test was used for comparison of continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. Results Among the 166 patients with SARS-CoV-2 Delta variant infection, 32 (19.3%) had abnormal liver function with mild-to-moderate increases in liver function parameters, and compared with the normal liver function group, the abnormal liver function group had a significantly higher proportion of critical patients ( χ 2 =38.689, P < 0.001) and significantly higher age and inflammatory cytokines [C-reactive protein type, serum amyloid A, and interleukin-6 (IL-6)](all P < 0.05). Among the 32 patients with abnormal liver function, 13 patients had abnormal liver function on admission (defined as primary group), while 19 patients had normal liver function on admission but were found to have abnormal liver function by reexamination after treatment (defined as secondary group). For the primary group, the evidence of abnormal liver function was not found for 3 patients (3/13, 23.1%), and the possibility of toxic liver injury directly associated with SARS-CoV-2 infection was considered. Among the 19 patients in the secondary group, 9 (47.4%) had mild/common type and 10 (52.6%) had critical type, and all critical patients had the evidence of liver injury indirectly caused by the significant increases in C-reactive protein type, serum amyloid A, and IL-6 and hypoxemia; the evidence of abnormal liver function was not found for only 1 patient (1/19, 5.3%), and the possibility of toxic liver injury directly associated with SARS-CoV-2 infection was considered. All 32 patients with abnormal liver function had [JP2]significant reductions in liver function parameters after treatment including liver protection. Conclusion As for the patients with SARS-CoV-2 Delta variant infection who belong to the same chain of transmission in Guangdong Province, the critical patients show a significantly higher proportion of patients with abnormal liver function than the patients with other clinical types, and other factors except SARS-CoV-2 infection and indirect injury caused by SARS-CoV-2 infection are the main cause of liver injury.