ObjectiveTo investigate the therapeutic effects and mechanism of decoctions from four kinds of processed products of Aconiti Radix Lateralis Praeparata（ARLP） in deficiency-cold syndrome. MethodsA total of 36 SD rats were randomly divided into the control group， model group， Shengfupian（SFP） group， Paofuzi（PFZ） group， Heishunpian（HSP） group and Paofupian（PFP） group with 6 rats in each group. Except for the control group， rats in other groups were administered hydrocortisone sodium succinate via intramuscular injection to induce a cold deficiency syndrome model. After 14 consecutive days， each ARLP decoction pieces was administered via continuous gastric lavage at a dose of 12 g·kg^-1·d^-1 for 7 d， while the control and model groups received an equivalent volume of physiological saline. After the end of administration， body weight， spleen weight and thymus weight were measured for calculating the spleen and thymus indexes. Hematoxylin-eosin（HE） staining was used to observe the pathological morphology of adrenal tissue. The fully automatic biochemistry analyzer was used to measure the total cholesterol（TC）， triglyceride（TG）， lactic dehydrogenase（LDH） and lactate（LAC） levels in serum. Enzyme-linked immunosorbent assay（ELISA） was employed to measure the contents of 17-hydroxycorticosteroid（17-OHCS）， cortisol（CORT）， triiodothyronine（T₃）， thyroxine（T₄）， thyrotropin（TSH）， immunoglobulin（Ig） M， IgG， cyclic adenosine monophosphate（cAMP） and cyclic guanosine monophosphate（cGMP）. Western blot was used to measure the protein expression levels of protein kinase A（PKA）， cAMP response element-binding protein（CREB）， silent information regulator 1（Sirt1） and peroxisome proliferator-activated receptor γ coactivator-1α（PGC-1α）. And high performance liquid chromatography（HPLC） was used to determine the content of major alkaloids， followed by Pearson correlation analysis with pharmacodynamic indicators. ResultsAfter modeling， compare with the control group， the model rats exhibited symptoms such as lethargy and loose stools， mild abnormalities were observed in adrenal tissue structure， and both spleen and thymus indices were significantly reduced（P<0.01）. Thyroid， adrenal and immune system functions were suppressed， with decreased serum cAMP level and significantly elevated cGMP level（P<0.01）. Compared with the model group， the adrenal injury by hydrocortisone sodium succinate were repaired and the spleen index were increased significantly in all four ARLP groups（P<0.05， P<0.01）. The thymus index in SFP and PFZ groups were increased significantly（P<0.05）. The contents of T₃， TSH， 17-OHCS and CORT were increased significantly in SFP and PFZ groups（P<0.05）. In addition， the content of IgG in SFP， PFZ and PFP groups were increased significantly（P<0.01）， while the content of IgM in PFZ and HSP groups were also increased significantly（P<0.05）. Regarding the cyclic nucleotide system， PFZ significantly elevated cAMP level while reducing cGMP level（P<0.05）， exhibiting the most pronounced effect among the four decoction pieces. For energy metabolism indicators， PFZ significantly improved abnormal markers including TC， TG， LDH， and LAC（P<0.05）. HSP showed marked improvement effects on TG， LDH， and LAC（P<0.05）. Both PFZ and SFP significantly elevated the expression levels of PKA， CREB， Sirt1， and PGC-1α proteins（P<0.01）. Additionally， the diester alkaloids in ARLP showed a strong positive correlation with TG， IgG， and CORT， a strong negative correlation with LAC， a moderate positive correlation with T₄， and moderate negative correlations with cAMP and spleen index. Monomeric alkaloids showed strong positive correlations with TG and IgG， strong negative correlations with LAC， moderate positive correlations with CORT and T₄， and moderate negative correlations with cAMP and spleen index. However， the content of water-soluble alkaloids showed strong positive correlations with TC， LDH， 17-OHCS， T₃， TSH， and thymus index， moderate positive correlations with cAMP， CORT， T₄， and spleen index， and moderate negative correlation with cGMP. ConclusionAmong different processed ARLP decoction pieces， PFZ processed according to ZHANG Zhongjing's method exhibits the most potent warming and cold-dispelling effects. Its pharmacological actions are mediated through regulating the thyroid， adrenal， immune， cyclic nucleotide systems， and material-energy metabolism pathways. Among these， water-soluble alkaloids show strong or moderate correlations with more indicators of deficiency-cold syndrome and exhibit the highest content in PFZ. Therefore， PFZ processed according to ZHANG Zhongjing's method may exert its warming and cold-dispelling effects through water-soluble alkaloids.

Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with poor prognosis and limited targeted treatment options. This investigation examined the anti-cancer potential of Caerulomycin A (Cae A), a natural compound derived from marine actinomycetes, against TNBC. Cae A demonstrated selective inhibition of viability and proliferation in TNBC cell lines, including 4T1, MDA-MB-231, and MDA-MB-468, through apoptosis induction. Mechanistic analyses revealed that the compound induced sustained endoplasmic reticulum (ER) stress and subsequent upregulation of C/EBP homologous protein (CHOP) expression, resulting in mitochondrial damage-mediated apoptosis. Inhibition of ER stress or CHOP expression knockdown reversed mitochondrial damage and apoptosis, highlighting the essential role of ER stress and CHOP in Cae A's anti-tumor mechanism. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) decreased in TNBC cells following Cae A treatment, indicating reduced mitochondrial respiratory and glycolytic capacities. This diminished energy metabolism potentially triggers ER stress and subsequent apoptosis. Furthermore, Cae A exhibited significant anti-tumor effects in the 4T1 tumor model in vivo without apparent toxicity. The compound also effectively inhibited human TNBC organoid growth. These results indicate that Cae A may serve as a potential therapeutic agent for TNBC, with its efficacy likely mediated through the disruption of glucose metabolism and the induction of ER stress-associated apoptosis.
Humans ; Endoplasmic Reticulum Stress/drug effects* ; Triple Negative Breast Neoplasms/genetics* ; Apoptosis/drug effects* ; Cell Line, Tumor ; Female ; Animals ; Glucose/metabolism* ; Mice ; Cell Proliferation/drug effects* ; Transcription Factor CHOP/genetics* ; Antineoplastic Agents/pharmacology* ; Mitochondria/metabolism* ; Mice, Inbred BALB C

Objective To analyze the characteristics of conventional ultrasound and contrast-enhanced ultrasound(CEUS)in hypovascular renal tumors,and to explore the application value of combining the 2 methods in diagnosing benign and malignant hypovascular renal tumors.Methods The conventional ultrasound and CEUS data of 104 hypovascular renal tumors(76 benign lesions[benign group]and 28 malignant lesions[malignant group])from 99 patients,who were confirmed by postoperative pathology,biopsy pathology or computed tomography(CT)/magnetic resonance imaging(MRI)enhancement combined with long-term follow-up in Ruijin Hospital,Shanghai Jiao Tong University School of Medicine and its Wuxi Branch from Oct.13,2009 to Oct.26,2022,were retrospectively analyzed.The location,size,internal echo,morphology,internal and peripheral blood supply of the lesions were observed by conventional ultrasound,and the perfusion mode,regression pattern,perfusion uniformity and ring enhancement signs were observed by CEUS.Taking the pathological results or confirmed results of CT/MRI enhancement combined with long-term follow-up as the gold standard,the value of conventional ultrasound combined with CEUS in the differential diagnosis of benign and malignant hypovascular renal tumors was analyzed.Results There were significant differences in gender,age of patients and internal echo,contrast agent regression and ring enhancement signs of lesions between the 2 groups(all P＜0.05).The malignant tumors were mostly found in males(78.6％,22/28)with an average age of(58.29±11.76)years old;the masses were mostly hypoechoic(64.3％,18/28),and rapid washout was predominant with CEUS(60.7％,17/28).In the benign group,most of the patients were female(55.3％,42/76),with an average age of(50.64±14.88)years old;the majority of the masses were hyperechoic(64.5％,49/76),and CEUS showed simultaneous washout as the main lesion(56.6％,43/76).Three patients(10.7％,3/28)with ring enhancement signs were all malignant.The diagnostic accuracy(82.7％)and specificity(88.2％)for benign and malignant hypovascular renal tumors were relatively high when combining the diagnostic indicators of ring enhancement signs and hypoechoic.The diagnostic sensitivity(85.7％)and negative predictive value(92.3％)were relatively high when combining the 3 diagnostic indicators of ring enhancement,hypoechoic,and rapid washout.Conclusion Conventional ultrasound combined with CEUS has significant clinical practical value in the differential diagnosis of benign and malignant hypovascular renal tumors.The ring enhancement sign is highly specific in the diagnosis of malignant hypovascular renal tumors.However,if this sign is not significant and conventional ultrasound shows hypoechoic or CEUS exhibits rapid washout,there is a strong suggestion that the mass may be a malignant lesion.

BACKGROUND:The risk factors for patellofemoral pain syndrome are still unclear and research on risk factors is gradually becoming a hot topic in order to improve the therapeutic outcome of this disease. OBJECTIVE:To investigate the relationship between lower limb alignment and patellofemoral pain syndrome in young male runners. METHODS:In the same running population,21 patients with bilateral knee pain,29 patients with single knee pain and 20 normal runners were collected from January 2021 to July 2022.Full-length X-ray examination of both lower limbs in standing position was performed in all subjects.The lateral distal femoral angle,medial tibial proximal angle,joint line congruence angle,hip-knee-ankle angle,and knee physical valgus angle were measured and statistically analyzed. RESULTS AND CONCLUSION:There was no significant difference in the parameters between the left and right knees in each group(P>0.05).Compared with the normal group,no significant changes in lateral distal femoral angle,medial tibial proximal angle,joint line congruence angle,and hip-knee-ankle angle were observed in the single knee pain group and double knee pain group,while the knee physical valgus angle was significantly increased in these two groups(P<0.05).To conclude,increased knee physical valgus angle may be a risk factor for patellofemoral pain syndrome.

Objective To investigate the association between microvariants at locus DYS570 and Y-SNPs haplogroup.Methods 89 Y-SNPs and 34 Y-STRs in AIYSNP42,AIYSNP47 and YfilerTM Platinum kits were used to detect the genotype of 116 microvariants at locus DYS570 in Kunming,and the Set-B kit was used to detect the core repeat sequences of the DYS570 locus.The data were statistically analyzed by direct counting method.Then,a network map was drawn by Network 10.2,in order to visualize the genetic information of the sample.Results The results demonstrated that 111 DYS570/18.3-21.3 samples had a core repeat sequence of TTT[TITC]18-21,belonging to subgroup O2a2b1a1a1a4-F14494.A DYS570/20.3 sample had a core repeat sequence of[TTTC]15TTC[TTTC]5,belonging to O2a1b1a1a1a1e-F1365 subgroup.A DYS570/17.1 sample had a core repeat sequence of[TTTC]17 T,belonging to the O2a1b1a1a1a-F11 subgroup.Three DYS570(19.2)samples had[TTTC]3 TT[TTTC]16,belonging to the D1a1a-M15 haplogroup.Conclusion The results indicated that the microvariant with the same core repeat structure at locus DYS570 was associated with haplogroups,and the ancestry origin of samples can be inferenced from microvariant characteristics during the practice of forensic medicine.

The macrophages,as a crucial component of the body's immune system,can be polarized into M1 and M2 types by different cellular molecules in various environments,and contribute to the progression of various diseases.In inflammatory responses,the M1 macrophages are primarily regarded as the pro-inflammatory cells,facilitate the inflammation progression,tissue destruction,and bone resorption,while M2 macrophages,as inflammatory cells,participate in tissue healing and bone repairment.In the tumor microenvironment,the roles of M1 and M2 macrophages are reversed.The periodontitis,pulpitis,and oral squamous cell carcinoma(OSCC)are the most prevalent inflammation and tumor in the oral cavity.Therefore,this article summarizes the relevant researches from home and abroad on the polarization of macrophages in oral inflammatory responses such as periodontitis,peri-implantitis,and pulpitis,bone remodeling during orthodontic treatment,and OSCC,and elucidate the metabolic activities of macrophages in infiammation,tumor,and bone remodeling and the mechanism of regulating the onset and development of diseases by the macrophage polarization,and provides new perspectives for the clinical treatment.

Objective: 18F-N-(2-(Diethylamino)ethyl)-5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy) picolinamide ( 18F-PFPN) is a novel positron emission tomography (PET) probe designed to specifically targets melanin. This study aimed to evaluate the diagnostic feasibility of 18F-PFPN in patients with ocular or orbital melanoma. Materials and Methods: Three patients with pathologically confirmed ocular or orbital melanoma (one male, two females; age 41–59 years) were retrospectively reviewed. Each patient underwent comprehensive 18F-PFPN and 18F-fluorodeoxyglucose ( 18F-FDG) PET scans. The maximum standardized uptake value (SUV max) of the lesion and the interference caused by background tissue were compared between 18F-PFPN and 18F-FDG PET imaging. In addition, the effect of intrinsic pigments in the uvea and retina on the interpretation of the results was examined. The contralateral non-tumorous eye of each patient served as a control. Results: All primary tumors (3/3) were detected using 18F-PFPN PET, while only two primary tumors were detected using 18F-FDG PET. Within each lesion, the SUV max of 18F-PFPN was 2.6 to 8.3 times higher than that of 18F-FDG. Regarding the quality of PET imaging, the physiological uptake of 18F-FDG PET in the brain and periocular tissues limited the imaging of tumors. However, 18F-PFPN PET minimized this interference. Notably, intrinsic pigments in the uvea and retina did not cause abnormal concentrations of 18F-PFPN, as no anomalous uptake of 18F-PFPN was detected in the healthy contralateral eyes. Conclusion Compared to 18F-FDG, 18F-PFPN demonstrated higher detection rates for ocular and orbital melanomas with minimal interference from surrounding tissues. This suggests that 18F-PFPN could be a promising clinical diagnostic tool for distinguishing malignant melanoma from benign pigmentation in ocular and orbital melanomas.

Objective To study the effect of autophagy regulation on hypoxia/reoxygenation injury(H/RI)in mouse spermatogonia,and to explore the effect of autophagy on ischemia-reperfusion injury(IRI)in mouse testicular tissue.Methods The mouse spermatogonial cell line GC1 spg was used as the research object to construct the H/RI model.Rapamycin(RAPA)and 3-methyladenine(3-MA)were used as autophagy ago-nists and inhibitors.The control group,the model group,the autophagy agonist intervention group(H/RI+autophagy agonist intervention),and the autophagy inhibitor intervention group(H/RI+autophagy inhibitor intervention)were set up.The cells proliferation ability of each group was detected by methyl thiazol tetrazoli-um(MTT)method.The release level of reactive oxygen species(ROS)and apoptosis level of each group were detected by flow cytometry.The expression levels of autophagy-related gene Beclin1 and apoptosis-relat-ed genes Bcl-2 and Bax mRNA in each group were detected by real-time fluorescence quantitative PCR(qPCR).The expression levels of autophagy-related proteins LC3-Ⅰ,LC3-Ⅱ,Beclin1,p62 and apoptosis-relat-ed proteins Bcl-2,Bax,caspase-3 in each group were detected by Western blot.Results Compared with the control group,the proliferation abiliy,the expression levels of Beclin1 and Bcl-2 mRNA in the model group were significantly decreased(P＜0.01),the relative expression levels of p62 and Bcl-2 proteins were significantly decreased(P＜0.01).The ROS level,apoptosis rate and the mRNA expression level of Bax were significantly increased(P＜0.01),and the protein expresion levels of Beclin1,Bax,caspase-3 and the protein ratio of LC3-Ⅱ/LC3-Ⅰ were significantly increased(P＜0.01).Compared with the model group,the cell proliferation a-bility,the expression levels of Beclin1 and Bcl-2 mRNA in the autophagy agonist intervention group were the protein ratio of significantly increased(P＜0.01),the protein expression levels of Beclin1 and Bcl-2 and the protein ration of LC3-Ⅱ/LC3-Ⅰ were significantly increased(P＜0.01).The ROS level,apoptosis rate and the expression level of Bax mRNA were significantly decreased(P＜0.01),and the protein expression levels of p62,Bax,caspase-3 and the protein ratio of LC3-Ⅱ/LC3-Ⅰ were significantly decreased(P＜0.01).Com-pared with the model group,the cell proliferation ability,the mRNA expression levels of Beclin1 and Bcl-2 in the autophagy inhibitor intervention group were significantly decreased(P＜0.01),the protein expression lev-els of Beclin1 and Bcl-2 protein were significantly decreased(P＜0.01).The ROS level,apoptosis rate and the mRNA expression level of Bax were significantly increased(P＜0.01),and the protein expression levels of p62,Bax,caspase-3 and the protein ratio of LC3-Ⅱ/LC3-Ⅰwere significantly iecreased(P＜0.01).Conclusion Enhanced au-tophagy can inhibit apoptosis of spermatogonia and repair H/RI in mice,which provides a theoretical basis for the treatment of testicular tissue IRI.

Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

OBJECTIVE To investigate the protective effects and mechanism of ziyuglycoside Ⅰ on acute lung injury in sepsis rats based on network pharmacology， and conduct experimental verification. METHODS The network pharmacology was used to predict the potential target of ziyuglycoside Ⅰ in the treatment of acute lung injury following sepsis. The rat model of sepsis was reproduced by cecum ligation and puncture for experimental verification. Totally 192 SD rats were randomly divided into the sham operation group （Sham group）， sepsis group （Sep group）， conventional therapy group （CT group） and ziyuglycoside Ⅰ group （Zg Ⅰ group）， respectively. Sham group and Sep group were given sterile normal saline， and CT group and ZgⅠ group were given relevant volume of Ringer’s solution and ziyuglycoside Ⅰ. The arterial blood gas， serum inflammatory factors， lung wet/dry mass ratio， pathological changes of lung tissue， pulmonary vascular permeability， the expressions of pulmonary vein tight junction protein 1 （ZO-1） and vascular endothelial cadherin （VE-cadherin） protein and 72-hour survival were observed in each group. RESULTS Results of network pharmacology showed that there were 47 potential targets of ziyuglycoside Ⅰ in the treatment of sepsis. The results of gene ontology function enrichment analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that the mechanism could 598486924@qq.com be correlated with biological processes such as positive regulation of reactive oxygen species metabolism， wound healing， regulation of endothelial cell proliferation， cell activation， blood vessel development， response to oxidative stress， etc.， and with signaling pathway such as apoptosis， tight junction， HIF-1 signaling pathway， etc. The results of experimental verification showed that compared with Sham group， pH value and the level of partial arterial oxygen pressure were decreased significantly in Sep group （P＜0.05）， while the level of partial pressure of carbon dioxide， serum levels of tumor necrosis factor α， interleukin 6 were increased significantly （P＜0.05）； the ratio of lung wet/dry mass was increased significantly （P＜0.05）； the protein expressions of ZO-1 and VE-cadherin were decreased significantly （P＜0.05）； 72 h survival rate decreased，the survival time was significantly shortened （P＜0.05）； the results of pathological observation of lung tissue showed that the rats’ alveoli were extensively ruptured， the alveolar wall was thickened and accompanied with edema， and there was obvious inflammatory cell infiltration； the results of pulmonary vascular permeability observation showed that the lung surface of rats was dark， with a large amount of Evans blue exudation， and the left lower lung was obviously dark blue. Compared with Sep group， the levels of above indexes almost were reversed significantly in CT group and ZgⅠ group （P＜0.05）； the lung histopathology and pulmonary vascular permeability were significantly improved， and the recovery degree of ZgⅠ group was greater than that of CT group， which was close to the results of Sham group. CONCLUSIONS Ziyuglycoside Ⅰ can significantly reduce inflammatory reaction and acute lung injury in septic rats， which is related to vascular function and tight junction signal pathway.