Metal ion-promoted chemodynamic therapy(CDT) combined with photodynamic therapy(PDT) offers broad application prospects for enhancing anti-tumor effects. In this study, glycyrrhizic acid(GA), copper ions(Cu~(2+)), and norcantharidin(NCTD) were co-assembled to successfully prepare a natural small-molecule, carrier-free hydrogel(NCTD Gel) with excellent material properties. Under 808 nm laser irradiation, NCTD Gel responded to the tumor microenvironment(TME) and acted as an efficient Fenton reagent and photosensitizer, catalyzing the conversion of endogenous hydrogen peroxide(H_2O_2) within the tumor into oxygen(O_2), and hydroxyl radicals(·OH, type Ⅰ reactive oxygen species) and singlet oxygen(~1O_2, type Ⅱ reactive oxygen species), while depleting glutathione(GSH) to stabilize reactive oxygen species and alleviate tumor hypoxia. In vitro and in vivo experiments demonstrated that NCTD Gel exhibited significant CDT/PDT synergistic therapeutic effects. Further safety evaluation and metabolic testing confirmed its good biocompatibility and safety. This novel hydrogel is not only simple to prepare, safe, and cost-effective but also holds great potential for clinical transformation, providing insights and references for the research and development of metal ion-mediated hydrogel-based anti-tumor therapies.
Hydrogels/chemistry* ; Animals ; Photochemotherapy ; Humans ; Mice ; Antineoplastic Agents/administration & dosage* ; Photosensitizing Agents/chemistry* ; Neoplasms/metabolism* ; Female ; Copper/chemistry* ; Reactive Oxygen Species/metabolism* ; Tumor Microenvironment/drug effects* ; Cell Line, Tumor ; Male

This study aims to investigate the molecular mechanism by which naringin alleviates cerebral ischemia/reperfusion(CI/R) injury through DRP1/LRRK2/MCU signaling axis. A total of 60 SD rats were randomly divided into the sham group, the model group, the sodium Danshensu group, and low-, medium-, and high-dose(50, 100, and 200 mg·kg~(-1)) naringin groups, with 10 rats in each group. Except for the sham group, a transient middle cerebral artery occlusion/reperfusion(tMCAO/R) model was established in SD rats using the suture method. Longa 5-point scale was used to assess neurological deficits. 2,3,5-Triphenyl tetrazolium chloride(TTC) staining was used to detect the volume percentage of cerebral infarction in rats. Hematoxylin-eosin(HE) staining and Nissl staining were employed to assess neuronal structural alterations and the number of Nissl bodies in cortex, respectively. Western blot was used to determine the protein expression levels of B-cell lymphoma-2 gene(Bcl-2), Bcl-2-associated X protein(Bax), cleaved cysteine-aspartate protease-3(cleaved caspase-3), mitochondrial calcium uniporter(MCU), microtubule-associated protein 1 light chain 3(LC3), and P62. Mitochondrial structure and autophagy in cortical neurons were observed by transmission electron microscopy. Immunofluorescence assay was used to quantify the fluorescence intensities of MCU and mitochondrial calcium ion, as well as the co-localization of dynamin-related protein 1(DRP1) with leucine-rich repeat kinase 2(LRRK2) and translocase of outer mitochondrial membrane 20(TOMM20) with LC3 in cortical mitochondria. The results showed that compared with the model group, naringin significantly decreased the volume percentage of cerebral infarction and neurological deficit score in tMCAO/R rats, alleviated the structural damage and Nissl body loss of cortical neurons in tMCAO/R rats, inhibited autophagosomes in cortical neurons, and increased the average diameter of cortical mitochondria. The Western blot results showed that compared to the sham group, the model group exhibited increased levels of cleaved caspase-3, Bax, MCU, and the LC3Ⅱ/LC3Ⅰ ratio in the cortex and reduced protein levels of Bcl-2 and P62. However, naringin down-regulated the protein expression of cleaved caspase-3, Bax, MCU and the ratio of LC3Ⅱ/LC3Ⅰ ratio and up-regulated the expression of Bcl-2 and P62 proteins in cortical area. In addition, immunofluorescence analysis showed that compared with the model group, naringin and positive drug treatments significantly decreased the fluorescence intensities of MCU and mitochondrial calcium ion. Meanwhile, the co-localization of DRP1 with LRRK2 and TOMM20 with LC3 in cortical mitochondria was also decreased significantly after the intervention. These findings suggest that naringin can alleviate cortical neuronal damage in tMCAO/R rats by inhibiting DRP1/LRRK2/MCU-mediated mitochondrial fragmentation and the resultant excessive mitophagy.
Animals ; Rats, Sprague-Dawley ; Reperfusion Injury/genetics* ; Flavanones/administration & dosage* ; Rats ; Dynamins/genetics* ; Male ; Brain Ischemia/genetics* ; Protein Serine-Threonine Kinases/genetics* ; Signal Transduction/drug effects* ; Humans ; Drugs, Chinese Herbal/administration & dosage*

The antidepressant activity and molecular mechanisms of Yueju Wan volatile oil were investigated. The Yueju Wan volatile oil was extracted by using supercritical CO_2. Gas chromatography-mass spectrometry(GC-MS) combined with network pharmacology identified 28 chemical constituents in Yueju Wan volatile oil, primarily terpenes and lactones. A total of 123 overlapping targets were associated with depression, including core targets of interleukin-1β(IL-1β), signal transducer and activator of transcription 3(STAT3), and caspase-3(CASP3). These targets were mainly involved in the prolactin, advanced glycation end products/receptor(AGE/RAGE), and phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) signaling pathways. A reserpine-induced depression mouse model was established to evaluate the therapeutic effects and mechanisms of Yueju Wan volatile oil. The effects of Yueju Wan volatile oil on depression-like behavior in mice were evaluated by analyzing body mass, body temperature index, tail suspension immobility time, forced swimming immobility time, and sucrose preference. Hematoxylin-eosin(HE) staining revealed neuronal protection of Yueju Wan volatile oil in the brain of mice. Enzyme-linked immunosorbent assay(ELISA) and Western blot were employed to detect the protein expression of AGEs, IL-1β, phosphorylated PI3K(p-PI3K), Akt, phosphorylated Akt(p-Akt), nuclear factor κB(NF-κB), and brain-derived neurotrophic factor(BDNF). Behavioral evaluation showed that Yueju Wan volatile oil could effectively control the decline of body mass and body temperature of depressed mice, reduce tail suspension and swimming immobility time, and enhance their preference for sucrose. Histopathological examination showed that Yueju Wan volatile oil could alleviate the neuronal damage in CA1 and dentate gyrus(DG) of the hippocampus of mice. ELISA and Western blot results showed that Yueju Wan volatile oil could significantly increase the protein expression levels of PI3K, Akt, and BDNF and significantly decrease the protein expression levels of AGEs, IL-1β, p-PI3K, p-Akt, and NF-κB in the hippocampus of mice. Furthermore, the p-PI3K/PI3K and p-Akt/Akt ratios were significantly decreased at medium and high doses. These findings suggest that the aromatherapy of Yueju Wan volatile oil can significantly improve reserpine-induced depression-like behavior in mice, which may be related to reducing the expression of neuronal membrane protein AGEs, reducing the phosphorylation levels of PI3K and Akt, inhibiting NF-κB entry into the nucleus, and alleviating the release of pro-inflammatory factors and nerve injury.
Animals ; Antidepressive Agents/chemistry* ; Mice ; Proto-Oncogene Proteins c-akt/immunology* ; Phosphatidylinositol 3-Kinases/immunology* ; Oils, Volatile/chemistry* ; Male ; Drugs, Chinese Herbal/chemistry* ; Signal Transduction/drug effects* ; Depression/metabolism* ; Glycation End Products, Advanced/immunology* ; Humans

As an indispensable trace element in the human body,copper plays an important role in various physiological and biochemical reactions.The dyshomeostasis of copper leads to the disorder of copper metabolism and the occurrence of related diseases.Cuproptosis,a newly proposed regulatory cell death mode,is different from the known apoptosis,pyroptosis,necroptosis,and ferroptosis.Recent studies have found that the dyshomeostasis of copper has been observed in a variety of cancers.Therefore,targeting copper for disease treatment may become a new strategy and a new idea.This article systematically summarizes the fundamental properties of copper,copper dyshomeostasis-related diseases (Menkes syndrome,Wilson's disease,and cancer) and their treatment,and reviews the research progress in cuproptosis.
Humans ; Copper/metabolism* ; Homeostasis ; Neoplasms/metabolism* ; Hepatolenticular Degeneration/metabolism* ; Menkes Kinky Hair Syndrome/metabolism*

Ferroptosis is a form of regulated cell death that depends on iron and reactive oxygen spe-cies.Different from apoptosis,necrosis,and autophagy,ferroptosis is characterized by the accumulation of lipid peroxides in cells.Studies have discovered that ferroptosis is closely associated with the occurrence and develop-ment of tumors and inducing ferroptosis in tumor cells can enhance the therapeutic effects of drugs on tumors.This article summarizes the latest research progress in ferroptosis regarding its mechanisms and associations with tumors,aiming to provide a reference for further understanding the interaction mechanisms between ferroptosis and tumors and offering new insights and targets for the treatment of tumors.

Age-related hearing loss(ARHL)is a common chronic disease that poses a serious threat to the physical and mental health of the elderly in an aging society.It is a sensorineural hearing loss characterized by the loss of auditory hair cells,stria vascularis lesions,apoptosis of spiral ganglia,and degeneration of the audi-tory central nervous system,reducing the quality of life of the patients.This article reviews the research progress in the relationship of ARHL with Alzheimer's disease,depression,and frailty,as well as the daily intervention in ARHL.This review aims to improve people's awareness and attention to the health hazards of ARHL and to delay the occurrence and development of ARHL by implementing daily intervention measures to form a healthy lifestyle.

Objective:To assess the value eosin-nigrosine(E-N)staining and hypo-osmotic swelling test(HOST)in the diag-nosis of necrospermia and investigate the correlation of the degree of sperm necrosis with sperm DNA fragmentation index(DFI)and high DNA stainability(HDS).Methods:Using computer-assisted sperm analysis(CASA),we examined the sperm motility of 7 333 males seeking medical care in Maternal and Child Health Hospital of Hunan Province from May 2023 to July 2024,detected the sperm viability of those with asthenozoospermia by E-N staining and HOST,and measured the sperm DFI and HDS of those with necro-spermia by sperm chromatin structure assay(SCSA).Based on sperm progressive motility(PR％),we divided the asthenozoospermia patients into three groups(PR％20％-＜30％,PR％10％-＜20％and PR％＜10％),assessed the value of E-N staining and HOST in the diagnosis of necrospermia,and analyzed the correlation of the severity of sperm necrosis with sperm DFI and HDS.Results:Asthenozoospermia was diagnosed in 1 374(18.74％)of the 7 333 males.The incidence rates of necrospermia revealed by E-N staining in the mild,moderate and severe asthenozoospermia groups were 0.55％(5/913),3.80％(12/316)and 35.86％(52/145),respectively,with a total incidence of 0.94％(69/7333),while those detected by HOST were 0.99％(9/913),6.96％(22/316)and 46.21％(67/145),respectively,with a total incidence of 1.34％(98/7333).There were no statistically significant differences in the results of diagnosis between the two methods(x2=0.97,P＞0.05).Both E-N staining and HOST showed that sperm DFI in the necrospermia males was negatively correlated with sperm viability(r=-0.366,r=-0.333,P＜0.05),and so was sperm HDS,though with no statistically significant difference(P＞0.05).Conclusion:For males with PR％＜30％,sperm viability test should be conducted,with E-N staining as the choice of priority for the diagnosis of necrospermia.Sperm necrosis and sperm nuclear chromatin damage may be interactive risk factors.

Objective:To investigate the clinical effect of proper management of inferior pancreaticoduodenal artery (IPDA) in laparoscopic pancreaticoduodenectomy (LPD).Methods:This is a retrospective case series study. The clinical and pathological data of 70 patients who received LPD due to pancreatic head tumors, periampullary tumors, or distal common bile duct tumors in the Pancreatic Center of the Second Clinical College of Guangzhou University of Chinese Medicine from January to December 2022 were retrospectively collected. There were 47 males(67.1%) and 23 females(32.9%),aged (59.9±12.8)years(range:13 to 87 years).The procedure of IPDA exposure was as follows:a middle approach was utilized to expose the right half of superior mesenteric artery(SMA) and its right branches between the SMA and superior mesenteric vein(SMV) in superior colonic region. In the subcolonic region,SMA trunk exposure via dissection along the jejunal artery from feet to head and identification the association between IPDA and jejunal artery were prior to IPDA root ligation and dissection. The safety and efficacy of intraoperative IPDA handling were assessed based on surgical videos. Follow-up was carried out in outpatient clinic or by telephone, and outpatient follow-up was conducted once every 1 to 3 months after surgery.Results:The percentage of total LPD was 98.6%(69/70),with all patients achieving R0 resection. Nine cases(12.9%) were involved in combined vascular resection and reconstruction,with 1 case (1.4%) requiring additional upper abdominal incision for vascular and gastrointestinal reconstruction,while the remaining eight cases (11.4%) were completed laparoscopically. The operative time was (432.7±115.4)minutes(range:282 to 727 minutes), and the blood loss was (140.0±125.7)ml(range:20 to 800 ml). Only two patients(2.9%) received fresh frozen plasma transfusion,with an average volume of 650 ml. Reliable ligation and safe handling of the IPDA were achieved in 91.4%(64/70) of cases, with 8.6%(6/70) suffering from IPDA injury-related bleeding. No one was converted to opened surgery. Pathologically,the mean tumor size was (3.3±1.6)cm (range:1 to 7 cm),and the mean number of harvested lymph nodes was 17.0±7.3(range:0 to 46). Lymph node metastasis was observed in 13 cases (18.6%). Five cases (13.2%) developed grade B pancreatic fistula,while no grade C pancreatic fistula occurred. Other complications included bile leakage in one case(1.4%),delayed gastric emptying in two cases(2.9%), lymphatic leakage in 2 cases(2.9%),intra-abdominal infection in 9 cases(12.9%),and fat liquefaction of surgical incision in 1 case(1.4%). Two cases(2.9%) experienced postoperative intra-abdominal bleeding,one due to mesangial bleeding of lesser curvature of the stomach and the other due to oozing from the hepatic arterial sheath. These bleeding events were not concerned with IPDA. The average length of postoperative hospital stay was (15.2±4.6)days(range:9 to 28 days).Conclusion:Proper intraoperative management of IPDA in LPD might reduce IPDA-related bleeding during and after surgery and improve the safety of LPD.

Objective To observe the clinical effect of Dongjing Tiaoshen Comprehensive Therapy combined with computerized cognitive behavioral therapy for insomnia(CCBT-I)in the treatment of chronic insomnia patients with liver depression and spleen deficiency syndrome.Methods A total of 60 patients with chronic insomnia of liver depression and spleen deficiency type were randomly divided into observation group and control group,30 cases in each group.Both groups of patients were treated with CCBT-I as the basic treatment,the observation group was additionally treated with Dongjing Tiaoshen Comprehensive Therapy,i.e.,mind-regulating acupuncture therapy combined with regular aerobic exercises and Dantian Qigong exercises,and the control group was additionally treated with cranial electrotherapy stimulation.The course of treatment for the two groups covered 4 weeks.The changes of Pittsburgh Sleep Quality Index(PSQI)score,Self-rating Anxiety Scale(SAS)score and Self-rating Depression Scale(SDS)score in the two groups were observed before and after treatment,and the clinical efficacy of the two groups was evaluated after treatment.Results(1)After 4 weeks of treatment,the total effective rate of the observation group was 86.67%(26/30),and that of the control group was 70.00%(21/30).The intergroup comparison(tested by rank sum test)showed that the curative effect of the observation group was significantly superior to that of the control group,and the difference was statistically significant(P＜0.05).(2)After treatment,the PSQI scores of the two groups were significantly lower than those before treatment(P＜0.05),and the decrease of PSQI scores in the observation group was significantly superior to that in the control group,the difference being statistically significant(P＜0.05).(3)After treatment,the SAS and SDS scores of the two groups were significantly lower than those before treatment(P＜0.05),and the decrease of SAS and SDS scores in the observation group tended to be superior to that in the control group,but there was no significant difference between the two groups(P＞0.05).Conclusion For the treatment of chronic insomnia of liver depression and spleen deficiency type,the combination of Dongjing Tiaoshen Comprehensive Therapy with CCBT-I can significantly improve the sleep quality,relieve anxiety and depression,and improve the quality of life of the patients,which exerts significant efficacy.

Objective:To investigate the clinical effect of proper management of inferior pancreaticoduodenal artery (IPDA) in laparoscopic pancreaticoduodenectomy (LPD).Methods:This is a retrospective case series study. The clinical and pathological data of 70 patients who received LPD due to pancreatic head tumors, periampullary tumors, or distal common bile duct tumors in the Pancreatic Center of the Second Clinical College of Guangzhou University of Chinese Medicine from January to December 2022 were retrospectively collected. There were 47 males(67.1%) and 23 females(32.9%),aged (59.9±12.8)years(range:13 to 87 years).The procedure of IPDA exposure was as follows:a middle approach was utilized to expose the right half of superior mesenteric artery(SMA) and its right branches between the SMA and superior mesenteric vein(SMV) in superior colonic region. In the subcolonic region,SMA trunk exposure via dissection along the jejunal artery from feet to head and identification the association between IPDA and jejunal artery were prior to IPDA root ligation and dissection. The safety and efficacy of intraoperative IPDA handling were assessed based on surgical videos. Follow-up was carried out in outpatient clinic or by telephone, and outpatient follow-up was conducted once every 1 to 3 months after surgery.Results:The percentage of total LPD was 98.6%(69/70),with all patients achieving R0 resection. Nine cases(12.9%) were involved in combined vascular resection and reconstruction,with 1 case (1.4%) requiring additional upper abdominal incision for vascular and gastrointestinal reconstruction,while the remaining eight cases (11.4%) were completed laparoscopically. The operative time was (432.7±115.4)minutes(range:282 to 727 minutes), and the blood loss was (140.0±125.7)ml(range:20 to 800 ml). Only two patients(2.9%) received fresh frozen plasma transfusion,with an average volume of 650 ml. Reliable ligation and safe handling of the IPDA were achieved in 91.4%(64/70) of cases, with 8.6%(6/70) suffering from IPDA injury-related bleeding. No one was converted to opened surgery. Pathologically,the mean tumor size was (3.3±1.6)cm (range:1 to 7 cm),and the mean number of harvested lymph nodes was 17.0±7.3(range:0 to 46). Lymph node metastasis was observed in 13 cases (18.6%). Five cases (13.2%) developed grade B pancreatic fistula,while no grade C pancreatic fistula occurred. Other complications included bile leakage in one case(1.4%),delayed gastric emptying in two cases(2.9%), lymphatic leakage in 2 cases(2.9%),intra-abdominal infection in 9 cases(12.9%),and fat liquefaction of surgical incision in 1 case(1.4%). Two cases(2.9%) experienced postoperative intra-abdominal bleeding,one due to mesangial bleeding of lesser curvature of the stomach and the other due to oozing from the hepatic arterial sheath. These bleeding events were not concerned with IPDA. The average length of postoperative hospital stay was (15.2±4.6)days(range:9 to 28 days).Conclusion:Proper intraoperative management of IPDA in LPD might reduce IPDA-related bleeding during and after surgery and improve the safety of LPD.