NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD⁺), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD⁺ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.
Humans ; NAD/metabolism* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Nicotinamide Phosphoribosyltransferase/metabolism* ; Cytokines/metabolism* ; Quinones ; Oxidoreductases

Phenylalanine ammonia-lyase (PAL) is the key entry enzyme of plant phenylpropanoid pathway. It plays an important role in the biosynthesis of podophyllotoxin, an anti-tumor lignan that is currently produced from its main natural source Sinopodophyllum hexandrum (Royle) Ying. In this study, we cloned the gene ShPAL encoding phenylalanine ammonia-lyase by RT-PCR from the root of S. hexandrum ecotype inhabited in the Aba' district, Sichuan, based on its public SRA transcriptome data-package. Bioinformatics analyses showed that the ShPAL-encoded protein is composed of 711 amino acids, contains the conserved domains of PAL, and has the signature motif within the active center of aromatic ammonia-lyases. Moreover, ShPAL protein was predicted to have a secondary structure mainly composed of α-helix and random coil, a typical 'seahorse' shape monomer tertiary structure, and a homologous tetramer three-dimensional structure by Swiss-Modelling. The phylogenetic lineage analysis indicated ShPAL was of the highest sequence identity and the shortest evolutionary distance with the PAL of Epimedium sagittatum from the same Berberidaceae family. Subcellular localization experiments showed that ShPAL protein was mainly distributed in the cytoplasm, despite of a minority on the endoplasmic reticulum membrane. Furthermore, ShPAL protein was recombinantly expressed in Escherichia coli and purified by histidine-tag affinity chromatography. Its enzymatic activity was determined up to 20.91 U/mg, with the optimum temperature of 41 ℃ and pH of 9.0. In contrast, the enzyme activity of its F130H mutant decreased by about 23.6%, yet with the same trends of change with temperature and pH, confirming that phenylalanine at this position does affect the substrate specificity of PAL. Both the wild type and the mutant have relatively poor thermostability, but good pH-stability. These results may help to further investigate the regulatory role of PAL in the process of podophyllotoxin biosynthesis and advance the heterologous synthesis of podophyllotoxin to protect the germplasm resource of S. hexandrum. They also demonstrate that ShPAL has a potential application in biochemical industry and biomedicine.
Phenylalanine Ammonia-Lyase/metabolism* ; Podophyllotoxin ; Phylogeny ; Cloning, Molecular

Objective:Exploring the clinical efficacy of using ultra-thin lobulated anterolateral thigh perforator flap(ALTPF) with retrograde separation of perforating vessels from the superficial and deep junction layer of the superficial fascia to repair large soft tissue defects in the foot.Methods:From August 2021 to November 2022, 8 patients (5 males and 3 females) were admitted to the Second Department of Hand and Foot Surgery, the Affiliated Central Hospital of Dalian University of Technology. The patients were 28 to 52 years old in age. The soft tissue defects were located in dorsal and plantar foot. At the plantar foot, the wound involved the weight-bearing area with explosion of bone, tendon or internal fixtures. The area of soft tissue defects was 6.0 cm × 5.0 cm - 16.0 cm × 8.0 cm, and the sizes of ALTPF were 8.0 cm ×5.5 cm - 18.0 cm × 8.5 cm. Preoperative high frequency CUD combined with CTA angiography were employed to locate the 2 flap perforator vessels. By keeping the perforator vessels at center and according to the soft tissue defect area and the wound shape, an ALTPF with a proper size and shape was designed in anterolateral thigh. The perforator were separated in the boundary layer between superficial and deep fascia, where it helped to obviously thin the flap. After the flap was harvested, it was further lobulated between the 2 perforators into 2 lobes after having confirmed the effective blood supply. Finally the lobulated ALTPF was transferred to covered the defect in foot. Cautions should be taken to ensure that the flap covered the weight-bearing area of foot. All the donor sites were directly sutured. Postoperative follow-up was conducted to observe the survival of flaps and the functional recovery of the reconstructed site, also to evaluate the clinical effect. Postoperative follow-up included outpatient visits and reviews over WeChat or telephone. Recovery of the ankle motor function was evaluated according to the American Orthopedic Foot and Ankle Societ (AOFAS) ankle-hind foot score scale.Results:All 8 ALTPF survived. Over 6 to 18 months (10.8 months in average) of follow-up, the transferred flaps had good blood supply, soft in texture, with good elasticity and thin in appearance. Appearance and function of donor sites recovered well, except 1 patient who had mild scar hyperplasia. The plantar flap had good abrasion resistance. No flap damage, bleeding or granulation tissue hyperplasia occurred when walking. The mean score of AOFAS ankle-hind foot score achieved 95.6.Conclusion:The application of ultra-thin lobulated ALTPF with retrograde separation of perforating vessels from the superficial fascia at the junction layer for repairing large soft tissue defects in the foot has good clinical efficacy.

Objective:To investigate the surgical treatment of mesh infection after lapa-roscopic inguinal hernia repair.Methods:The retrospective and descriptive study was conducted. The clinical data of 32 patients with mesh infection after laparoscopic inguinal hernia repair who were admitted to the Affiliated Beijing Chaoyang Hospital of Capital Medical University from January 2018 to December 2020 were collected. There were 30 males and 2 females, aged 59(range, 19-81)years. All patients underwent debridement. Observation indicators: (1) surgical and postopera-tive situations; (2) follow-up. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers or percentages, and comparison between was conducted using Fisher exact probability. Results:(1) Surgical and postoperative situations. All 32 patients underwent debridement success-fully, with the operation time and volume of intraoperative blood loss as 110(range, 45-220)minutes and 24(range, 5-200)mL. Of the 32 patients, there were 6 cases undergoing open debridement, 26 cases undergoing laparoscopic exploration with 12 cases clarified the cause of infection, in which 4 cases had intestinal fistula by mesh infection breaking through the peritoneum and invading the intestinal tract and underwent laparoscopic intestinal fistula repair, 3 cases had significant amount of residual medical glue, 3 cases had mesh wrinkling and curling, 2 cases underwent peritoneum suturing with black silk thread. There were 18 cases undergoing complete removal of infected mesh and 14 cases undergoing partial mesh removal. There were 18 cases undergoing removal of infected mesh by laparoscopic posterior approach and 14 cases undergoing removal of infected mesh by open anterior approach. Twenty-nine of the 32 patients had bacterial culture and drug allergy testing, including 24 cases with positive cultures, while 5 cases with negative cultures. The duration of hospital stay of the 32 patients was 27.0(range, 9.0-85.0)days. (2) Follow-up. All 32 patients were followed up for 37.9(range, 18.7-52.5)months. There were 5 cases and 2 cases with postoperative incision infection in the 18 patients undergoing complete removal of infected mesh and 14 cases undergoing partial mesh removal, respectively, showing no significant difference between them ( P>0.05). There were 7 cases, 4 cases with seroma, recurrent sinus in the 18 patients undergoing complete removal of infected mesh and 5 cases, 6 cases in the 14 cases undergoing partial mesh removal, respectively, showing no significant difference between them ( P>0.05). None of patient in the two groups had hematoma, recurrent inguinal hernia or chronic pain. The 7 patients with incision infec-tion recovered effectively after symptomatic treatment. The 12 patients with seroma received no special treatment. The 10 patients with recurrent sinus underwent debridement, in which 9 cases did not experience any further abdominal wall infections and 1 case underwent the third debride-ment. Conclusion:The management of mesh infection following laparoscopic inguinal hernia repair necessitates the expertise of hernia specialists to complete remove the infected mesh or partial remove the infected mesh based on the specific clinical scenario.

Esophageal Achalasia/surgery* ; Esophagoscopy ; Humans ; Muscles ; Myotomy ; Tissue Adhesions

Objective: To investigate the knowledge, attitude, and practice on disposable plastic tableware and self reported gastrointestinal symptoms in college students. Methods: Stratified sampling method was applied in 338 students of a medical university during the 2020-2021 academic year. The study investigated knowledge, attitude and practice on disposable plastic tableware and self reported gastrointestinal symptoms among students. Results: There were 24.0% students were unaware of the specific material of plastic tableware, 82.0% students had no idea about the meaning of "plastic products logo". About 94.1% of the students thought that plastic tableware might contaminate food, and female students (97.1%) were more worried than male (86.3%) ( χ 2=14.32, P <0.05). The attitude towards the use of disposable tableware was not consistent with the cumulative use score of disposable plastic tableware ( F=1.31, P =0.25),students with high consumption had higher score of accumulative use of disposable plastic tableware ( F=8.32, P <0.01). About 18.3% of the students were prone to report gastrointestinal symptoms. The cumulative scores of disposable plastic tableware weekly using frequency in students who reported gastrointestinal symptoms(14.85±4.01) was still higher than that of no gastrointestinal symptoms group(13.78±3.50), regardless of the effect of takeout ordering frequency( F=4.53，P = 0.03 ). Conclusion College students have limited knowledge of disposable plastic products. However, the use of disposable plastic products may be associated with gastrointestinal diseases. It is suggested to active the propaganda and education, to reduce the use of disposable tableware, and enhance the awareness of health and environment.

Objective:To retrospectively analyze the treatment of 25 cases of lower necrotizing fasciitis.Methods:A total of 25 patients with lower limb necrotizing fasciitis (13 males and 12 females), with mean age 63 years old (48-75 years old) in Dalian Municipal Central Hospital from September 2016 to December 2020. After admission, the patient′s general physical condition was strictly evaluated, the relevant preoperative examination was improved, and the necrotizing fasciitis laboratory risk index (LRINEC) score was performed. In the absence of surgical contraindication, multiple debridement was performed, leaving the necrotic tissue removed for general bacterial culture and drug sensitivity test in parallel. After debridement, eight patients showed a large area of skin necrosis, and amputation was selected. The other 17 patients chose limb protection treatment after debridement, and adopted debridement and free skin grafting. After surgery, patients were encouraged to strengthen rehabilitation exercise to restore limb function to the maximum extent.Results:With followed up 0.6 to 3.0 years, with an average of 1.8 years. Methods include outpatient return visit, WeChat contact or telephone inquiry. The skin survived in 17 patients with mean healing time (27.5 ± 6.9) d. Eighteen patients were multiple bacterial infections and seven patients were single bacterial infections. All patients had no joint dysfunction caused by scar contracture, and reinfection in the skin grafting area.Conclusions:Necrotizing fasciitis requires early diagnosis and early treatment, with correct choice of treatment method is closely related to the patient′s prognosis.

Objective:To evaluate the methodological quality and reporting quality of clinical practice guidelines or consensuses in the field of Chinese pancreatic diseases from 2016 to 2021, and provide reference for formulating clinical practice guidelines and consensuses in this field.Methods:VIP, Wanfang , CNKI and CBM databases were searched for articles published from January 2016 to March 2021. The main index terms were " pancreas" , " guideline" , " consensus" , and the supplementary index terms were " pancreatitis" , " pancreatic cancer" , " pancreatic head cancer" . Two researchers independently selected the literature. The appraisal of guidelines for research and evaluation (AGREE-China) was utilized to assess the methodological quality of the guidelines or consensuses, and the reporting items for practice guidelines in healthcare (RIGHT) tool was used to assess the reporting quality.Results:A total of 14 literature were included, including 7 literature on pancreatic cancer, 3 literature on acute pancreatitis, 1 literature on chronic pancreatitis and 3 literature on others. The results of the assessment by the AGREE-China tool showed that there were no document with a total score greater than or equal to 60.0 points, two with 40.0 to 59.9 points, eleven with 20.0 to 39.9 points, and one with less than 20.0 points. Among the results of RIGHT list, basic information was reported the highest(72.62%) and funding and declaration was the lowest(0).Conclusions:The methodological and reporting quality of the guidelines or consensuses on pancreatic disease in China from 2016 to 2021 are generally not high. In the process of developing domestic guidelines or consensuses on pancreatic diseases, the guideline developer should refer to AGREE-China and RIGHT to improve the quality of clinical practice guidelines or consensuses.

Objective:To investigate the factors related to recurrence and prognosis of retroperitoneal liposarcoma.Method:The clinical data of patients with primary retroperitoneal liposarcoma who underwent surgical treatment in the First Affiliated Hospital of Zhengzhou University from June 2011 to January 2020 were analyzed retrospectively. There were 42 males and 47 females and patients’median age was 53 (26-78). Sixty-five cases were treated by operation in our hospital, and 24 cases were primarily treated by the operation in another hospital. The clinical manifestations of the initial diagnosis included retroperitoneal mass in 41 cases, abdominal distension in 12 cases, abdominal pain in 10 cases, fever in 11 cases, nausea, vomiting and poor appetite in 8 cases, frequent urination and dysuria in 6 cases, and bilateral lower limb edema in 1 case. Preoperative CT imaging showed that the tumor body was located in the retroperitoneal kidney area in 58 cases, while in the retroperitoneal space or the pelvic extraperitoneal space in 31 cases. There were 55 single cases and 34 multiple cases. The median tumor length was 20(3-52) cm. Among the primarily treated 65 patients, 47(72.3%) were considered as primary retroperitoneal liposarcoma by preoperative imaging examination. Among the 89 patients treated by surgery, 78 underwent endoscopic surgery, among which 21 underwent laparoscopic surgery, 38 cases of retroperitoneal laparoscopic surgery, 19 cases of Da Vinci robot-assisted laparoscopic surgery. Open operation was performed in 11 cases. There were 87 patients undergoing radical resection and 2 patients undergoing palliative resection. Forty-two patients underwent intraoperative combined resection of the adjacent organs. The recurrence and survival status of patients were followed up.Results:All the 89 patients underwent the operation successfully, with the median operative blood loss of 200 (10-2000) ml. There were 23 cases being diagnosed of well differentiated liposarcoma, 40 cases of dedifferentiated, 20 cases of myxoid/round, 5 cases of myxoid liposarcoma, and 1 cases of mixed type. Pathologically, there 42 cases with low grade histology and 47 cases with high grade histology. In this study, 89 patients were followed up for 3 to 108 months, and the median follow-up time was 28 months. The 5-year recurrence free survival rate, disease-free survival rate and overall survival rate of the patients were 16.7%, 16.1% and 52.6%, respectively. There were 57 patients presenting local recurrence, 1 patient of lung metastasis, and 1 patient of liver metastasis, and the median disease-free survival time was 24 months. There were 42 patients died of the disease, with a median survival time of 64 months. Univariate analysis showed that intraoperative blood loss( P<0.01), whether multiple cases( P<0.01), pathologic types( P<0.01), and histological grades ( P<0.01) were related to disease-free survival.The intraoperative blood loss( P<0.01), multiple cases( P<0.05), pathologic types ( P<0.05), and recurrence ( P<0.01)were related with overall survival. Gender, age, tumor size, tumor location, whether primary surgery, radical resection or combined resection of adjacent organ had no effect on the prognosis of patients ( P>0.05). Cox regression model multivariate analysis revealed that surgical bleeding ( RR=2.360, 95% CI 1.313-4.241, P=0.004), multiple tumor ( RR=1.899, 95% CI 1.068-3.375, P=0.029), and pathological type ( RR=4.976, 95% CI 1.622-15.264, P=0.005) were independent factors affecting disease-free survival. The recurrence was an independent factor affecting the overall survival of patients ( RR=31.495, 95% CI 1.062-933.684, P=0.046). Conclusions:Retroperitoneal liposarcoma is a rare disease with high recurrence rate. The intraoperative blood loss, whether multiplicity and pathological type are independent factors affecting the disease-free survival, and recurrence is independent factors affecting the overall survival.

OBJECTIVE: To explore the genetic basis for a pedigree affected with Alport syndrome. METHODS: Next generation sequencing and Sanger sequencing was carried out to detect potential variant of the COL4A5 gene among members from the pedigree and 100 unrelated healthy controls. RESULTS: A novel missense c.3293G>T (p.Gly1098Val) variant was found in the COL4A5 gene among 6 affected members but not the unaffected members of the pedigree or the 100 healthy controls. According to the American College of Medical Genetics and Genomics standards and guidelines, the c.3293G>T variant was classified as pathogenic (PP1-strong+PM1+PM2+PP3+PP4). CONCLUSION By destructing the Gly-X-Y structure of its protein product, the c.3293G>T variant of the COL4A5 gene probably underlies the Alport syndrome in this pedigree. Above finding has enriched the spectrum of COL4A5 variants.