The development and benefits of metformin in various diseases / 医学前沿

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.

Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation / 医学前沿

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD+/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.

Endoscopic cryoablation for upper tract urothelial carcinoma: pilot clinical experience / 中华泌尿外科杂志

Objective:To evaluate the safety and efficacy of endoscopic cryoablation (ECA) in patients with upper tract urothelial carcinoma (UTUC).Methods:The clinical data of 9 patients with UTUC treated with ECA from April 2018 to September 2019 were retrospectively analyzed. Patients consisted of 3 males and 6 females, with median age of 76 years old (ranging from 50 to 88 years old). Among the patients, 6 cases had tumors of ureter, 1 case had tumor of renal pelvis and 2 cases had tumors of renal pelvis combined with ureter. Of the 9 patients, two had bilateral UTUC, six were presented with single lesion, three were presented with multiple lesion. The size of tumors were (1.53±0.91)cm. The tumors of all cases were localized (≤stage T 2), and there was no carcinoma or suspicious lymph node/distant metastasis. All patients enrolled in this study had strong will to choose kidney-sparing therapy. Biopsy, resection of intraluminal lesion with laser and cryoablation under ureteroscopy or percutaneous nephroscopy was performed under general aneasthesia.Ureteroscopy was performed 3 months after cryoablation. Perioperative complications and follow-up results were recorded and assessed. Results:Cryoablation was successfully performed in patients under ureteroscopy (n=8) or nephroscopy (n=1). The median cryoablation time was 6 (ranging from 4-16) minutes. The median follow-up was 16 months (ranging from 4-24 months). No tumor recurrence was observed at primary sites during follow-up. Two patients with multiple lesions were observed denovo ureteral neoplasms outside the primary sites 3 months and 6 months after cryoablation and treated with second cryoablation. One case died due to cardiovascular events 4 months after surgery. One patient underwent ureteral stricture during follow-up and received ureteroscopic balloon dilatation. No recurrent stricture was found in this case during the subsequent follow-up of 16 months. The other 5 cases showed no recurrence or complications like stricture during follow-up.Conclusions:ECA could probably be a promising treatment for localized UTUC. No recurrence in primary site and low incidence of ureteral stricture was observed during follow-up. The efficacy and safety of ECA need to be verified with large sample study.

Role of Med19 in the proliferation and tumorigenicity of human bladder cancer cells / 中华泌尿外科杂志

Objective To study the role of Med19 in bladder cancer by analyzing the effects of lentivirus-mediated suppression of Med19 expression on T24 bladder cancer cells in vitro.Methods The lentivirus vectors containing a small hairpin RNA (shRNA) to target Med19 were constructed.After T24 bladder cancer cells were infected,real-time PCR and Western-blotting were used to study the Med19 expressions in the CON group (non-infected cells),the NC group (Lv-NC-infected cells) and the KD group (Lv-shMed19-infected cells).The influence of Med19 on the proliferation of bladder cancer cells were assessed using MTT,BrdU,colony formation assay and tumorigenicity experiment in mice.Cell cycle was analyzed with flow cytometry assay.Results Med19 relative mRNA level (0.35 ± 0.03) and Med19 protein expressing in the KD group were significantly inhibited (P ＜ 0.05).The KD group displayed an increased proportion of cells (77.50 ± 0.29)％ in the G0/G1 phase compared with the CON group (69.81 ± 0.81)％and NC group (67.53 ± 0.67) ％ (P ＜ 0.05).Compared with the CON group and the NC group,the KD group displayed a significant cell proliferation defect by MTT and BrdU assay and the number of colonies (91.33 ± 6.11) was significant decreased (P ＜ 0.05).On the day 24,the tumor volume (596.64 ± 485.36) mm3 and weight (0.57 ± 0.44) g of the KD group mice were decreased after inoculation into nude mice (P ＜ 0.05).Specific lentivirus-mediated knockdown of Med19 significantly impacted the cell cycle and proliferation of bladder cancer cells.Infected T24 cells nearly lost their tumorigenicity when being inoculated into nude mice.Conclusion Our results provide new evidence of an important role for Med19 in the development of bladder cancer,suggesting that lentiviruses delivering shRNA against Med19 may be a promising tool for bladder cancer therapy.

Expression of pigment epithelium-derived factor in bladder tumour is correlated with interleukin-8 yet not with interleukin-1α / 华中科技大学学报（医学）（英德文版）

Pigment epithelium-derived factor (PEDF) is an antiangiogenic factor which is effective in tumour inhibition in a variety of tumours and has not yet been studied in bladder tumour before. In this study the expression of PEDF, interleukin-1α (IL-1α) and -8 (IL-8) in bladder tumours was investigated. Immunohistochemistry was performed on 64 bladder tumour and 23 normal uroepithelium samples. Expression change of the factors was compared with clinicopathological parameters. Correlations between PEDF, IL-1α and IL-8 were analyzed. None of the factors was in relation to gender, tumour occurrence, and size or onset pattern. PEDF (P=0.014) and IL-1α (P=0.049) expression was down-regulated with grade progression. PEDF expression was lower in normal uroepithelium than in papillary urothelial neoplasm of low malignant potential (PUNLMP) (P=0.000) and carcinoma (P=0.009) whilst IL-1α (P=0.000 and P=0.000 respectively) and IL-8 (P=0.000 and P=0.023 respectively) expression was higher in the same grouping. PEDF expression had a negative correlation with IL-8 in PUNLMP (P=0.049, r=-0.578) as well as in tumour grouping (P=0.033, r=-0.276). Deranged expressional change of PEDF, IL-1α and IL-8 could be in relation to loss of differentiation from normal uroepithelium to papillary lesion and eventually to carcinoma.

The clinical significance of the expression level of PMEPA1 in prostate cancer / 复旦学报（医学版）

Objective To study the clinical significance of the mRNA expression level of a novel gene which encodes a kind of transmembrane prostate protein induced by androgen-PMEPA1, as it may predict the progress of prostate cancer from hormone-dependent to hormone-independent. Methods We used Real-time PCR to detect the mRNA expression of PMEPA1 and GSTP1 in prostate cancer cell lines (LNCaP, PC-3), epithelia cells of benign prostatic hyperplasia and tissues from 33 patients with prostate cancers and 16 cases of prostatic hyperplasia. Results We found the mRNA expression of GSTP1 and PMEPA1 were both down-regulated in prostate cancer cell lines. The mRNA expression of GSTP1 was up-regulated in 6.1% of cases, down-regulated in 81.8%, and showed no difference in 12.1%. While PMEPA1 was highly expressed in 27.3% of cases, lowly expressed in 27.3%, and not differently expressed in 45.4%. Statistical analysis showed that the mRNA expression of GSTP1 was relevant to ages, but had no relationship with PSA, TNM stage, osseous metastasis or tumor differentiation, while the mRNA expression of PMEPA1 was relevant to osseous metastasis and tumor differentiation, but had no relationship with age, PSA or TNM stage. Conclusions PMEPA1 is possibly a useful biomarker, as it can identify patients with unfavourable prognosis, however, this hypothesis needs to be further studied with large samples.

Diagnostic efficacy and complication of transperineal prostate biopsy: less than 10 cores vs more than 10cores / 中华泌尿外科杂志

Objective To compare the diagnostic efficacy and complications of transperineal prostate biopsy for<10 cores biopsy vs≥10 cores biopsy. Methods Nine hundred transrectal ul-trasound-guided transperineal prostate biopsies were performed. Patients were divided into 2 groups, <10 cores group and ≥10 cores group. Patient numbers of the 2 groups were 759 and 141, respec-tively. Cancer positive rate and complications were compared between the 2 groups retrospectively. Results Cancer positive rates were 41.6%(316/759) and 51.8%(73/141) in 2 groups (P<0.05). In patients of PSA≤10.0 ng/ml, cancer positive rates were 6.8% (16/235) and 17.8% (8/45) in 2 groups (P<0.05). Gross hematuria was the most common complication associated with biopsy. There was no statistical difference between the 2 groups in post-biopsy gross hematuria rate. Conclu-sions The diagnostic efficacy is higher in≥10 cores prostate biopsy than that in <10 cores prostate biopsy, There is no difference in biopsy related complications regarding biopsy core numbers.

Efficacy and safety of Bicalutamide 150 mg as the monotherapy in the treatment of locally advanced prostate cancer / 中华泌尿外科杂志

vides com-parable efficacy with medical castration in regard of decreasing PSA level and reducing prostate vol-ume. It is a safe and well tolerated treatment option as well.

The correlation in transcriptional expression with promoter hypermethylation of AKAP12 gene in bladder transitional cell carcinoma / 中华检验医学杂志

Objective To investigate transcriptional expression and promoter CpG methylation status of A-kinase anchoring protein 12 (AKAP12) gene and analyze their correlation with clinical pathological stage in bladder transitional cell carcinoma. Methods AKAP12 mRNA expression level and promoter CpG metbylation status was measured by fluorescent quantitative RT-PCR (FQ-RT-PCR) and methylation specific PCR (MSP) in 30 bladder transitional cell carcinoma and adjacent normal tissues. The products of PCR were cloned and bisulfite sequenced. Results Decreased AKAP12 mRNA expression was demonstrated in 22 carcinomas (73. 3% ) and was significantly associated with turnout grade (P =0. 02).The frequency of promoter methylation of AKAP12 gene was 53. 3 % (16/30) and correlated with the tumor stage(r =0.52,Pn =0.03)and grade(r =0.61,Pn =0.01). Conclusion Aberrant promoter methylation of AKAP12 can result in the loss of gene expression and may association with bladder transitional cell carcinoma.

Morphological studies in the apoptosis of PC3 cell-line induced by chlorophyll derivative based photodynamic therapy / 中华泌尿外科杂志

Objective To investigate the effect of a newly developed photosensitizer—chlorophyll derivative combined with irradiation of 650 nm laser for PC3, an androgen independent cell line in vitro. Methods PC3 was cultured and designed to 4 groups,including blank control,laser irradiation,medication of photosensitizer and medication of photosensitizer with laser irradiation (treated).The medicated concentration of chlorophyll was 0.1 g/L and irradation fluence of 650 nm semiconductor laser was 6 J/cm2.Intracellular distribution of photosensitizer and cellular morphological alterations were studied through light microscopy, electron microscopy and laser confocal microscopy. Results It showed the shrinkage, round-up and membrane integrity of treated PC3 under light microscopy.Sable deposits were observed in cytoplasm of cells in both photosensitizer and treated groups.Transmission electron microscopy showed the fragmentation of DNA and condensation of chromatin beneath the karyolemma in treated cells.In cytoplasm,the endoplasmic reticulum and mitochondria swell to form vesicles and vacuoles.It showed the strong red fluorescence in the cytoplasm of treat cells compared with the red fluorescence indifferent to the background through laser confocal microscopy. Conclusions Chlorophyll derivative based photodynamic therapy is able to induce apoptosis of PC3 in vitro.Mitochondria is presumed to be the primary target of photodynamic therapy and trigger the apoptotic pathway.

Holmium laser lithotripsy for the treatment of urinary calculi: Report of 1216 cases / 中国微创外科杂志

Objective To evaluate the efficacy and safety of holmium laser lithotripsy for the treatment of urinary calculi.Methods A total of 1216 cases of urinary calculi underwent ureteropyeloscopic and cyctocopic holmium laser lithotripsy.There were 1 006 cases of ureteral stones(302 cases of upper ureteral stones,364 cases of middle ureteral stones,and 340 cases of lower ureteral stones) and 210 cases of bladder stones.Results In 1 case of upper ureteral stones,failure to access the ureteral orifice due to enlarged prostate was encountered,and extracorporeal shock wave lithotripsy(ESWL) was employed.In 1006 cases of ureteral stones,the rate of successful fragmentation on single session was 95.5%(961/1 006),with 89.4%(270/302),96.4%(351/364),and 100%(340/340) for upper,middle,and lower ureteral stones,respectively.Ureteral perforation was encountered during lithotripsy in 6 cases.In 210 cases of bladder stones,the rate of successful fragmentation on one session was 100%(210/210).No bleeding or bladder perforation was observed during lithotripsy.Follow-up checkups for 0.5~40 months(mean,18.6 months) in 881 cases of ureteral stones showed that the stone-free rates were 91.1%(224/246),98.5%(318/323),and 100%(312/312) for upper,middle,and lower ureteral stones,respectively.The overall stone-free rate for all levels of ureteral stones achieved 96.9%((854/881)).Ureteral stenosis was found in 6 cases.Follow-up checkups for 0.5~31 months(mean,12.4 months) in 187 cases of bladder stones revealed a stone-free rate of 98.4%(184/187). Conclusions Holmium laser lithotripsy is a highly effective,minimally invasive,and safe therapy for urinary calculi.It is indicated as the first choice of treatment for patients with ureteral stones and bladder stones.

Single instillation of epirubicin for the prophylaxis of recurrent primary superficial bladder carcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To determine the feasibility of single dose intravesical epirubicin in the prevention of recurrent superficial bladder carcinoma.</p><p><b>METHODS</b>We compared the effect of intravesical epirubicin or mitomycin C on tumor recurrence and disease free interval and their side effects after treatment of superficial bladder tumor. 47 postoperative patients with stages Ta to T1 primary superficial bladder carcinoma of grades 1 or 2 were randomized into groups A: single 80 mg epirubicin; B: 40 mg consecutive epirubicin; C: 40 mg consecutive mitomycin C. Patients were followed up for clinical, analytical, and cystoscopic evaluations every 3 months.</p><p><b>RESULTS</b>The disease free intervals of the three groups were found no significant differences (F = 3.25, P > 0.05). The recurrence rate was 6.25% (1/16), 13.3% (2/15), 12.5% (2/16) (chi(2) = 0.496, P > 0.05) in groups A, B, and C at 1 year, and 33.3% (5/15), 26.7% (4/15), 25% (4/16) (chi(2) = 0.290, P > 0.05) at 3 years after operation, respectively. Side effects of group A (13.3%) were lower than those of group B (46.7%) or C (43.8%) (chi(2) = 14.56, P < 0.01).</p><p><b>CONCLUSIONS</b>Single dose of epirubicin given intravesically immediately after tumor resection is effective in preventing tumor recurrence.</p>

Holmium: YAG laser lithotripsy for the treatment of ureteral stones: Report of 238 / 中国微创外科杂志

Objective To evaluate the efficacy and safety of holmium laser lithotripsy for ureteral stones. Methods A total of 238 patients with ureteral stones (upper segment, 60 patients; middle segment, 93; lower segment, 85) received the holmium laser lithotripsy under a semi-rigid ureteropyeloscope. Results Stones were successfully fragmented on one session in 97.1% of patients (231/238). The success rate was 91.7% in patients with stones in the upper ureteral segment (55/60) and 98.9% in patients with stones in the!mid-lower ureteral segment (176/178). Five patients with bilateral ureteral stones associated with acute renal failure and anuria returned to normal rapidly. No complications such as perforation or severe trauma were encountered during the operation. The postoperative hospital stay of the 231 patients was 1~2 days (mean, 1.3 days). Follow-up for 0.5~12 months (mean, 4.1 months) revealed a stone-free rate of 98.7% (228/231). No stricture of the ureter was found. Conclusions Holmium: YAG laser lithotripsy is effective, mini-invasive and safe. It is indicated as the first choice in the treatment of ureteral stones, especially stones located in the mid-lower ureteral segment.

Ureteropyeloscopy and holmium:YAG laser lithotripsy for treatment of ureteral calculi / 中华泌尿外科杂志

Objective To evaluate the efficacy and safety of ureteropyeloscopic lithotripsy with holmium:YAG laser for treatment of ureteral calculi. Methods We retrospectively reviewed the data of 186 patients (123 males and 63 females,with an average age of 51 years) who underwent ureteropyeloscopic lithotripsy using holmium:YAG laser with a semi rigid ureteropyeloscope. Among these patients,51 had stones in the upper,64 in the middle,and 71 in the lower ureter.The stones were 0.6 to 2.5 cm (mean 1.3 cm) in diameter. Results The success rates of fragmentation in a single procedure for the upper and mid lower levels of ureteral stones were 90% (46/51) and 99% (133/135), respectively.The overall rate of successful fragmentation for all levels of ureteral stones in a single procedure achieved 96% (179/186).The mean operative time was 28 min,and the mean postoperative hospital stay was 1.2 days.No complications such as perforation occurred during the operation.In 179 patients,the postoperative follow up of 2 weeks to 3 months revealed that the stone free rate was 99% (177/179) and the hydronephrosis was markedly improved from preoperative (3.6?0.7) cm to postoperative (1.5?0.4) cm according to B ultrasound,IVU or renogram ( P

Liver dysfunction and the treatment in combined androgen blockade for patients with prostate cancer / 中华泌尿外科杂志

Objective To evaluate the incidence of liver dysfunction and the relevant treatment in patients with prostate cancer with combined androgen blockade. Methods Twenty three patients (mean age,73 years;range,63-80 years) with histologically confirmed prostate cancer showed liver dysfunction during the course of combined blockade with bilateral orchiectomy and flutamide at a dose of 250 mg,3 times per day.After 6.2 months of therapy, ALT level was increased from pre treatment of (37?7.2)U/L to (63.5?7.53)U/L in 17 patients without jaundice and (87.2?7.34)U/L in 6 patients with jaundice.In the 17 patients without jaundice,herbal medicines were used together with vitamin C and vitamin B complex for 1-2 months (first line therapy).In the 6 severely disordered patients,flutamide was stopped, while glucurolactone at a dose of 1.2 g and (or) TAD of 0.6-1.2 g were administered intravenously per day for 4 weeks (second line therapy).Liver function was monitored every week. Results The 17 patients with mild liver dysfunction recovered after application of first line therapy for 1-2 months.The other 6 patients with relatively severe dysfunction had recovery or improvement with additional second line therapy.Of these patients,4 died of hepatic metastases after 2.1 years. Conclusions It is necessary to monitor liver function during the course of combined androgen blockade and to adopt liver protecting therapy for patients with prostate cancer who previously had hepatitis.