Environmental toxicants have been linked to aging and age-related diseases. The emerging evidence has shown that the enhancement of detoxification gene expression is a common transcriptome marker of long-lived mice, Drosophila melanogaster, and Caenorhabditis elegans. Meanwhile, the resistance to toxicants was increased in long-lived animals. Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr ^-/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.

Among tumor microenvironment (TME), the entire metabolic characteristics of tumor-resident cells are reprogrammed to benefit the expansion of tumor cells, which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support. Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME, also rely on glutaminolysis as the "engine" of angiogenesis. Additionally, the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well. Herein, we developed a type of siRNA micelleplexes (MH@siGLS1) to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization- and TAMs repolarization-enhanced photo-immunotherapy. Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy, which was available to trigger immunogenic cell death for adaptive antitumor immune responses. Meanwhile, glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification. This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.

Temporomandibular joint (TMJ) disc displacement is one of the most significant subtypes of temporomandibular joint disorders, but its etiology and mechanism are poorly understood. In this study, we elucidated the mechanisms by which destruction of inflamed collagen fibrils induces alterations in the mechanical properties and positioning of the TMJ disc. By constructing a rat model of TMJ arthritis, we observed anteriorly dislocated TMJ discs with aggravated deformity in vivo from five weeks to six months after a local injection of Freund's complete adjuvant. By mimicking inflammatory conditions with interleukin-1 beta in vitro, we observed enhanced expression of collagen-synthesis markers in primary TMJ disc cells cultured in a conventional two-dimensional environment. In contrast, three-dimensional (3D)-cultivated disc cell sheets demonstrated the disordered assembly of inflamed collagen fibrils, inappropriate arrangement, and decreased Young's modulus. Mechanistically, inflammation-related activation of the nuclear factor kappa-B (NF-κB) pathway occurs during the progression of TMJ arthritis. NF-κB inhibition reduced the collagen fibril destruction in the inflamed disc cell sheets in vitro, and early NF-κB blockade alleviated collagen degeneration and dislocation of the TMJ discs in vivo. Therefore, the NF-κB pathway participates in the collagen remodeling in inflamed TMJ discs, offering a potential therapeutic target for disc displacement.
Animals ; NF-kappa B/metabolism* ; Temporomandibular Joint Disorders/pathology* ; Temporomandibular Joint Disc/metabolism* ; Rats ; Rats, Sprague-Dawley ; Disease Models, Animal ; Male ; Collagen/metabolism* ; Cells, Cultured ; Joint Dislocations/pathology* ; Interleukin-1beta ; Arthritis, Experimental

Objective To investigate the clinical efficacy and safety of tirofiban and rt-PA alteplase in the treatment of minor stroke patients.Methods A total of 171 patients with minor stroke ad-mitted to Department of Neurology of Zhengzhou People's Hospital from January 2021 to January 2024 were prospectively and continuously enrolled,and were randomly divided into tirofiban group(84 cases)and rt-PA group(87 cases).The tirofiban group received intravenous infusion of tirofiban but not intravenous thrombolysis therapy.The rt-PA group was treated with intravenous thrombolysis.The 90-day mRS score was observed in all patients.NIHSS was used to score the improvement of neurological function.3-month all-cause death was observed during follow-up.Results The tirofiban group had a significant larger proportion of mRS score of 0-1 at 90 d(92.86％vs 82.76％,P＜0.05),lower NIHSS scores at 24 h and 7 d after treatment and smaller proportion of early neurological deterioration than the rt-PA group(P＜0.05).Larger proportion of mRS score of 0-2 in the 90 day and slightly smaller proportion of the score of 4-6 at 90 d were observed in the tirofiban group than the rt-PA group(P＞0.05).There were no statistical difference in the incidence of 3-month all-cause death between the two groups(P＞0.05).Conclusion Compared with rt-PA,tirofiban can significantly improve the clinical prognosis of pa-tients with minor stroke,reduce the risk of early neurological deterioration,and has higher safety.

Plant-derived nanovesicles have gained attention given their similarity to mammalian exosomes and advantages such as low cost, sustainability, and tissue targeting. Thus, they hold promise for disease treatment and drug delivery. In this study, we proposed a time-efficient method, PEG 8000 combined with sucrose density gradient centrifugation to prepare ginger-derived nanovesicles (GDNVs). Subsequently, curcumin (CUR) was loaded onto GDNV by ultrasonic incubation. The optimum conditions for ginger-derived nanovesicles loaded with curcumin (CG) were ultrasound time of 3 min, a carrier-to-drug ratio (GDNV:CUR) of 1:1. The study achieved a high loading capacity (94.027% ± 0.094%) and encapsulation efficiency (89.300% ± 0.344%). Finally, the drugs' in vivo distribution and anti-colitis activity were investigated in mice. CG was primarily distributed in the colon after oral administration. Compared to CUR and GDNV, CG was superior in improving disease activity, colon length, liver and spleen coefficients, myeloperoxidase activity, and biochemical factor levels in ulcerative colitis (UC) mice. In addition, CG plays a protective role against UC by modulating serum metabolite levels and gut flora. In summary, our study demonstrated that GDNV can be used for CUR delivery with enhanced therapeutic potential.

Objective:To investigate the composition characteristics of urolithiasis patients in Chongqing.Methods:From May 2017 to July 2021, clinical data of 1 972 urinary stone patients treated in the Second Affiliated Hospital of Chongqing Medical University was retrospectively analyzed. Among 1 972 patients, there were 1 323 males and 649 females, the average age was (52.7±13.8) years (aged 14-92 years). In this study, all of the patients were first divided into the central and western areas of Chongqing group ( n=1 532) and southeastern areas of Chongqing group ( n=440) according to regional differences; then according to the difference of economic development level, all patients were divided into the more developed area of Chongqing group ( n=1 491) and the less developed area of Chongqing group ( n=481). To study and analyze the influence of gender, age, region and economic development level on stone composition in patients. The distribution characteristics of urinary calculi constituents in different groups of region, gender and age were analyzed by Chi-square test, and analysis of the proportion of various urinary calculi with age were conducted by Cochran-Armitage trend test. Results:The results of stone composition analysis showed that, among the 1 972 cases, the mixed urinary stones were dominant in the urinary stones [92.9%(1 832/1 972)], in which, the most component was the calcium oxalate monohydrate+ calcium oxalate dehydrate [40.8%(805/1 972)]; among the pure stones, the most component was the calcium oxalate dehydrate [2.5%(50/1 972)]. The proportion of carbonated apatite stones [53.6%(348/649) vs 43.5%(576/1 323), P<0.05], hydroxyapatite stones [25.1%(163/649) vs 17.2%(228/1 323), P<0.05] and magnesium ammonium phosphate stones [20.6%(134/649) vs 6.3%(83/1 323), P<0.05] in female patients were significantly higher than those in male patients, but the proportion of calcium oxalate stones [91.4%(1 209/1 323) vs 80.7%(524/649), P<0.05] and uric acid stones [9.4%(125/1 323) vs 1.5%(10/649), P<0.05] in male patients were significantly higher than those in female patients. Compared with patients aged 40-70 years and ≥70 years, the proportion of carbonated apatite stones [39.6%(155/391) vs 48.4%(673/1 391), 50.5%(96/190), P<0.05], magnesium ammonium phosphate stones [6.1% (24/391) vs 12.0% (167/1 391), 13.7% (26/190), P<0.05] and uric acid stones [3.3% (13/391) vs 7.4% (103/1 391), 10.0% (19/190), P<0.05] was significantly lower for patients aged <40 years; but the proportion of calcium oxalate stones in patients aged < 40 years was significantly higher [93.6%(366/391) vs 87.2%(1 213/1 391), 81.0%(154/190), P<0.05]. In this study, there were no significant difference in stone composition between the central and western areas of Chongqing and the southeastern areas of Chongqing, and between the more developed areas of Chongqing and the less developed areas of Chongqing ( P>0.05). Conclusions:There are gender and age differences in the distribution of urinary stone components in Chongqing, but the regional and economic development level differences are not particularly obvious. Carbonated apatite stones, hydroxyapatite stones and magnesium ammonium phosphate stones were more prevalent in females, calcium oxalate stones and uric acid stones were more common in males. Calcium oxalate stones were the most common in patients aged< 40 years, carbonate apatite, magnesium ammonium phosphate and uric acid stones were more common in patients aged ≥40 years.

Objective:To compare the application value of prefabricated path with an awl for guiding pin and traditional screw placement during anterior odontoid screw fixation.Methods:A retrospective case-control study was conducted to analyze 35 patients with fresh odontoid fractures treated from January 2010 to August 2017 in Henan Provincial People's Hospital, including 25 males and 10 females with age range of 19-55 years (mean, 36.9 years). The preoperative odontoid fractures were classified into type IIA in 15 patients, type IIB in 20 patients according to Anderson and D'Alonzo classification. Among them, 16 patients in Group A were treated with prefabricated path by an awl for guiding pin during anterior odontoid screw fixation, and 19 patients in Group B were implanted screws according to traditional experience in anterior odontoid screw fixation. Operation time, intraoperative fluoroscopy time, success rate of first-time guiding pin implantation, intraoperative blood loss, fracture healing outcomes and American Spinal Injury Association (ASIA) grade at the latest follow-up were collected and compared between the two groups.Results:All patients were followed up for 13-20 months [(16.8±1.5)months]. Two groups had significant differences in operation time [Group A: (73.5±12.9)minutes; Group B: (82.6±13.6)minutes], intraoperative fluoroscopy time [Group A: (3.1±0.6)minutes, Group B: (7.0±0.9)minutes], and success rate of first-time guiding pin implantation (Group A: 94%, Group B: 58%) ( P<0.05), but not in intraoperative blood loss [Group A: (129.4±40.6)ml; Group B: (135.8±38.4)ml] and fracture healing rate (Group A: 94%, Group B: 95%) and ASIA grade at the latest follow-up (Group A: grade C in 1 patient, grade D in 3, grade E in 12; Group B: grade C in 2 patients, grade D in 2, grade E in 15) ( P>0.05). All patients were successfully operated without occurrence of cerebrospinal fluid leakage, neurovascular injury or incision infection. Conclusions:Prefabricated path with an awl for guiding pin during anterior odontoid screw fixation is superior to traditional experience, which can reduce operation time, intraoperative fluoroscopy time and improve the success rate of first-time guiding pin implantation. Meanwhile, there is no effect on intraoperative blood loss or fracture healing outcomes.

Objective To investigate the clinical efficacy of non-fusion and fusion internal fixation with posterior pedicle screw for odontoid fractures. Methods A retrospective case control study was conducted to analyze the clinical data of 46 patients with odontoid fractures admitted to Henan Provincial People's Hospital from January 2013 to June 2015. There were 35 males and 11 females, aged 19-62 years [(36. 9 ± 1. 6)years]. The preoperative odontoid fractures were classified as type IIA in five patients, type IIB in eight, type IIC in 22, shallow type III in six according to Anderson and D'Alonzo typing. The fractures of five patients were not classified. According to the ASIA grading, the preoperative spinal cord function was graded as D or E in the 46 patients. Among the patients, 15 underwent posterior pedicle screw non-fusion internal fixation ( Group A) , with 60 pedicle screws removed 12-29 months after operation. A total of 31 patients were treated with fusion internal fixation with posterior pedicle screw ( Group B) , with 124 pedicle screws free from removal after operation. The follow-up time, operation time, intraoperative fluoroscopy time, intraoperative blood loss as well as visual analog scale (VAS), cervical rotation degree, and neck disability index ( NDI) before operation, 1 year after surgery ( when no internal fixation was removed ) and at the last follow-up were compared between the two groups. Results There were no significant differences between the two groups in the follow-up time, operation time, intraoperative fluoroscopy time, intraoperative blood loss, VAS score, neck rotation degree, NDI score before operation and at 1 year after operation (P >0. 05). There were significant differences between two groups in VAS scores, neck rotation degree, NDI scores indicating driving and walking and recreational activities at the last follow-up ( P <0. 05 ) . There were no significant differences between two groups in other NDI scores items, including neck discomfort, personal care, lifting heavy objects, reading & watching TV, headache situation, attention, working status, and sleep disorder at the last follow-up ( P> 0. 05 ) . Conclusions Posterior pedicle screw internal fixation for odontoid process fracture has good curative effect. Non-fusion internal fixation with posterior pedicle screw is more conducive to the recovery of cervical spine rotation function, the relief of neck and back pain, and the improvement of patients' driving, walking and entertainment activities.

Objective To study the functions and mechanisms of glutamine 1 (GLS1) in intrahepatic cholangiocarcinoma (ICC) cell to 5-fluorouraeil (5-FU) chemosensitivity.Methods The expression and relation between GLS1 and major vault protein (MVP) in cholangiocarcinoma were analyzed by bioinformatics database.Western blot and immunohistochemistry were used to detect the expression of GLS1 and MVP in 42 ICC tissues,and the correlation between GLS1 and MVP was studied by statistics.The regulation of GLS1 in ICC cell were evaluated by siRNA interference and pcDNA overexpression,and then tested the interference and overexpression efficiency of GLS1 by Western blotting.The chemosensitivity to 5-Fu was tested by cell counting kit-8 (CCK-8).Results The expression of GLS1 and MVP in ICC tissues was significantly up-regulated (tGLSI =3.963;tMVP =3.131,P ＜ 0.05),and the expression of GLS1 was positively correlated with MVP(r2 =0.351 7,P ＜ 0.05).Knockdown of GLS1 in QBC939 cells enhanced chemosensitivity of QBC939 cells to 5-Fu and notably downregulated MVP expression,while enforced expression of GLS1 in RBE cells promoted MVP expression and reduce cell sensitivity to 5-fluorouracil chemosensitivity.Conclusions GLS1 regulates the chemosensitivity of ICC cells to 5-Fu,and its mechanism may relates to the regulation of MVP.

Collagen is the building component of temporomandibular joint (TMJ) discs and is often affected by inflammation in temporomandibular disorders.The macromechanical properties of collagen are deteriorated by chronic inflammation.However,the mechanism by which inflammation influences disc function remains unknown.The relationship between the ultrastructure and nanomechanical properties of collagen in inflamed discs should be clarified.Seven-week-old female Sprague-Dawley rats were randomly divided into two groups.Chronic TMJ inflammation was induced by intra-articular injection of complete Freund's adjuvant,and samples were harvested after 5 weeks.Picrosirius staining revealed multiple colours under polarized light,which represented alternative collagen bundles in inflamed discs.Using atomic force microscopy scanning,the magnitude of Young's modulus was reduced significantly accompanied with disordered collagen fibril arrangement with porous architecture of inflamed discs.Transmission electron microscopy scanning revealed a non-uniform distribution of collagen fibres,and oversized collagen fibrils were observed in inflamed discs.Fourier transform infrared microspectroscopy revealed a decrease in 1 338 cm-1/amide Ⅱ area ratio of collagen in different regions.The peak positions of amide Ⅰ and amide Ⅱ bands were altered in inflamed discs,indicating collagen unfolding.Our results suggest that sustained inflammation deteriorates collagen structures,resulting in thedeterioration of the ultrastructure and nanomechanical properties of rat TMJ discs.