Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

Acute leukaemia is a group of aggressive malignancies with a high mortality rate.The reduction in functional immune cells due to the disease itself and radiotherapy/chemotherapy makes the patients susceptible to co-infections,of which pulmonary infection is a major cause of death.Early accurate diagnosis and appropriate treatment may prevent the spread of infection in patients with acute leukaemia complicated with pulmonary infection,thus reduce serious complications such as sepsis,respiratory failure and multi-organ failure.However,there are still clinical difficulties in the diagnosis and treatment of pulmonary infections in acute leukemia patients.Therefore,the current research advances in the diagnosis and treatment of bacterial,fungal and viral infections in the lungs of patients with acute leukemia were briefly summarized in this review.

Cervical spondylotic radiculopathy(CSR)is a condition caused by the degeneration of cervical intervertebral discs and facet joints,primarily manifesting as the pain,sensory abnormalities,and motor dysfunction in the cervical nerve innervation area of neck,shoulder,and upper limb.For the treatment of CSR,tendon-bone syndrome differentiation in traditional Chinese medicine often faces the issues of conceptual confusion and non-standard syndrome differentiation.Based on the traditional tendon-bone syndrome differentiation and by integrating modern anatomical insights,Professor LIN Ding-Kun,an esteemed scholar of Traditional Chinese Medicine,proposed a classification system for the cervical spine that includes the categories of tendons,joints,bones and marrow.This paper explored the thoughts of Professor LIN for the tendon-bone syndrome differentiation of CSR,summarized the targets of manual therapy,and proposed the four kinds of pathological changes such as tendon overstrain,joint dislocation,bone lesion,and marrow injury,as well as the four techniques of traditional Chinese medicine manipulations,i.e.relaxation of tendons,reduction of joints,protection of marrow,and treatment of bones.The aim is to improve the syndrome-differentiation and treatment for CSR with orthopedic and traumatologic manipulations,and to provide reference for clinical practice.

The fenrou zhijian is defined as potential gap between different layers in the three-dimensional network structure formed by the twelve meridian tendons. Various pathological changes of the meridian tendons lead to the adhesion and closure of fenrou zhijian, causing abnormal mechanical conduction of the meridian tendon system, which in turn leads to painful bi syndrome of meridian tendons. As such, restarting the fenrou zhijian is the key to acupuncture treatment for painful bi syndrome of meridian tendons. Under the guidance of musculoskeletal ultrasound, the level and the angle of needle insertion of acupuncture at fenrou zhijian could be accurately controlled, the efficacy of acupuncture is improved.
Humans ; Meridians ; Acupuncture Therapy ; Needles ; Pain ; Tendons/diagnostic imaging*

Objective:To analyze the fail mode of neoadjuvant therapy combined with surgery for locally advanced esophageal squamous cell carcinoma (ESCC) after long-term follow-up.Methods:Clinical data of consecutive 238 patients with locally advanced resectable ESCC who underwent neoadjuvant therapy combined with surgery in Zhejiang Cancer Hospital from September 2012 to October 2019 were retrospectively analyzed. The failure mode in the whole cohort was analyzed after long-term follow-up. The overall survival (OS) and disease free survival (DFS) rates were analyzed by Kaplan-Meier method. Survival differences were determined by log-rank test.Results:The pathological complete response (pCR) rate was 42.0% in 238 patients. After a median follow-up of 46.1 months, tumor progression occurred in 96 patients (40.3%), including 25 patients (10.5%) with local recurrence, 61 patients (25.6%) with distant metastases, and 10 patients (4.2%) with simultaneous local recurrence and distant metastases. The median OS and DFS were 64.7 months and 49.9 months. And the 3-, 5-, and 7-year OS and DFS rates were 70.0%, 52.8%, 36.4% and 63.5%, 42.5%, and 30.0%, respectively. The 3-, 5-, and 7-year locoregional recurrence-free survival rates and distant metastasis-free survival rates were 86.0%, 71.4%, 61.2% and 70.6%, 55.9%, 43.0%. Compared with non-pCR patients, the overall progression rate and distant metastasis rate of pCR patients were lower (26.0% vs. 50.7%, 16.0% vs. 32.6%, both P<0.05). And the 3-, 5-, and 7-year OS (83.0% vs. 60.2%, 69.7% vs. 41.7%, 50.4% vs. 27.7%, all P<0.001) and DFS rates (80.4% vs. 51.4%, 63.9% vs. 31.2%, 45.9% vs. 20.3%, all P<0.001) were significantly better in pCR patients. Conclusions:Distant metastasis is the main failure mode of patients with locally advanced ESCC after neoadjuvant therapy. Patients with postoperative pCR can achieve better long-term survival.

Objective To prepare Compound Nanxing Pain Relief Gel(CNPRG)and evaluate its quality and sensitization.Methods CNPRG uses Carbopol 980 NF as the matrix;Appearance,viscosity,coating,centrifugal stability,cold stability,thermal stability as comprehensive indicators,single test and Box-Behnken effector method to optimize the prescription;The quality evaluation methods of appearance,pH,viscosity,stability,vapor phase identification of volatile components,and determination of diaconitine and eugenol content of CNPRG were preliminarily established;CNPRG sensitization was assessed by Active Cutaneous Anaphylaxis.Results The best prescription for CNPRG was Carbopol 980 NF 0.35 g,drug 1.02 g,glycerol 5.00 g,and pH 6.20.CNPRG ′s appearance likes jelly,is smooth,uniform and delicate;pH=6.20±0.03;viscosity 68.43±1.14 Pa·s;Centrifugation,high,low temperature stability,no stratification and precipitation;Identify camphor,(±)-Borneol and(±)-Isoborneol,Cinnamaldehyde,eugenol,phenol;Hypaconitine content 0.2983±0.0073 μg·g-1;Eugenol content 155.66±0.97 μg·g-1;CNPRG confirmed no sensitization.Conclusion CNPRG has good appearance,stable quality and no sensitization,and it can provide a choice for the development of new dosage forms of compound Nanxing pain relief cream to alleviate sensitization.

Objective:To compare the temperature rise curve and steady-state temperature of thulium and holmium laser in lithotripsy.Methods:This study was conducted from November to December 2021. Firstly, we designed an experimental water tank(10 cm×10 cm×10 cm) that can carry out constant temperature water bath, with a 8ml simulated renal pelvis, and can carry out constant velocity perfusion in the simulated renal pelvis. A 1 cm×1 cm×1 cm cubic artificial stone was placed in the simulated renal pelvis to perform 36.5℃-37.5 ℃ water bath. The simulated renal pelvis was closed with an oak plug, the temperature measuring probe and flexible ureteroscope were placed through the hole on the oak plug and entered into the simulated renal pelvis. Flexible ureteroscope was carried out by urologists. The lithotripsy lasted a total of 180 seconds for thulium and holmium laser respectively under different parameter settings (10 Hz×1.0 J, 10 Hz×2.0 J, 10 Hz×3.0 J, 20 Hz×0.5 J, 20 Hz×1.0 J, 20 Hz×1.5 J, the corresponding gravel power is 10 W, 20 W and 30 W respectively), the constant speed water pump flow rate was separate as the high flow rate group (35 ml/min) and low flow rate group (15ml/min), and leave a temperature probe 5mm around the optical fiber. Water temperature change during the lithotripsy was recorded by probes, the average of 10 temperature values of two probes measured every 5 seconds was taken as the water temperature value of this period, with a total of 216 time points in 6 parameter settings. Under the same parameter settings, the temperature of two lasers at each time point was plotted and compared to form the corresponding temperature rise curve. The average temperature in the last 30 seconds during lithotripsy in the record was used as the steady-state temperature, which of thulium and holmium laser lithotripsy was compared under the same parameter setting and the same water flow velocity. Finally, 43℃ was taken as the safety threshold temperature to evaluate whether the temperature of the two lasers during lithotripsy exceeds the safety threshold.Results:According to the temperature rise curve, the water temperature of thulium laser during lithotripsy was higher than that of holmium laser at 77.7% (168/216)of time points. At the flow rate of 15 ml/min, thulium laser was significantly higher than that of holmium laser at 10 Hz×1.0 J[(32.43±2.19℃)vs. (30.99±0.90)℃, P<0.01], 10 Hz×2.0 J[(41.21±3.30℃) vs. (38.13±1.26)℃, P<0.01], 10 Hz×3.0 J[(49.54±2.44)℃vs. (44.91±0.65)℃, P<0.01], 20 Hz×0.5 J[(32.75±1.41)℃vs. (30.84±1.16)℃, P<0.01], 20 Hz×1.0 J[(41.67±1.76)℃vs. (37.51±1.25)℃, P<0.01], 20 Hz×1.5 J [(47.54 ± 3.48)℃vs. (46.12±1.04)℃, P<0.01]. At the flow rate of 35 ml/min, the thulium laser was significantly higher than that of holmium laser at 10 Hz×1.0 J[(28.01±0.57)℃ vs. (26.84±0.97)℃, P<0.01], 10 Hz×2.0 J[(31.31±1.07)℃vs.(30.41±1.39)℃, P<0.01], 10 Hz×3.0 J[(33.29±0.70)℃vs.(32.25±2.55)℃, P<0.01], 20 Hz×0.5 J[(28.36±0.99)℃vs.(26.22±0.66)℃, P<0.01], 20 Hz×1.0 J [(30.80±2.06)℃vs.(30.08±0.78)℃, P=0.012], and the steady-state temperature was not significant different between two laser at 20 Hz×1.5 J [(34.54±3.08)℃ and(33.93±1.49)℃, P=0.163]. In the low flow rate group, thulium laser at 10 Hz×1.0 J, 10 Hz×2.0 J, 20 Hz×0.5 J and 20 Hz×1.0 J does not exceed the safety threshold temperature, while in the high flow rate group, any combination of laser parameters of the two lasers does not exceed the safety threshold temperature. Conclusion:Under the same laser parameter setting and flow rate, the thermal eff of thulium laser is more obvious. When using thulium laser for lithotripsy, the flow rate in the process of lithotripsy being faster than that of holmium laser with the same laser setting should be ensured to avoid tissue damage.

【Objective】 The thermal effects of super-pulsed thulium fiber laser (TFL) at different powers,lithotripsy modes and irrigation rates were studied using a 3D kidney model to simulate ureteral lithotripsy in vivo. 【Methods】 A thermal effect model was established in vitro. Under the same conditions of laboratory temperature and equipment,the temperature around the optical fiber was measured and compared when different optical fiber diameters,powers,lithotripsy modes and irrigation rates were used to simulate lithotripsy by TFL. 【Results】 There was significant difference in the temperature around the optical fiber caused by two fibers with different diameters under the same conditions (P<0.05). Under the same conditions,different lithotripsic modes produced different temperatures,and the temperature of "high energy and low frequency" was lower than that of "low energy and high frequency" (P<0.05). When the power was 10 W and the minimum irrigation rate was 10 mL/min,the plateau temperature did not reach the safety threshold (43 ℃). When the power was 20 W and the minimum irrigation rate was 10 mL/min,the platform temperature exceeded the safety threshold. When the irrigation rate was 20 mL/min,the platform temperature did not reach the safety threshold. 【Conclusion】 In the study of ureteral lithotripsy in vitro,the power,mode,irrigation rate and optical fiber diameter are factors affecting the thermal effects of TFL. No matter what kind of lithotripsy mode and fiber diameter,the temperature around the fiber is safe when the lithotripsy power is ≤10 W and the irrigation rate is ≥10 mL/min;when the lithotripsy power is ≤20 W and the irrigation rate is ≥20 mL/min,the temperature around the fiber is safe.

Curcuma wenyujin, as one of the eight Daodi-herbs in Zhejiang province, is widely used. It has the effects of eliminating stasis and dissipating mass, moving Qi and activating blood, and clearing heart and relieving depression. Modern studies have shown that it has anti-tumor, anti-inflammatory, anti-oxidation, anti-thrombus and liver-protecting effects and mainly contains sesquiterpenoids, monoterpenoids, diterpenoids, and curcumins. This paper reviews the research progress in the chemical constituents and pharmacological effects of C. wenyujin in the last decade, discusses the modern clinical applications combined with the traditional efficacy, and predicts its quality markers(Q-markers) from plant consanguinity, medicinal properties, efficacy, processing and measurability of chemical components based on the theory of Q-markers, so as to provide a reference for the establishment of a scientific quality evaluation system and the research and application of this herb in the future.
Anti-Inflammatory Agents ; Curcuma/chemistry* ; Liver

The ethanol precipitation process of Nauclea officinalis extract was optimized based on the concept of quality by design(QbD). Single factor tests were carried out to determine the levels of test factors. The ethanol volume fraction, pre-ethanol precipitation drug concentration, and ethanol precipitation time were taken as critical process parameters(CPPs). With the comprehensive scores of strictosamide transfer rate and solid removal rate as the critical quality attributes(CQAs), Box-Behnken design was employed to establish the mathematical models and space design between CPPs and CQAs, and the obtained optimal operating space was validated. The optimal operating space included ethanol volume fraction of 65%-70%, pre-ethanol precipitation drug concentration of 22-27 mg·mL~(-1), and ethanol precipitation time of 12 h. Based on the concept of QbD, this study adopted the design space to optimize the ethanol precipitation process of N. officinalis extract, which provided a reliable theoretical basis for the quality control in the production process of N. officinalis preparations. Moroever, this study provided a reference value for guiding the research and industrial production of traditional Chinese medicines.
Drugs, Chinese Herbal ; Ethanol ; Medicine, Chinese Traditional ; Quality Control ; Models, Theoretical