This study investigated the effect of Wuling San on transforming growth factor-β1(TGF-β1)-induced fibrosis, inflammation, and oxidative stress in human renal tubular epithelial cells(HK-2) and its mechanism of antioxidant stress injury. HK-2 cells were cultured in vitro and divided into a control group, a TGF-β1 model group, and three treatment groups receiving Wuling San-containing serum at low(2.5%), medium(5.0%), and high(10.0%) doses. TGF-β1 was used to establish the model in all groups except the control group. CCK-8 was used to analyze the effect of different concentrations of Wuling San on the activity of HK-2 cells with or without TGF-β1 stimulation. The expression of key fibrosis molecules, including actin alpha 2(Acta2), collagen type Ⅰ alpha 1 chain(Col1α1), collagen type Ⅲ alpha 1 chain(Col3α1), TIMP metallopeptidase inhibitor 1(Timp1), and fibronectin 1(Fn1), was detected using qPCR. The expression levels of inflammatory cytokines, including tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-8(IL-8), and interleukin-4(IL-4), were measured using ELISA kits. Glutathione peroxidase(GSH-Px), malondialdehyde(MDA), catalase(CAT), and superoxide dismutase(SOD) biochemical kits were used to analyze the effect of Wuling San on TGF-β1-induced oxidative stress injury in HK-2 cells, and the expression of nuclear factor E2-related factor 2(Nrf2), heme oxygenase 1(HO-1), and NAD(P)H quinone oxidoreductase 1(NQO1) was analyzed by qPCR and immunofluorescence. The CCK-8 results indicated that the optimal administration concentrations of Wuling San were 2.5%, 5.0%, and 10.0%. Compared with the control group, the TGF-β1 model group showed significantly increased levels of key fibrosis molecules(Acta2, Col1α1, Col3α1, Timp1, and Fn1) and inflammatory cytokines(TNF-α, IL-1β, IL-6, IL-8, and IL-4). In contrast, the Wuling San administration groups were able to dose-dependently inhibit the expression levels of key fibrosis molecules and inflammatory cytokines compared with the TGF-β1 model group. Wuling San significantly increased the activities of GSH-Px, CAT, and SOD enzymes in TGF-β1-stimulated HK-2 cells and significantly inhibited the level of MDA. Furthermore, compared with the control group, the TGF-β1 model group exhibited a significant reduction in the expression of Nrf2, HO-1, and NQO1 genes and proteins. After Wuling San intervention, the expression of Nrf2, HO-1, and NQO1 genes and proteins was significantly increased. Correlation analysis showed that antioxidant stress enzymes(GSH-Px, CAT, and SOD) and Nrf2 signaling were significantly negatively correlated with key fibrosis molecules and inflammatory cytokines in the TGF-β1-stimulated HK-2 cell model. In conclusion, Wuling San can inhibit TGF-β1-induced fibrosis in HK-2 cells by activating the Nrf2 signaling pathway, improving oxidative stress injury, and reducing inflammation.
Humans ; Oxidative Stress/drug effects* ; Transforming Growth Factor beta1/metabolism* ; Fibrosis/genetics* ; Cell Line ; Drugs, Chinese Herbal/pharmacology* ; Epithelial Cells/immunology* ; Inflammation/metabolism*

OBJECTIVE: To investigate the effect of the sequence of intermediate instrumentation and distraction-reduction of the injured vertebra on the surgical efficacy of short-segment percutaneous pedicle screw fixation for thoracolumbar burst fractures with high rate of spinal canal encroachment. METHODS: From January 2016 to January 2022, 38 patients with thoracolumbar burst fractures with high rate of spinal canal encroachment (spinal canal encroachment rate >40%, complete posterior longitudinal ligament, no flipping bone block in the posterior marginal of the vertebra) without spinal cord injury who were were treated with short-segment percutaneous pedicle screw fixation were retrospectively analyzed. During the operation, 18 cases were used distraction-reduction first and then intermediate instrumentation on injured vertebral and sequential distraction-reduction again(the distraction-reduction first group) including 8 females and 10 males with a mean age of 46.5 (38.5, 50.0) years old, and the other 20 cases were used intermediate instrumentation on injured vertebral first and then direct distraction-reduction(the intermediate instrumentation first group) including 10 males and 10 females with a mean age of 46.0 (35.8, 50.8) years. The anterior height ratio of the injured vertebra, local Cobb's angle of the injured vertebrae, the spinal canal encroachment rate, and the improvement rate of spinal canal encroachment were compared and evaluated. RESULTS: All patients were followed up for more than 1 year, and no complications such as spinal cord and root injury, screw loosening and screw rod fracture were found. The anterior height ratio of the injured vertebra, local Cobb' angle of the injured vertebra in the two groups were significantly improved compared with preoperative data(P<0.05), and those at 3 months and 1 year after operation was lost compared with that at the previous time point(P<0.05). Although the spinal canal encroachment rate of the two groups 1 day and 1 year after operation was improved compared with that before operation(P<0.05), the improvement of spinal canal volume in the distraction-reduction first group was significantly better than that in the intermediate instrumentation first group (P<0.01). CONCLUSION In the treatment of patients with thoracolumbar fractures with high rate of spinal canal encroachment, short-segment percutaneous pedicle screw internal fixation with distraction-reduction first and then intermediate instrumentation and sequential distraction-reduction again can more effectively reduce the bony encroachment in the spinal canal and achieve indirect decompression effect better.
Humans ; Female ; Male ; Adult ; Middle Aged ; Spinal Fractures/surgery* ; Thoracic Vertebrae/surgery* ; Lumbar Vertebrae/surgery* ; Fracture Fixation, Internal/instrumentation* ; Pedicle Screws ; Retrospective Studies ; Spinal Canal/surgery*

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

In recent years, nucleic acid therapy, as a revolutionary therapeutic tool, has shown great potential in the treatment of genetic diseases, infectious diseases and cancer. Lipid nanoparticles (LNPs) are currently the most advanced mRNA delivery carriers, and their emergence is an important reason for the rapid approval and use of COVID-19 mRNA vaccines and the development of mRNA therapy. Currently, mRNA therapeutics using LNP as a carrier have been widely used in protein replacement therapy, vaccines and gene editing. Conventional LNP is composed of four components: ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG) lipids, which can effectively load mRNA to improve the stability of mRNA and promote the delivery of mRNA to the cytoplasm. However, in the face of the complexity and diversity of clinical diseases, the structure, properties and functions of existing LNPs are too homogeneous, and the lack of targeted delivery capability may result in the risk of off-targeting. LNPs are flexibly designed and structurally stable vectors, and the adjustment of the types or proportions of their components can give them additional functions without affecting the ability of LNPs to deliver mRNAs. For example, by replacing and optimizing the basic components of LNP, introducing a fifth component, and modifying its surface, LNP can be made to have more precise targeting ability to reduce the side effects caused by treatment, or be given additional functions to synergistically enhance the efficacy of mRNA therapy to respond to the clinical demand for nucleic acid therapy. It is also possible to further improve the efficiency of LNP delivery of mRNA through machine learning-assisted LNP iteration. This review can provide a reference method for the rational design of engineered lipid nanoparticles delivering mRNA to treat diseases.

Objective To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage(HIBD)and to explore its mechanisms via the PI3K/AKT signaling pathway,aiming to provide a basis for the clinical application of melatonin.Methods Seven-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group,an HIBD group,and a melatonin group(n=9 each).The neonatal rat HIBD model was established using the classic Rice-Vannucci method.Neuronal morphology in the neonatal rat cerebral cortex was observed with hematoxylin-eosin staining and Nissl staining.Autophagy-related protein levels of microtubule-associated protein 1 light chain 3(LC3)and Beclin-1 were detected by immunofluorescence staining and Western blot analysis.Phosphorylated phosphoinositide 3-kinase(p-PI3K)and phosphorylated protein kinase B(p-AKT)protein expression levels were measured by immunohistochemistry and Western blot.The correlation between autophagy and the PI3K pathway in the melatonin group and the HIBD group was analyzed using Pearson correlation analysis.Results Twenty-four hours post-modeling,neurons in the sham operation group displayed normal size and orderly arrangement.In contrast,neurons in the HIBD group showed swelling and disorderly arrangement,while those in the melatonin group had relatively normal morphology and more orderly arrangement.Nissl bodies were normal in the sham operation group but distorted in the HIBD group;however,they remained relatively intact in the melatonin group.The average fluorescence intensity of LC3 and Beclin-1 was higher in the HIBD group compared to the sham operation group,but was reduced in the melatonin group compared to the HIBD group(P<0.05).The number of p-PI3K+and p-AKT+cells decreased in the HIBD group compared to the sham operation group but increased in the melatonin group compared to the HIBD group(P<0.05).LC3 and Beclin-1 protein expression levels were higher,and p-PI3K and p-AKT levels were lower in the HIBD group compared to the sham operation group(P<0.05);however,in the melatonin group,LC3 and Beclin-1 levels decreased,and p-PI3K and p-AKT increased compared to the HIBD group(P<0.05).The correlation analysis results showed that the difference of the mean fluorescence intensity of LC3 and Beclin-1 protein in the injured cerebral cortex between the melatonin and HIBD groups was negatively correlated with the difference of the number of p-PI3K+and p-AKT+cells between the two groups(P<0.05).Conclusions Melatonin can inhibit excessive autophagy in cortical neurons of neonatal rats with HIBD,thereby alleviating HIBD.This mechanism is associated with the PI3K/AKT pathway.

OBJECTIVE: To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine. METHODS: Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients. RESULTS: Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes >60 months (OR=3.562, P=0.010), anemia (OR=4.176, P<0.001), hyperuricemia (OR=3.352, P<0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD. CONCLUSIONS Male, course of diabetes >60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).
Humans ; Male ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Hyperuricemia ; Kidney ; Proteinuria ; Renal Insufficiency, Chronic/complications*

Objective: To explore the change of hearing threshold of workers exposed to noise, establish an individual-based hearing loss early warning model, accurately and differentiated the health of workers exposed to noise. Methods: In September 2019, all physical examination data of 561 workers exposed to noise from an enterprise were collected since their employment. Three indicators of average hearing threshold of the better ear, namely, at high frequency, 4000 Hz and speech frequency, were constructed. The generalized estimating equation (GEE) was used to adjust gender and age and establish the warning model of each indicator. Finally, sensitive indicators and warning models were screened according to AUC and Yoden index. Results: Among the 561 workers exposed to noise, 26 (4.6%) workers had hearing loss. The sensitivity indicators were the average hearing threshold at speech frequency ≥20 dB, high frequency ≥30 dB and 4000 Hz ≥25 dB. The AUC of each index was 0.602, 0.794 and 0.804, and the Youden indexes were 0.204, 0.588 and 0.608, respectively. In GEE of hearing loss warning models, high-frequency hearing threshold ≥20 dB and 4000 Hz hearing threshold ≥25 dB were the optimal models, with AUC of 0.862. Conclusion: Combined with the changes of individual hearing threshold over the years, can accurately assess the risk of individual hearing loss of workers exposed to noise.
Humans ; Hearing Loss, Noise-Induced/diagnosis* ; Noise, Occupational/adverse effects* ; Audiometry ; Deafness ; Employment ; Occupational Exposure/adverse effects* ; Occupational Diseases/diagnosis*

Aim To evaluate the protective effect of Dexrazoxane(Dex)on onco-Cardiology caused by chemotherapeutic drugs other than anthracycline antitumor drugs using zebrafish embryos, including:cisplatin, paclitaxel, vincristine sulfate, 5-fluorouracil and cyclophosphamide. Methods Zebrafish embryos at 24 hpf(hours post-fertilization)were exposed to different concentrations of drugs. The survival rate and the overall animal morphology at 48 hpf, 72 hpf and 96 hpf were observed with a microscope. Heart rate, ventricular contraction fraction, ventricular volume, and cardiac output were measured and calculated by video recordings made with a VCD system. The protective effect of Dex was evaluated using the established model of onco-Cardiology induced by anti-tumor drugs other than anthracyclines. Results In terms of acute toxicity, cisplatin, vincristine sulfate, 5-fluorouracil and cyclophosphamide all significantly reduced the survival rate of zebrafish embryos. The LC50 value was 437.655, 25.538, 65.606 and 19.021 mmol·L-1, respectively. In addition to paclitaxel, the other four anti-tumor drugs all showed significant changes in overall animal morphology and cardiac function indicators. In the study of the protective effect of Dex on four kinds of tumor heart diseases except anthracyclines, only cisplatin had a significant protective effect, which could improve the cardiotoxicity caused by cisplatin. The optimal concentration of Dex was 80 μmol·L-1. Conclusions Zebrafish models of drug toxicity caused by cisplatin, vincristine sulfate, 5-fluorouracil, and cyclophosphamide is established, which proves that Dex only has a protective effect on the toxicity caused by cisplatin.

Colorectal cancer (CRC) is a common malignancy burdening people globally, with increasing morbidity and mortality nowadays, due to the alternation in the diet type and lifestyle in modern society. Berberine, a type of benzylisoquinoline alkaloid, is widely present in numerous medicinal plants, particularly including Coptidis Rhizoma. Mounting evidence reveals that berberine possesses an array of pharmacological effects, such as anti-inflammation, anti-bacterium, anti-cancer, anti-diabetes mellitus and so on. In particular, berberine exhibits substantial inhibition on various types of cancers including CRC. Hereby, we sought to systematically review the suppressive effect of berberine on CRC through the diminishment of the proliferation and metastasis, induction of apoptosis, arrest of cell cycle, regulation of inflammatory reaction, the reverse of chemotherapeutic resistance and restoration of gut microbiota in CRC, so as to shed light on the in-depth mechanisms underlying the treatment of CRC with berberine in the clinical setting.

Humans ; Neurothekeoma/surgery* ; Skin Neoplasms/surgery* ; Soft Tissue Neoplasms