Objective:To evaluate the efficacy and safety of mild hypothermia for patients with severe traumatic brain injury (sTBI).Methods:PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Disc, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and VIP Database were searched for prospective randomized controlled researches on mild hypothermia and normothermia for patients with sTBI. The search time was from the establishment of the databases to February 2023. RevMan 5.3 software was used for Meta-analysis. The evaluation indicators included literature search results, basic characteristics and quality of the literature, poor prognosis rate and mortality at 6 and 12 months after treatment, incidence of pulmonary infection, arrhythmia, thrombocytopenia, intracranial infection, renal insufficiency, gastrointestinal ulcer/bleeding and electrolyte disorder during the treatment, and publication bias.Results:A total of 16 papers involving 2 640 patients were included, comprising 1 381 patients in the mild hypothermia group and 1 259 patients in the normothermia group. The poor prognosis rate in the mild hypothermia group was significantly lower than that in the normothermia group at 6 and 12 months after treatment ( RR=0.81, 95% CI 0.69, 0.95, P<0.01; RR=0.65, 95% CI 0.51, 0.84, P<0.01). There was no significant difference in the mortality between the two groups at 6 and 12 months after treatment ( RR=0.81, 95% CI 0.61, 1.08, P>0.05; RR=0.69, 95% CI 0.47, 1.03, P>0.05). In contrast with the the normothermia group, in the mild hypothermia group the incidence of pulmonary infection was significantly different ( RR=1.18, 95% CI 1.04, 1.34, P<0.01); the incidence of arrhythmia was not significantly different ( RR=1.35, 95% CI 0.73, 2.49, P>0.05); the incidence of thrombocytopenia was significantly different ( RR=1.78, 95% CI 1.34, 2.37, P<0.01); the incidence of intracranial infection was not significantly different ( RR=1.32, 95% CI 0.54, 3.23, P>0.05); the incidence of renal insufficiency was not significantly different ( RR=1.22, 95% CI 0.71, 2.09, P>0.05); the incidence of gastrointestinal ulcer/bleeding was not significantly different ( RR=0.98, 95% CI 0.73, 1.31, P>0.05); the incidence of electrolyte disorders was not significantly different ( RR=1.39, 95% CI 1.00, 1.94, P>0.05). The funnel plot was approximately symmetrical and the scattered points were concentrated in the narrow area in the upper part of the funnel plot, suggesting no publication bias. Conclusions:In comparison with normothermia for sTBI, mild hypothermia can not reduce the mortality at 6 and 12 months after treatment, but it can reduce the incidence of poor prognosis at 6 and 12 months after treatment. Moreover, mild hypothermia has no obvious effect on the incidence of arrhythmia, intracranial infection, renal insufficiency, gastrointestinal ulcer/bleeding, and electrolyte disorder, but it can increase the incidence of pulmonary infection and thrombocytopenia.

DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.

Alkaloids are a class of naturally occurring bioactive compounds that are widely distributed in various food sources and Traditional Chinese Medicine. This study aimed to investigate the therapeutic effects and underlying mechanisms of alkaloid extract from Codonopsis Radix (ACR) in ameliorating hepatic lipid accumulation in a mouse model of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD). The results revealed that ACR treatment effectively mitigated the abnormal weight gain and hepatic injury associated with HFD. Furthermore, ACR ameliorated the dysregulated lipid metabolism in NAFLD mice, as evidenced by reductions in serum triglyceride, total cholesterol, and low-density lipoprotein levels, accompanied by a concomitant increase in the high-density lipoprotein level. ACR treatment also demonstrated a profound anti-oxidative effect, effectively alleviating HFD-induced oxidative stress and promoting ATP production. These effects were achieved through the up-regulation of the activities of mitochondrial electron transfer chain complexes I, II, IV, and V, in addition to the activation of the AMPK/PGC-1α pathway, suggesting that ACR exhibits therapeutic potential in alleviating the HFD-induced dysregulation of mitochondrial energy metabolism. Moreover, ACR administration mitigated HFD-induced endoplasmic reticulum (ER) stress and suppressed the overexpression of ubiquitin-specific protease 14 (USP14) in NAFLD mice. In summary, the present study provides compelling evidence supporting the hepatoprotective role of ACR in alleviating lipid deposition in NAFLD by improving energy metabolism and reducing oxidative stress and ER stress. These findings warrant further investigation and merit the development of ACR as a potential therapeutic agent for NAFLD.
Mice ; Animals ; Non-alcoholic Fatty Liver Disease/metabolism* ; Codonopsis ; Liver ; Lipid Metabolism ; Antineoplastic Agents/pharmacology* ; Alkaloids/pharmacology* ; Endoplasmic Reticulum Stress ; Energy Metabolism ; Lipids ; Diet, High-Fat/adverse effects* ; Mice, Inbred C57BL

Chang-Kang-Fang (CKF) formula, a Traditional Chinese Medicine (TCM) prescription, has been widely used for the treatment of irritable bowel syndrome (IBS). However, its potential material basis and underlying mechanism remain elusive. Therefore, this study employed an integrated approach that combined ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) with network pharmacology to systematically characterize the phytochemical components and metabolites of CKF, as well as elucidating its underlying mechanism. Through this comprehensive analysis, a total of 150 components were identified or tentatively characterized within the CKF formula. Notably, six N-acetyldopamine oligomers from CicadaePeriostracum and eight resin glycosides from Cuscutae Semen were characterized in this formula for the first time. Meanwhile, 149 xenobiotics (58 prototypes and 91 metabolites) were detected in plasma, urine, feces, brain, and intestinal contents, and the in vivo metabolic pathways of resin glycosides were elaborated for the first time. Furthermore, network pharmacology and molecular docking analyses revealed that alkaloids, flavonoids, chromones, monoterpenes, N-acetyldopamine dimers, p-hydroxycinnamic acid, and Cus-3/isomer might be responsible for the beneficial effects of CKF in treating IBS, and CASP8, MARK14, PIK3C, PIK3R1, TLR4, and TNF may be its potential targets. These discoveries offer a comprehensive understanding of the potential material basis and clarify the underlying mechanism of the CKF formula in treating IBS, facilitating the broader application of CKF in the field of medicine.
Humans ; Tandem Mass Spectrometry/methods* ; Irritable Bowel Syndrome/drug therapy* ; Molecular Docking Simulation ; Drugs, Chinese Herbal/chemistry* ; Glycosides ; Chromatography, High Pressure Liquid/methods*