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The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity.The objective of this study was to determine whether Paeonol (Pae) has the ability to protect against Dox-induced cardiotoxicity and if so, what are the underlying mechanisms involved.Sprague-Dawley rats and primary cardiomyocytes were used to create Dox-induced cardiotoxicity models. Pae's effects on myocardial damage, mitochondrial function, mitochondrial dynamics and signaling pathways were studied using a range of experimental methods.Pae enhanced Mfn2-mediated mitochondrial fusion, restored mitochondrial function and cardiac performance both in vivo and in vitro under the Dox conditions. The protective properties of Pae were blunted when Mfn2 was knocked down or knocked out in Dox-induced cardiomyocytes and hearts respectively. Mechanistically, Pae promoted Mfn2-mediated mitochondria fusion by activating the transcription factor Stat3, which bound to the Mfn2 promoter in a direct manner and up-regulated its transcriptional expression. Furthermore, molecular docking, surface plasmon resonance and co-immunoprecipitation studies showed that Pae's direct target was PKCε, which interacted with Stat3 and enabled its phosphorylation and activation. Pae-induced Stat3 phosphorylation and Mfn2-mediated mitochondrial fusion were inhibited when PKCε was knocked down. Furthermore, Pae did not interfere with Dox's antitumor efficacy in several tumor cells.Pae protects the heart against Dox-induced damage by stimulating mitochondrial fusion via the PKCε-Stat3-Mfn2 pathway, indicating that Pae might be a promising therapeutic therapy for Dox-induced cardiotoxicity while maintaining Dox's anticancer activity.

Platinum-based chemotherapy (PBC) remains the mainstay of treatments for triple-negative breast cancer (TNBC). TNBC is a heterogeneous group, the issue of whether BRCA1/2 mutation carriers have a particular sensitivity to platinum agents is inconclusive. We conducted a meta-analysis to explore the relationship between BRCA1/2 mutation and PBC susceptibility in individuals with TNBC, aiming to gain more information on the size of the benefit of PBC in BRCA1/2 mutation carriers.All studies applying PBC with a subgroup of BRCA1/2 status were included. All endpoints, including pCR and RCB in the neoadjuvant phase, DFS in the adjuvant phase, ORR, PFS, and OS in the advanced phase, were assessed using HRs and 95% Cl.From the 22 studies included, there were 2158 patients with TNBC, with 392 (18%) bearing the BRCA1/2 gene mutation. Based on 13 studies applying neoadjuvant PBC, we discovered that BRCA1/2 mutation was substantially associated with a 17.6% increased pCR rate (HR 1.32, 95% CI 1.17-1.49, p 0.00001; IAccording to our meta-analysis of 22 trials in TNBC, BRCA1/2 mutation carriers were significantly more sensitive to PBC regimens, especially in neoadjuvant and advanced therapy.

As an essential micronutrient element in organisms, copper controls a host of fundamental cellular functions. Recently, copper-dependent cell growth and proliferation have been defined as "cuproplasia". Conversely, "cuproptosis" represents copper-dependent cell death, in a nonapoptotic manner. So far, a series of copper ionophores have been developed to kill cancer cells. However, the biological response mechanism of copper uptake has not been systematically analyzed. Based on quantitative proteomics, we revealed the crosstalk between copper stress and cuproptosis in cancer cells, and also explored the feasibility of curcumin as anticancer copper ionophore. Copper stress not only couples with cuproptosis, but also leads to reactive oxygen species (ROS) stress, oxidative damage and cell cycle arrest. In cancer cells, a feedback cytoprotection mechanism involving cuproptosis mediators was discovered. During copper treatment, the activation of glutamine transporters and the loss of Fe-S cluster proteins are the facilitators and results of cuproptosis, respectively. Through copper depletion, glutathione (GSH) blocks the cuproptosis process, rescues the activation of glutamine transporters, and prevents the loss of Fe-S cluster proteins, except for protecting cancer cells from apoptosis, protein degradation and oxidative damage. In addition, the copper ionophore curcumin can control the metabolisms of lipids, RNA, NADH and NADPH in colorectal cancer cells, and also up-regulates positive cuproptosis mediators. This work not only established the crosstalk between copper stress and cuproptosis, but also discolored the suppression and acceleration of cuproptosis by GSH and curcumin, respectively. Our results are significant for understanding cuproptosis process and developing novel anticancer reagents based on cuproptosis.

To describe the perioperative clinical features, management, and outcomes of patients with seizure after percutaneous endoscopic spine surgery (PESS).Patients who experienced seizure after PESS in a tertiary orthopedic hospital between January 2016 and June 2022 were retrospectively recruited, and patient charts were reviewed.Twenty-nine patients were recruited, and the incidence of seizure after PESS was 0.52%. The operation time was 110.0 minutes (interquartile range [IQR], 82.5-235.0 minutes) and the irrigation speed was 109.0 mL/minute (IQR, 86.5-145.5 mL/minute). Definitive dural tears were reported in 15 patients (51.7%). In addition to agitation and myotonia, significant increased respiratory rate (29.9 ± 6.5 breaths/minute), tachycardia (112.1 ± 20.6 beats/minute), and hypertension (systolic, 189.5 ± 21.9 mm Hg; diastolic, 98.3 ± 10.6 mm Hg) were observed. Arterial blood gas analysis showed hypocapnia, metabolic acidosis, and hyperlactatemia. All patients received analgesia and sedation as well as hyperosmolar therapy. The estimated duration of seizure was 3.0 hours (IQR, 2.5-4.0 hours) and the postoperative length of hospital stay was 3.0 (IQR, 3.0-5.5) days. The Japanese Orthopaedic Association score and visual analog scale score improved markedly within 6 months after surgery.Despite the low incidence and short duration, seizure after PESS should be considered a critical and urgent syndrome. Management strategies for seizure mainly involve intensive care, securing the airway, analgesia and sedation, hyperosmolar therapy, and negative fluid balance. No significant adverse effects of seizure on clinical outcomes were observed during 6 months of follow-up.

Ischemic stroke (IS) is an acute brain injury and a major cause of disability and mortality worldwide, resulting from permanent or temporary cerebral artery occlusion. Thrombolysis and antithrombotic therapy or thrombectomy over a wider therapeutic window led to reduced stroke mortality. However, the post-stroke pathological mechanism is still elusive, involving sustaining inflammation and cellular dysfunction, which hinders the recovery after IS. Thus, more attention is shifting towards the complex interactions of the neurovascular unit (NVU) and its important role in the progress of inflammation recently. This review summarized the physiological function of each component of the NVU and their functions on blood brain barrier permeability, cerebral blood flow regulation and the inflammation progress after IS. In addition, we described the inflammation-related pathological changes affected by the NVU and concluded that the dysfunction of the NVU contributed to the inflammation progress after IS. This review may provide ideas for the potential therapies targeting the NVU for improving the prognosis of IS.

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17β-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury. There are currently no approved effective pharmacological treatments for NAFLD. Traditional Chinese medicine (TCM) has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms. More recently, TCM has been shown to have unique advantages in the treatment of NAFLD. We performed a systematic review of the medical literature published over the last two decades and found that many TCM formulas have been reported to be beneficial for the treatment of metabolic dysfunctions, including Potentilla discolor Bunge (PDB). PDB has a variety of active compounds, including flavonoids, terpenoids, organic acids, steroids and tannins. Many compounds have been shown to exhibit a series of beneficial effects for the treatment of NAFLD, including anti-oxidative and anti-inflammatory functions, improvement of lipid metabolism and reversal of insulin resistance. In this review, we summarize potential therapeutic effects of TCM formulas for the treatment of NAFLD, focusing on the medicinal properties of natural active compounds from PDB and their underlying mechanisms. We point out that PDB can be classified as a novel candidate for the treatment and prevention of NAFLD.

The complex physiological and pathological conditions form barriers against efficient drug delivery. Cell penetrating peptides (CPPs), a class of short peptides which translocate drugs across cell membranes with various mechanisms, provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers. After years of development, the function of CPPs is beyond cell penetrating. Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor, myocardial ischemia, ocular posterior segment disorders, etc. In this review, we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology, ophtalmology, mucus, neurology and cancer, etc. We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.

Five new iridoid glucosides, cannabifolisides A–E (1 – 5), together with nine analogues (6 – 14), were isolated from the leaves of Vitex negundo var. cannabifolia. Their structures were elucidated by spectroscopic data (NMR, UV, IR, and MS) analyses and comparison of their spectroscopic and physical data with the literature values. The protective effect of isolated compounds on human gastric epithelial cells were evaluated by measuring the enhanced cell viability of GES-1 cell insulted by TCA. Among these, compounds 4, 6, 8, 10, 12, and 14 remarkably increased the cell viability in a concentration-depend manner.

Excessive rainfall provides a favorable condition for field mold infection of plants, which triggers field mold (FM) stress. If FM stress occurs during the late maturation stage of soybean seed, it negatively affects seed yield and quality. To investigate the responses of soybean seed against FM stress and identify the underlying biochemical pathways involved, a greenhouse was equipped with an artificial rain producing system to allow the induction of mold growth on soybean seed. The induced quality changes and stress responses were revealed on the levels of both transcriptome and metabolome. The results showed that soybean seeds produced under FM stress conditions had an abnormal and inferior appearance, and also contained less storage reserves, such as protein and polysaccharide. Transcriptional analysis demonstrated that genes involved in amino acid metabolism, glycolysis, tricarboxylic acid, β-oxidation of fatty acids, and isoflavone biosynthesis were induced by FM stress. These results were supported by a multiple metabolic analysis which exhibited increases in the concentrations of a variety of amino acids, sugars, organic acids, and isoflavones, as well as reductions of several fatty acids. Reprogramming of these metabolic pathways mobilized and consumed stored protein, sugar and fatty acid reserves in the soybean seed in order to meet the energy and substrate demand on the defense system, but led to deterioration of seed quality. In general, FM stress induced catabolism of storage reserves and diminished the quality of soybean seed in the field. This study provides a more profound insight into seed deterioration caused by FM stress.