Latest Issue
Issue 2 ， 2023
-
Multiple characteristic alterations and available therapeutic strategies of cellular senescence Cover Article
Abstract：Given its state of stable proliferative inhibition, cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis. Cells undergoing senescence are often associated with the alteration of a series of specific features and functions, such as metabolic shifts, stemness induction, and microenvironment remodeling. However, recent research has revealed more complexity associated with senescence, including adverse effects on both physiological and pathological processes. How organisms evade these harmful consequences and survive has become an urgent research issue. Several therapeutic strategies targeting senescence, including senolytics, senomorphics, immunotherapy, and function restoration, have achieved initial success in certain scenarios. In this review, we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.Keywords：Senescence;Metabolism;Stemness;Microenvironment;Senolytic;Immune surveillance- 45
- |
- 1
- |
- 0
Published：2023-02-09 -
Novel perspective in transplantation therapy of mesenchymal stem cells: targeting the ferroptosis pathway
Abstract：Ex vivo culture-amplified mesenchymal stem cells (MSCs) have been studied because of their capacity for healing tissue injury. MSC transplantation is a valid approach for promoting the repair of damaged tissues and replacement of lost cells or to safeguard surviving cells, but currently the efficiency of MSC transplantation is constrained by the extensive loss of MSCs during the short post-transplantation period. Hence, strategies to increase the efficacy of MSC treatment are urgently needed. Iron overload, reactive oxygen species deposition, and decreased antioxidant capacity suppress the proliferation and regeneration of MSCs, thereby hastening cell death. Notably, oxidative stress (OS) and deficient antioxidant defense induced by iron overload can result in ferroptosis. Ferroptosis may inhibit cell survival after MSC transplantation, thereby reducing clinical efficacy. In this review, we explore the role of ferroptosis in MSC performance. Given that little research has focused on ferroptosis in transplanted MSCs, further study is urgently needed to enhance the in vivo implantation, function, and duration of MSCs.Keywords：Mesenchymal stem cells (MSCs);Ferroptosis;Oxidative stress (OS);Iron metabolism;Lipid peroxidation;Glutathione peroxidase 4 (GPX4)- 53
- |
- 1
- |
- 0
Published：2023-02-09
Review
-
Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B, endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society
Abstract：Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.Keywords：Polymyxin B;Therapeutic drug monitoring (TDM);Pharmacokinetics;Clinical efficacy- 114
- |
- 12
- |
- 0
Published：2023-02-09
Guideline
-
USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancerAbstract：This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‒1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‒2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48‒1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‒1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A (USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‒0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‒0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‒8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‒6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12C mutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.Keywords：Immune checkpoint inhibitor (ICI);Lung cancer;Usher syndrome type-2A (USH2A) missense mutation;Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation;Epidermal growth factor receptor (EGFR) mutation- 92
- |
- 1
- |
- 0
Published：2023-02-09 -
Lycium barbarum polysaccharides ameliorate canine acute liver injury by reducing oxidative stress, protecting mitochondrial function, and regulating metabolic pathwaysAbstract：The development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lycium barbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl4). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl4 solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl4-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes I‒V. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.Keywords：Acute liver injury;Oxidative stress;Mitochondrial dysfunction;Metabolomics;Lycium barbarum polysaccharides- 83
- |
- 6
- |
- 0
Published：2023-02-09 -
AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerizationAbstract：Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.T260A, p.R422W, and p.R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%‒49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‒17.9%, which was significantly higher than that (6.9%‒7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.Keywords：Auditory neuropathy spectrum disorder;Apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants;Dimerization;Caspase-independent apoptosis;Nicotinamide adenine dinucleotide (NADH) treatment- 89
- |
- 5
- |
- 0
Published：2023-02-09
Research Article
Loading...
0