Off-pump versus on-pump coronary artery bypass grafting in elderly patients at 30 days: a propensity score matching study.

BACKGROUND: Elderly patients are at increased risk of perioperative morbidity and mortality after conventional on-pump coronary artery bypass grafting (ONCABG). This study was to determine whether such high-risk population would benefit from off-pump coronary artery bypass grafting (OPCABG). METHODS: A retrospective analysis was performed on patients aged 65 years or older who underwent isolated coronary artery bypass grafting for the first time in Wuhan Union Hospital from January 2015 to January 2021. We used propensity score matching to adjust for differences in baseline characteristics between the ONCABG and OPCABG groups. Morbidity and mortality within 30 days after surgery were compared between the two groups. All operations were performed by experienced cardiac surgeons. RESULTS: A total of 511 patients (ONCABG 202, OPCABG 309) were included. After 1:1 matching, the baseline characteristics of the two groups were comparable (ONCABG 173, OPCABG 173). The OPCABG group had higher rate of incomplete revascularization (13.9% vs. 6.9%; P = .035) than the ONCABG group. However, OPCABG reduced the risk of postoperative renal insufficiency (15.0% vs. 30.1%; P = .001) and reoperation for bleeding (0.0% vs. 3.5%; P = .030). There were no significant differences in early postoperative mortality, myocardial infarction, stroke, and other outcomes between the two groups. CONCLUSIONS: OPCABG is an alternative revascularization method for elderly patients. It reduces the risk of early postoperative renal insufficiency and reoperation for bleeding.

Characteristics of older-patient-specif ic oncological trials: a cross-sectional analysis of ClinicalTrials.gov.

BACKGROUND: clinical trials dedicated to the older patients with cancer are essential to help to define optimal cancer therapy for this rapidly growing population. Our study aimed to analyse the characteristics and the evolution of older-patient-specific oncological trials registered in ClinicalTrials.gov. METHODS: a dataset of 61,120 oncological trials registered in ClinicalTrials.gov between 2000 and 2019 was downloaded. Characteristics of older-patient-specific trials were compared with characteristics of age-unspecified trials. Chronological shifts in older-patient-specific trials were also analysed. RESULTS: of the 49,273 interventional trials eligible for analysis, only 490 (1.0%) were older-patient-specific. More than half of the older-patient-specific trials were phase 2 and enrolled less than 100 patients. Compared with age-unspecified trials, older-patient-specific trials were less likely to be funded by industry (26.9 vs 37.1%), and more likely to be conducted in Europe (44.5 vs 28.3%). During the two time periods between 2000 and 2009, and 2010 and 2019, the proportion of supportive care-oriented trials increased from 1.9 to 13.9%. Concerningly, the use of clinically meaningful end points in older patients such as disease-specific survival, patient-reported outcomes and functional status as a primary end point was uncommon (0.4, 8.1 and 7.3%, respectively). There was no correlation between the number of trials for a given cancer type and relative incidence and mortality. 196/490 (40.0%) of the trials were conducted for patients with haematological cancer. CONCLUSION: our study helps us to better understand the current state of older-patient-specific oncological trials and provide insights for future development, resulting in the improvement of the care of older patients with cancer.

LINC00313 alleviates osteoarthritis progression in mice through promoting TRAF1 promoter methylation and inhibiting the ASK1/JNK signaling pathway.

OBJECTIVES: This study aimed to explore the underlying role and mechanism of LINC00313 in osteoarthritis (OA) progression. METHODS: CHON-001 chondrocytes were treated with interleukin (IL)-1ß to induce OA in vitro, and then transfected with LINC00313 overexpression plasmids (pcDNA-LINC00313) or small interfering RNA against tumor necrosis factor (TNF) receptor-associated factor 1 (si-TRAF1). Cell viability, apoptosis, levels of inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-6 and IL-8, and expression of extracellular matrix (ECM) degradation related proteins in CHON-001 cells were determined. TRAF1 promoter methylation were was detected with methylation-specific polymerase chain reaction (MSP) assay. Furthermore, a c-Jun N-terminal kinase (JNK) signaling activator was used to confirm whether the apoptosis signal-regulating kinase 1 (ASK1)/JNK signaling pathway was involved in the function of LINC00313/TRAF1 axis in chondrocytes. In addition, an OA mouse model was established and lentivirus LINC00313 overexpression vector (Lv-LINC00313) was injected, and then inflammatory cytokine levels, ECM protein expression, and pathological changes in cartilage tissues were detected. RESULTS: LINC00313 was downregulated and TRAF1 was upregulated in OA cartilage tissues. LINC00313 overexpression or TRAF1 silencing attenuated IL-1ß-induced viability inhibition, apoptosis, inflammation and ECM degradation in CHON-001 cells. Moreover, LINC00313 inhibited TRAF1 expression through promoting DNA methyltransferase 1 (DNMT1) mediated promoter methylation. TRAF1 overexpression reversed the effects of LINC00313 on IL-1ß-induced chondrocyte injury. LINC00313 overexpression inhibited the ASK1/JNK signaling pathway, and JNK activator reversed the effect. In addition, Lv-LINC00313 treatment alleviated cartilage tissue damage and cartilage matrix degradation in OA mice. CONCLUSIONS: LINC00313 alleviated OA progression through inhibiting TRAF1 expression and the ASK1/JNK signaling pathway.

Genome-wide identification and characterization of long non-coding RNAs conferring resistance to Colletotrichum gloeosporioides in walnut (Juglans regia).

BACKGROUND: Walnut anthracnose caused by Colletotrichum gloeosporioides (Penz.) Penz. and Sacc. is an important walnut production problem in China. Although the long non-coding RNAs (lncRNAs) are important for plant disease resistance, the molecular mechanisms underlying resistance to C. gloeosporioides in walnut remain poorly understood. RESULTS: The anthracnose-resistant F26 fruits from the B26 clone and the anthracnose-susceptible F423 fruits from the 4-23 clone of walnut were used as the test materials. Specifically, we performed a comparative transcriptome analysis of F26 and F423 fruit bracts to identify differentially expressed LncRNAs (DELs) at five time-points (tissues at 0 hpi, pathological tissues at 24 hpi, 48 hpi, 72 hpi, and distal uninoculated tissues at 120 hpi). Compared with F423, a total of 14,525 DELs were identified, including 10,645 upregulated lncRNAs and 3846 downregulated lncRNAs in F26. The number of upregulated lncRNAs in F26 compared to in F423 was significantly higher at the early stages of C. gloeosporioides infection. A total of 5 modules related to disease resistance were screened by WGCNA and the target genes of lncRNAs were obtained. Bioinformatic analysis showed that the target genes of upregulated lncRNAs were enriched in immune-related processes during the infection of C. gloeosporioides, such as activation of innate immune response, defense response to bacterium, incompatible interaction and immune system process, and enriched in plant hormone signal transduction, phenylpropanoid biosynthesis and other pathways. And 124 known target genes for 96 hub lncRNAs were predicted, including 10 known resistance genes. The expression of 5 lncRNAs and 5 target genes was confirmed by qPCR, which was consistent with the RNA-seq data. CONCLUSIONS: The results of this study provide the basis for future functional characterizations of lncRNAs regarding the C. gloeosporioides resistance of walnut fruit bracts.

Interleukin-35 in immune-related diseases: protection or destruction.

Interleukin-35 (IL-35) is a recently identified heterodimeric cytokine in the IL-12 family. It consists of an IL-12 subunit α chain (P35) and IL-27 subunit Epstein-Barr virus-induced gene 3 (EBI3) ß chain. Unlike the other IL-12 family members, it signals through four unconventional receptors: IL-12Rß2-IL-27Rα, IL-12Rß2-IL-12Rß2, IL-12Rß2-GP130, and GP130-GP130. Interleukin-35 signaling is mainly carried out through the signal transducer and activator of transcription family of proteins. It is secreted not only by regulatory T (Treg) cells, but also by CD8+ Treg cells, activated dendritic cells and regulatory B cells. It exhibits immunosuppressive functions distinct from those of other members of the IL-12 family; these are mediated primarily by the inhibition of T helper type 17 cell differentiation and promotion of Treg cell proliferation. Interleukin-35 plays a critical role in several immune-associated diseases, such as autoimmune diseases and viral and bacterial infections, as well as in tumors. In this review, we summarize the structure and function of IL-35, describe its role in immune-related disorders, and discuss the mechanisms by which it regulates the development and progression of diseases, including inflammatory bowel disease, collagen-induced arthritis, allergic airway disease, hepatitis, and tumors. The recent research on IL-35, combined with improved techniques of studying receptors and signal transduction pathways, allows for consideration of IL-35 as a novel immunotherapy target.

A potent aminonaphthalimide platinum(IV) complex with effective antitumor activities in vitro and in vivo displaying dual DNA damage effects on tumor cells.

A new aminonaphthalimide platinum(IV) complex was developed by incorporating aminonaphthalimide, a DNA intercalator, into the platinum(IV) system. This complex displayed potent antitumor activities against all tested tumor cell lines in vitro and showed great potential in overcoming drug resistance of cisplatin. Moreover, it remarkably inhibited the growth of CT26 xenografts in BALB/c mice without severe side effects in vivo. Then, the compound exhibited a dual DNA damage antitumor mechanism that it could interact with DNA in tetravalent form via the naphthalimide group to cause DNA lesion, and the further liberation of platinum(II) complex after reduction would induce remarkable secondary damage to DNA. Meanwhile, it caused cell apoptosis through an intrinsic apoptosis pathway by up-regulating the expression of caspase 3 and caspase 9.

Synthesis and evaluation of bi-functional 7-hydroxycoumarin platinum(IV) complexes as antitumor agents.

A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.

Hyperbaric oxygen treatment of spinal cord injury in rat model.

BACKGROUND: The purpose of this study was to investigate the therapeutic effects and mechanisms of hyperbaric oxygen (HBO) treatment on rats following spinal cord injury (SCI). METHODS: A total of 45 Sprague-Dawley (SD) rats were randomly divided into three groups. Sham-SCI group was surgically exposed but not subjected to the SCI procedure. SCI-control group was administered SCI and treated with regular air. SCI-HBO group was administered SCI and HBO treatment. Neuromotor functions were examined using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and the inclined plane assessment at before SCI (baseline) and after SCI. Superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels were measured. RESULTS: Starting from Day 1 after SCI but except Day 2, the SCI-HBO group has significantly higher BBB scores than the SCI-control group. After SCI, the maximum inclination angles at which rats could maintain were significantly lower in both SCI groups. But the maximum angles were significantly bigger for the rats in the SCI-HBO group than those on the SCI-control group at 5, 10 and 20 days after SCI. SOD activities in SCI-HBO rats were significantly higher and MDA levels were significantly lower than in SCI-control rats, at two and five days after SCI. There was also less cystic degeneration of spinal cord in SCI-HBO rats, compared to SCI-control rats. CONCLUSIONS: These results suggest that HBO treatment has a therapeutic value in treating SCI. Increased oxygen free radical scavenging and reduced lipid oxidation may be one of the mechanisms.

A High MCT-Based Ketogenic Diet Suppresses Th1 and Th17 Responses to Ameliorate Experimental Autoimmune Encephalomyelitis in Mice by Inhibiting GSDMD and JAK2-STAT3/4 Pathways.

SCOPE: Inflammation and pyroptosis play important roles in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we evaluated the therapeutic potential of ketogenic diet (KD) in EAE. METHODS AND RESULTS: The administration of KD reduces demyelination and microglial activation in the spinal cord of EAE mice. Meanwhile, KD decreases the levels of Th1 and Th17 associated cytokines/transcription factors production (T-bet, IFN-γ, RORγt, and IL-17) and increases those of Th2 and Treg cytokines/transcription factors (GATA3, IL-4, Foxp3, and IL-10) in the spinal cord and spleen. Corresponding, KD reduces the expression of chemokines in EAE, which those chemokines associate with T-cell infiltration into central nervous system (CNS). In addition, KD inhibits the GSDMD activation in microglia, oligodendrocyte, CD31+ cells, CCR2+ cells, and T cells in the spinal cord. Moreover, KD significantly decreases the ratios of p-JAK2/JAK2, p-STAT3/STAT3, and p-STAT4/STAT4, as well as GSDMD in EAE mice. CONCLUSIONS: this study demonstrates that KD reduces the activation and differentiation of T cells in the spinal cord and spleen and prevents T cell infiltration into CNS of EAE via modulating the GSDMD and STAT3/4 pathways, suggesting that KD is a potentially effective strategy in the treatment of MS.

Ursodeoxycholic Acid Platinum(IV) Conjugates as Antiproliferative and Antimetastatic Agents: Remodel the Tumor Microenvironment through Suppressing JAK2/STAT3 Signaling.

Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to the failure of tumor therapy. Here, a series of ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling the TME through suppressing JAK2/STAT3 signaling was developed. A candidate was screened out, which displayed potent antiproliferative and antimetastatic performance both in vitro and in vivo. It displayed superior pharmacokinetic properties compared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated apoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The JAK2/STAT3 and TGF-ß1 signaling pathways were remarkably inhibited, and pro-death autophagy was subsequently promoted. The inflammatory and hypoxic TME was suppressed by downregulating COX-2, MMP9, and HIF-1α, which resulted in inhibited angiogenesis in tumors by inhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive TME was reversed by blocking the immune checkpoint PD-L1, further improving the density of CD3+ and CD8+ tumor-infiltrating lymphocytes, and promoting macrophage polarization from M2- to M1-type.

Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial-Mesenchymal Transition and Arousing Immune Response.

Metastasis is the major obstacle to the survival of cancer patients. Herein, a series of new desloratadine platinum(IV) conjugates with promising antiproliferative and antimetastatic activities were developed and evaluated. The candidate complex caused significant DNA damage and stimulated mitochondrial apoptosis through the Bcl-2/Bax/caspase3 pathway. Then, it suppressed the epithelial-mesenchymal transition (EMT) process in tumors effectively through NMT-1/HPCAL1 and ß-catenin signaling. Subsequently, the angiogenesis was inhibited with the downregulation of key proteins HIF-1α, VEGFA, MMP-9, and CD34. Moreover, the antitumor immunity was effectively aroused by the synergism of EMT reversion and decrease of the histamine level; then, the macrophage polarization from M2- to M1-type and the increase of CD4+ and CD8+ T cells were triggered simultaneously in tumors.

Multi-spectroscopic and molecular docking studies for the pH-dependent interaction of ß-lactoglobulin with (-)-epicatechin gallate and/or piceatannol: Influence on antioxidant activity and stability.

(-)-Epicatechin gallate (ECG) and piceatannol (PIC) are commonly polyphenols with excellent biological activities. ß-Lactoglobulin (BLG) is a food-grade globule protein and its morphologies are sensitive to pH. This study used experimental and computational methods to determine the interaction of single or combined ECG and PIC with BLG at different pHs. The static quenching process was determined through fluorescence and ultraviolet-visible spectroscopy. Compared with ECG, PIC could significantly bind to BLG with higher affinity. Their binding affinity for BLG with different morphologies followed the tendency of monomer > dimer > tetramer. The negative contribution of van der Waals forces, electrostatic interactions, and hydrogen bonds to ΔHo exceeded the positive contribution of hydrophobic interactions in the spontaneous and exothermic process. The reduced binding affinity in the ternary systems demonstrated the competitive binding between ECG and PIC on BLG, and the hinder effect of ECG or PIC was enhanced with increasing pH. Molecular docking studies revealed the same binding sites of ECG and PIC on various conformations of BLG and identical driven forces as thermodynamic results. Tryptophan and tyrosine were the main participators in the BLG + ECG and BLG + PIC systems, respectively. The conformational changes in the binary and ternary systems could be ascertained through synchronous fluorescence, circular dichroism, and dynamic light scattering. Furthermore, the effects of pH and BLG encapsulation on the antioxidant capacity and stability of ECG or PIC were also implemented. ECG or PIC was the most stable in the (BLG + PIC) + ECG system at pH 6.0. This study could clarify the interaction mechanism between ECG/PIC and BLG and elucidate the pH effect on their binding information. The results will provide basic support for their usage in food processing and applications.

Transferrin-Modified Carprofen Platinum(IV) Nanoparticles as Antimetastasis Agents with Tumor Targeting, Inflammation Inhibition, Epithelial-Mesenchymal Transition Suppression, and Immune Activation Properties.

The inflammatory microenvironment is a central driver of tumor metastasis, intimately associated with the promotion of epithelial-mesenchymal transition (EMT) and immune suppression. Here, transferrin-modified carprofen platinum(IV) nanoparticles Tf-NPs@CPF2-Pt(IV) with promising antiproliferative and antimetastatic properties were developed, which activated by inhibiting inflammation, suppressing EMT, and activating immune responses besides causing DNA injury. The nanoparticles released the active ingredient CPF2-Pt(IV) in a sustained manner and offered enhanced pharmacokinetic properties compared to free CPF2-Pt(IV) in vivo. Additionally, they possessed satisfactory tumor targeting effects via the transferrin motif. Serious DNA damage was induced with the upregulation of γ-H2AX and P53, and the mitochondria-mediated apoptotic pathway Bcl-2/Bax/caspase3 was initiated. Inflammation was alleviated by inhibiting COX-2 and MMP9 and decreasing inflammatory cytokines TNF-α and IL-6. Subsequently, the EMT was reversed by inhibiting the Wnt/ß-catenin pathway. Furthermore, the antitumor immunity was provoked by blocking the immune checkpoint PD-L1 and increasing CD3+ and CD8+ T lymphocytes in tumors.

Non-covalent complexes of lutein/zeaxanthin and whey protein isolate formed at different pH levels: Binding interactions, storage stabilities, and bioaccessibilities.

Lutein (Lut) and zeaxanthin (Zx) are promising healthy food ingredients; however, the low solubilities, stabilities, and bioavailabilities limit their applications in the food and beverage industries. A protein-based complex represents an efficient protective carrier for hydrophobic ligands, and its ligand-binding properties are influenced by the formulation conditions, particularly the pH level. This study explored the effects of various pH values (2.5-9.5) on the characteristics of whey protein isolate (WPI)-Lut/Zx complexes using multiple spectroscopic techniques, including ultraviolet-visible (UV-Vis), fluorescence, and Fourier transform infrared (FTIR) spectroscopies and dynamic light scattering (DLS). UV-Vis and DLS spectra revealed that Lut/Zx were present as H-aggregates in aqueous solutions, whereas WPI occurred as nanoparticles. The produced WPI-Lut/Zx complexes exhibited binding constants of 104-105 M-1, which gradually increased with increasing pH from 2.5 to 9.5. FTIR spectra demonstrated that pH variations and Lut/Zx addition caused detectable changes in the secondary WPI structure. Moreover, the WPI-Lut/Zx complexes effectively improved the physicochemical stabilities and antioxidant activities of Lut/Zx aggregates during long-term storage and achieved bioaccessibilities above 70% in a simulated gastrointestinal digestion process. The comprehensive data obtained in this study offer a basis for formulating strategies that can be potentially used in developing commercially available WPI complex-based xanthophyll-rich foods.

Decreased formulation pH and protein preheating treatment enhance the interaction, storage stability, and bioaccessibility of caseinate-bound lutein/zeaxanthin.

Heat treatment and pH are crucial factors in the formulation and processing of food and beverages; thus, a thorough understanding of the impact of these factors on the interactions between bioactive constituents and proteins is essential to developing effective protein-based delivery systems. This study explores the influences of pH (ranged from 1.5 to 7.5) and preheating treatment on the characteristics of caseinates-lutein (LU)/zeaxanthin (ZX) complexes and evaluates the potential application of caseinates as protective carriers in xanthophyll-fortified beverages. The properties and interactions of caseinates and two xanthophylls were systematically investigated utilizing a range of spectroscopic techniques, including ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), fluorescence spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. Caseinates were bound to LU/ZX with a binding constant of the order 105 M-1. Furthermore, ZX exhibited a higher affinity for caseinates than LU. In particular, the decreased pH level of complex formulation and the preheating of caseinates at 85 °C strengthened the binding affinity between LU/ZX and caseinates. The caseinate-LU/ZX complexes effectively improved the chemical stability of LU/ZX and achieved a bioaccessibility rate of over 70 %. This study provides a guide for developing commercially available xanthophyll-fortified beverages and further expanding the application of caseinates as encapsulation carriers for extremely hydrophobic nutrients in the food industry.

Canadine Platinum(IV) Complexes Targeting Epithelial-Mesenchymal Transition as Antiproliferative and Antimetastatic Agents.

Epithelial-mesenchymal transition (EMT) is a critical process for cancer progression, which is crucial in inhibiting the immunity in tumors and further boosting tumor metastasis. The suppression of EMT represents a promising strategy for inhibiting metastatic tumors. Herein, a series of new canadine platinum(IV) conjugates with potent antiproliferative and antimetastatic activities were developed, which activated by suppressing EMT and provoking immune response in tumors besides causing DNA injury. The complexes could covalently conjugate to DNA and induce mitochondria-mediated apoptosis via Bcl-2/Bax/caspase3 signaling. The EMT process was remarkably inhibited by suppressing the Wnt/ß-catenin pathway, reversing the inflammatory tumor microenvironment, and inhibiting the HIF-1α pathway, which further resulted in the inhibited angiogenesis in tumors. Moreover, the antitumor immunity was elevated by blocking immune checkpoints PD-L1 and CD47 accompanied by the improvement of CD3+ and CD8+ T lymphocytes and the macrophage polarization from M2- toward M1-type simultaneously in tumors.

A hydroxychloroquine platinum(IV) conjugate displaying potent antimetastatic activities by suppressing autophagy to improve the tumor microenvironment.

Protective autophagy is a promising target for antitumor drug exploration. A hydroxychloroquine (HCQ) platinum(IV) complex with autophagy suppressing potency was developed, which displayed potent antitumor activities with a TGI rate of 44.2% against 4T1 tumors in vivo and exhibited a rather lower toxicity than cisplatin. Notably, it exhibited satisfactory antimetastatic activities toward lung pulmonary metastasis models with an inhibition rate of 49.6% and was obviously more potent than CDDP, which has an inhibition rate of 21.6%. Mechanism detection revealed that it caused serious DNA damage and upregulated the expression of γ-H2AX and p53. More importantly, the incorporation of an autophagy inhibitor HCQ endowed the platinum(IV) complex with potent autophagy impairing properties by perturbing the lysosomal function in tumor cells, which promoted apoptosis synergistically with DNA injury. Then, the impaired autophagy further led to the suppression of hypoxia and inflammation in the tumor microenvironment by downregulating ERK1/2, HIF-1α, iNOS, caspase1 and COX-2. Adaptive immune response was improved by inhibiting the immune checkpoint PD-L1 and further increasing CD4+ and CD8+ T cells in tumors. Then, tumor metastasis was effectively inhibited by restraining angiogenesis through inhibiting VEGFA, MMP-9, and CD34.

Ciclopirox platinum(IV) conjugates suppress tumors by promoting mitophagy and provoking immune responses.

Mitophagy is an important target for antitumor drugs development. A series of ciclopirox (CPX) platinum(IV) hybrids targeting PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitophagy were designed and prepared as antitumor agents. The dual CPX platinum(IV) complex with cisplatin core was screened out as a candidate, which displayed promising antitumor activities both in vitro and in vivo. Mechanistically, it caused serious DNA damage in tumor cells. Then, remarkable mitochondrial damage was induced accompanied by the mitochondrial membrane depolarization and reactive oxygen species generation, which further promoted apoptosis through the Bcl-2/Bax/Caspase3 pathway. Furthermore, mitophagy was ignited via the PINK1/Parkin/P62/LC3 axis, and exhibited positive influence on promoting the apoptosis of tumor cells. The antitumor immunity was boosted by the block of immune check point programmed cell death ligand-1 (PD-L1), which further increased the density of T cells in tumors. Subsequently, the metastasis of tumor cells was inhibited by inhibiting angiogenesis in tumors.

Ketogenic diet attenuates neuroinflammation and induces conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-κB/NLRP3 pathway and inhibiting HDAC3 and P2X7R activation.

Multiple sclerosis (MS) is an autoimmune disorder characterized by demyelination and neurodegeneration in the central nervous system (CNS); severe symptoms lead MS patients to use complementary treatments. Ketogenic diet (KD) shows wide neuroprotective effects, but the precise mechanisms underlying the therapeutic activity of KD in MS are unclear. The present study established a continuous 24 days experimental autoimmune encephalomyelitis (EAE) mouse model with or without KD. The changes in motor function, pathological hallmarks of EAE, the status of microglia, neuroinflammatory response and intracellular signaling pathways in mice were detected by the rotarod test, histological analysis, real-time PCR (RT-PCR) and western blotting. Our results showed that KD could prevent motor deficiency, reduce clinical scores, inhibit demyelination, improve pathological lesions and suppress microglial activation in the spinal cord of EAE mice. Meanwhile, KD shifted microglial polarization toward the protective M2 phenotype and modified the inflammatory milieu by downregulating the production of pro-inflammatory cytokines, including TNF-α, IL-1ß and IL-6, as well as upregulating the release of anti-inflammatory cytokines such as TGF-ß. Furthermore, KD decreased the expression levels of CCL2, CCR2, CCL3, CCR1, CCR5, CXCL10 and CXCR3 in the spinal cord and spleen with reduced monocyte/macrophage infiltration in the CNS. In addition, KD inhibits NLRP3 activation in the microglia, as revealed by the significantly decreased co-expression of NLRP3+ and Iba-1+ in the KD + EAE group. Further studies demonstrated that KD suppresses inflammatory response and M1 microglial polarization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway, the JAK1/STAT1 pathway, HDAC3 and P2X7R activation, as well as up-regulation of JAK3/STAT6.

A series of ligustrazine platinum(IV) complexes with potent anti-proliferative and anti-metastatic properties that exert chemotherapeutic and immunotherapeutic effects.

The development of novel anticancer drugs with antiproliferative and antimetastatic activities is of great importance in the pharmaceutical field. Herein, a series of ligustrazine (LSZ) platinum(IV) complexes with chemotherapeutic and immunotherapeutic effects were designed, prepared and evaluated as antitumor agents for the first time. Complex 4 with potent antitumor activities both in vitro and in vivo was screened out as a candidate. Notably, it displays significantly more effective anti-metastatic activities than the platinum(II) drugs cisplatin and oxaliplatin. Mechanism detection discloses that it causes serious DNA damage and increases the expression of γ-H2AX and P53. Then, the apoptosis of tumor cells is promoted by activating the mitochondrial apoptotic pathway Bcl-2/Bax/caspase-3 and causing autophagy via modulating LC3-I/II and P62 expression. Furthermore, the immune therapeutic responses are significantly elevated by blocking HIF-1α, ERK 1/2 and COX-2 pathways to reduce PD-L1 expression, and further increasing CD3+ and CD8+ T cells to elevate T cell immunity in tumors. Tumor metastasis is blocked by the synergistic functions of DNA damage, hypoxia modulation and immune activation.