Organelle-Mediated Dissipative Self-Assembly of Peptides in Living Cells.

Implementing dissipative assembly in living systems is meaningful for creation of living materials or even artificial life. However, intracellular dissipative assembly remains scarce and is significantly impeded by the challenges lying in precisely operating chemical reaction cycles under complex physiological conditions. Here, we develop organelle-mediated dissipative self-assembly of peptides in living cells fueled by GSH, via the design of a mitochondrion-targeting and redox-responsive hexapeptide. While the hexapeptide undergoes efficient redox-responsive self-assembly, the addition of GSH into the peptide solution in the presence of mitochondrion-biomimetic liposomes containing hydrogen peroxide allows for transient assembly of peptides. Internalization of the peptide by LPS-stimulated macrophages leads to the self-assembly of the peptide driven by GSH reduction and the association of the peptide assemblies with mitochondria. The association facilitates reversible oxidation of the reduced peptide by mitochondrion-residing ROS and thereby dissociates the peptide from mitochondria to re-enter the cytoplasm for GSH reduction. The metastable peptide-mitochondrion complexes prevent the thermodynamically equilibrated self-assembly, thus establishing dissipative assembly of peptides in stimulated macrophages. The entire dissipative self-assembling process allows for elimination of elevated ROS and decrease of pro-inflammatory cytokine expression. Creating dissipative self-assembling systems assisted by internal structures provides new avenues for the development of living materials or medical agents in the future.

Stimulus-Responsive Amino Acids Behind In Situ Assembled Bioactive Peptide Materials.

In situ self-assembly of peptides into well-defined nanostructures represents one of versatile strategies for creation of bioactive materials within living cells with great potential in disease diagnosis and treatment. The intimate relationship between amino acid sequences and the assembling propensity of peptides has been thoroughly elucidated over the past few decades. This has inspired development of various controllable self-assembling peptide systems based on stimuli-responsive naturally occurring or non-canonical amino acids, including redox-, pH-, photo-, enzyme-responsive amino acids. This review attempts to summarize the recent progress achieved in manipulating in situ self-assembly of peptides by controllable reactions occurring to amino acids. We will highlight the systems containing non-canonical amino acids developed in our laboratory during the past few years, primarily including acid/enzyme-responsive 4-aminoproline, redox-responsive (seleno)methionine, and enzyme-responsive 2-nitroimidazolyl alanine. Utilization of the stimuli-responsive assembling systems in creation of bioactive materials will be specifically introduced to emphasize their advantages for addressing the concerns lying in disease theranostics. Eventually, we will provide the perspectives for the further development of stimulus-responsive amino acids and thereby demonstrating their great potential in development of next-generation biomaterials.

In Situ Self-Sorting Peptide Assemblies in Living Cells for Simultaneous Organelle Targeting.

Self-sorting is a common phenomenon in eukaryotic cells and represents one of the versatile strategies for the formation of advanced functional materials; however, developing artificial self-sorting assemblies within living cells remains challenging. Here, we report on the GSH-responsive in situ self-sorting peptide assemblies within cancer cells for simultaneous organelle targeting to promote combinatorial organelle dysfunction and thereby cell death. The self-sorting system was created via the design of two peptides E3C16E6 and EVMSeO derived from lipid-inspired peptide interdigitating amphiphiles and peptide bola-amphiphiles, respectively. The distinct organization patterns of the two peptides facilitate their GSH-induced self-sorting into isolated nanofibrils as a result of cleavage of disulfide-connected hydrophilic domains or reduction of selenoxide groups. The GSH-responsive in situ self-sorting in the peptide assemblies within HeLa cells was directly characterized by super-resolution structured illumination microscopy. Incorporation of the thiol and ER-targeting groups into the self-sorted assemblies endows their simultaneous targeting of endoplasmic reticulum and Golgi apparatus, thus leading to combinatorial organelle dysfunction and cell death. Our results demonstrate the establishment of the in situ self-sorting peptide assemblies within living cells, thus providing a unique platform for drug targeting delivery and an alternative strategy for modulating biological processes in the future.

Self-Amplifying Assembly of Peptides in Macrophages for Enhanced Inflammatory Treatment.

Enzyme-regulated in situ self-assembly of peptides represents one versatile strategy in the creation of theranostic agents, which, however, is limited by the strong dependence on enzyme overexpression. Herein, we reported the self-amplifying assembly of peptides precisely in macrophages associated with enzyme expression for improving the anti-inflammatory efficacy of conventional drugs. The self-amplifying assembling system was created via coassembling an enzyme-responsive peptide with its derivative functionalized with a protein ligand. Reduction of the peptides by the enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) led to the formation of nanofibers with high affinity to the protein, thereby facilitating NQO1 expression. The improved NQO1 level conversely promoted the assembly of the peptides into nanofibers, thus establishing an amplifying relationship between the peptide assembly and the NQO1 expression in macrophages. Utilization of the amplifying assembling system as vehicles for drug dexamethasone allowed for its passive targeting delivery to acute injured lungs. Both in vitro and in vivo studies confirmed the capability of the self-amplifying assembling system to enhance the anti-inflammatory efficacy of dexamethasone via simultaneous alleviation of the reactive oxygen species side effect and downregulation of proinflammatory cytokines. Our findings demonstrate the manipulation of the assembly of peptides in living cells with a regular enzyme level via a self-amplification process, thus providing a unique strategy for the creation of supramolecular theranostic agents in living cells.

Iron overload impairs renal function and is associated with vascular calcification in rat aorta.

Vascular calcification (VC) has been associated with a risk of cardiovascular diseases. Iron may play a critical role in progressive VC. Therefore, we investigated the effects of iron overload on the aorta of rats. A rat model of iron overload was established by intraperitoneal injection of Iron-Dextran. The levels of iron, calcium, and ALP activity were detected. Von Kossa staining and Perl's staining were conducted. The expression of iron metabolism-related and calcification related factors were examined in the aortic tissue of rats. The results showed serum and aortic tissue iron were increased induced by iron overload and excessive iron induced hepatic and renal damage. In iron overload rats, the expression of divalent metal transporter 1 (DMT1) and hepcidin were higher, but ferroportin1 (FPN1) was lower. Von Kossa staining demonstrated calcium deposition in the aorta of iron overload rats. The calcium content and ALP activity in serum and aortic tissue were increased and iron level in aortic tissue highly correlated with calcium content and ALP activity. The expressions of the osteogenic markers were increased while a decrease of Alpha-smooth muscle actin (α-SMA) in the aortic tissue of iron overload rats. IL-24 was increased during the calcification process induced by iron. Overall, we demonstrated excessive iron accumulation in the aortic tissue and induced organs damage. The iron metabolism-related factors were significantly changed during iron overload. Moreover, we found that iron overload leads to calcium deposition in aorta, playing a key role in the pathological process of VC by mediating osteoblast differentiation factors.

Supramolecular Antagonists Promote Mitochondrial Dysfunction.

Mitochondrion-targeting therapy exhibits great potential in cancer therapy but significantly suffers from limited therapeutic efficiency. Here we report on mitochondrion-targeting supramolecular antagonist-inducing tumor cell death via simultaneously promoting cellular apoptosis and preventing survival. The supramolecular antagonist was created via coassembly of a mitochondrion-targeting pentapeptide with its two derivatives functionalized with a BH3 domain or the drug camptothecin (CPT). While drug CPT released from the antagonist induced cellular apoptosis via decreasing the mitochondrial membrane potential, the BH3 domain prevented cellular survival through facilitating the association between the supramolecular antagonists and antiapoptotic proteins, thereby initiating mitochondrial permeabilization. Both in vitro and in vivo studies confirmed the combinatorial therapeutic effect arising from the BH3 domain and CPT drug within the supramolecular antagonist on cell death and thereby inhibiting tumor growth. Our findings demonstrate an efficient combinatorial mechanism for mitochondrial dysfunction, thus potentially serving as novel organelle-targeting medicines.

Phylogenetic identification of symbiotic protists of five Chinese Reticulitermes species indicates a cospeciation of gut microfauna with host termites.

Symbiotic protists play important roles in the wood digestion of lower termites. Previous studies showed that termites generally possess host-specific flagellate communities. The genus Reticulitermes is particularly interesting because its unique assemblage of gut flagellates bears evidence for transfaunation. The gut fauna of Reticulitermes species in Japan, Europe, and North America had been investigated, but data on species in China are scarce. For the first time, we analyzed the phylogeny of protists in the hindgut of five Reticulitermes species in China. A total of 22 protist phylotypes were affiliated with the family Trichonymphidae, Teranymphidae, Trichomonadidae, and Holomastigotoididae (Phylum Parabasalia), and 45 protist phylotypes were affiliated with the family Pyrsonymphidae (Phylum Preaxostyla). The protist fauna of these five Reticulitermes species is similar to those of Reticulitermes species in other geographical regions. The topology of Trichonymphidae subtree was similar to that of Reticulitermes tree. All Preaxostyla clones were affiliated with the genera Pyrsonympha and Dinenympha (Order Oxymonadida) as in the other Reticulitermes species. The results of this study not only add to the existing information on the flagellates present in other Reticulitermes species but also offer the opportunity to test the hypotheses for the coevolution of symbiotic protists with their host termites.

Effects and Mechanism of Noninvasive Positive-Pressure Ventilation in a Rat Model of Heart Failure Due to Myocardial Infarction.

BACKGROUND Impaired heart function induced by myocardial infarction is a leading cause of chronic heart failure (HF). This study aimed to investigate the effects and mechanism of noninvasive positive-pressure ventilation (NIPPV) in a rat model of HF due to myocardial infarction. MATERIAL AND METHODS To explore the therapeutic effect and mechanism of NIPPV on acute myocardial infarction-induced HF, we established a rat model of HF by ligating the anterior descending branch of the left coronary artery and confirmed by ultrasonic cardiography and brain natriuretic peptide 45 detection. RESULTS The levels of heat-shock protein (HSP)-70 increased and matrix metalloproteinase (MMP)-2, MMP-9, and tumor necrosis factor (TNF)-alpha decreased in the group that received NIPPV treatment compared with the control group. In addition, the histopathologic results showed less severe inflammatory infiltration and a smaller area of myocardial fibrosis in the NIPPV treatment group. CONCLUSIONS In a rat model of HF due to myocardial infarction, NIPPV resulted in increased levels of HSP70 and reduced expression of MMP2, MMP9, and TNF-alpha and reduced myocardial neutrophil infiltration and fibrosis. Taken together, we showed that NIPPV is an effective treatment for HF induced by myocardial infarction by inhibiting the release of inflammatory factors and preventing microvascular embolism.

Downregulation of miR-637 promotes vascular smooth muscle cell proliferation and migration via regulation of insulin-like growth factor-2.

BACKGROUND: Dysregulation of the proliferation and migration of vascular smooth muscle cells (VSMCs) is a crucial cause of atherosclerosis. MiR-637 exerts an antiproliferative effect on multiple human cells. Its impact on atherosclerosis remains largely unexplored. METHODS: Real-time PCR was used to determine miR-637 expression in samples from atherosclerosis patients and animal models. Its expression in VSMC dysfunction models (induced by ox-LDL) was also measured. The proliferation and migration of VSMCs were respectively tested using CCK-8 and Transwell assays, and apoptosis was measured using flow cytometry. The Targetscan database was used to predict the target genes of miR-637. Interaction between miR-637 and the potential target gene was validated via real-time PCR, western blotting and a luciferase reporter assay. RESULTS: MiR-637 expression was significantly lower in atherosclerosis patient and animal model samples. It also decreased in a dose- and time-dependent manner in animal models with ox-LDL-induced atherosclerosis. Transfection with miR-637 mimics suppressed the proliferation and migration of VSMCs while promoting apoptosis, while transfection with miR-637 inhibitors had the opposite effects. We also validated that insulin-like growth factor-2 (IGF-2), a crucial factor in the pathogenesis of atherosclerosis, serves as a target gene for miR-637. CONCLUSION: MiR-637 targeting IGF-2 contributes to atherosclerosis inhibition and could be a potential target for this disease.

Genetic variants in the calcium signaling pathway genes are associated with cutaneous melanoma-specific survival.

Remodeling or deregulation of the calcium signaling pathway is a relevant hallmark of cancer including cutaneous melanoma (CM). In this study, using data from a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center, we assessed the role of 41,377 common single-nucleotide polymorphisms (SNPs) of 167 calcium signaling pathway genes in CM survival. We used another GWAS from Harvard University as the validation dataset. In the single-locus analysis, 1830 SNPs were found to be significantly associated with CM-specific survival (CMSS; P ≤ 0.050 and false-positive report probability ≤ 0.2), of which 9 SNPs were validated in the Harvard study (P ≤ 0.050). Among these, three independent SNPs (i.e. PDE1A rs6750552 T>C, ITPR1 rs6785564 A>G and RYR3 rs2596191 C>A) had a predictive role in CMSS, with a meta-analysis-derived hazards ratio of 1.52 (95% confidence interval = 1.19-1.94, P = 7.21 × 10-4), 0.49 (0.33-0.73, 3.94 × 10-4) and 0.67 (0.53-0.86, 0.0017), respectively. Patients with an increasing number of protective genotypes had remarkably improved CMSS. Additional expression quantitative trait loci analysis showed that these genotypes were also significantly associated with mRNA expression levels of the genes. Taken together, these results may help us to identify prospective biomarkers in the calcium signaling pathway for CM prognosis.

Michael-Addition-Mediated Photonic Crystals Allow Pretreatment-Free and Label-Free Sensoring of Ciprofloxacin in Fish Farming Water.

Abuse of antibiotics results in a large number of antibiotics residues in the environment and even causes the problem of "super bacteria". Therefore, it is crucial to develop a powerful analytic method to monitor antibiotics quickly and simply. Photonic crystal (PC), as a sensing material, has promising application prospects. Herein, we try to use PC to realize pretreatment-free and label-free detection of Ciprofloxacin (CF) through Michael addition reaction. The recognition process is carried out by the Michael addition reaction between the piperazine group of CF and the o-benzoquinone group on the PC. The monodisperse microspheres with o-benzoquinone groups are prepared by polymerization and oxidation and then stacked to form PC. During the detection, the peak intensity of the PC decreases with the increasing CF concentration, and the linear range is from 2 to 512 µg/L. The limit of detection (LOD) is 0.76 µg/L. Furthermore, the PC retains 97% of the initial response after storage in a Petri dish at room temperature for 1 month, which shows that it has good stability. Moreover, CF in fish farming water can be detected directly without any pretreatment and label, and the results are in good accordance with the LC-MS-MS results. This Michael-addition-mediated PC is accurate, easily prepared, cost-efficient, and long-term stable. In addition, it is environmentally friendly, because little organic solvent is needed during both the preparation and the detection.

Elevated Interleukin-38 Level Associates with Clinical Response to Atorvastatin in Patients with Hyperlipidemia.

BACKGROUND/AIMS: Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. And it is tightly related to chronic inflammation. Interleukin-38 (IL-38) represents a new member of anti-inflammatory cytokines. Thus we studied the important role of IL-38 in hyperlipidemia development and treatment. METHODS: The mRNA level of IL-38 in PBMCs (peripheral blood mononuclear cells) and serum IL-38 levels in hyperlipidemia patients and healthy controls were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunoassay (ELISA). The hyperlipidemia patients were further divided into two groups (Sensitive and Resistant Group) according to their clinical response to Atorvastatin therapy. Finally, the effects of IL-38 on hyperlipidemia was evaluated in the mice model. RESULTS: Data showed that the IL-38 mRNA and serum protein levels were higher in patients with hyperlipidemia compared with healthy controls. And the IL-38 mRNA and serum protein levels were higher in patients sensitive to Atorvastatin therapy than the resistant group. In vitro, IL-38 inhibited the production of IL-6, IL-1ß and CRP in PBMCs of patients with hyperlipidemia. In the mice model of hyperlipidemia, IL-38 was also elevated during the hyperlipidemia development. Furthermore, the IL-38 over-expressed by adeno-associated virus significantly inhibited the hyperlipidemia development, inflammatory factor secretion and also the atherosclerosis process. CONCLUSION: Thus our data showed that IL-38 might present protective effects on hyperlipidemia treatment.

An intelligent 1:2 demultiplexer as an intracellular theranostic device based on DNA/Ag cluster-gated nanovehicles.

The logic device demultiplexer can convey a single input signal into one of multiple output channels. The choice of the output channel is controlled by a selector. Several molecules and biomolecules have been used to mimic the function of a demultiplexer. However, the practical application of logic devices still remains a big challenge. Herein, we design and construct an intelligent 1:2 demultiplexer as a theranostic device based on azobenzene (azo)-modified and DNA/Ag cluster-gated nanovehicles. The configuration of azo and the conformation of the DNA ensemble can be regulated by light irradiation and pH, respectively. The demultiplexer which uses light as the input and acid as the selector can emit red fluorescence or a release drug under different conditions. Depending on different cells, the intelligent logic device can select the mode of cellular imaging in healthy cells or tumor therapy in tumor cells. The study incorporates the logic gate with the theranostic device, paving the way for tangible applications of logic gates in the future.

[A multicenter, randomized, controlled, phase â ¢ clinical study of PEG-rhG-CSF for preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer].

OBJECTIVE: To explore the safety and efficacy of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer (NSCLC), and to provide the basis for clinical application. METHODS: According to the principle of open-label, randomized, parallel-group controlled clinical trial, all patients were randomized by 1∶1∶1 into three groups to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg, respectively. The patients with breast cancer received two chemotherapy cycles, and the NSCLC patients received 1-2 cycles of chemotherapy according to their condition. All patients were treated with the combination chemotherapy of TAC (docetaxel+ epirubicin+ cyclophosphamide) or TA (docetaxel+ epirubicin), or the chemotherapy of docetaxel combined with carboplatin, with a 21 day cycle. RESULTS: The duration of grade 3-4 neutropenia in the PEG-rhG-CSF 100 µg/kg and PEG-rhG-CSF 6 mg groups were similar with that in the rhG-CSF 5 µg/kg group (P>0.05 for all). The incidence rate of grade 3-4 neutropenia in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group, and G-CSF 5 µg/kg group were 69.7%, 68.4%, and 69.5%, respectively, with a non-significant difference among the three groups (P=0.963). The incidence rate of febrile neutropenia in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 µg/kg group were 6.1%, 6.4%, and 5.5%, respectively, showing no significant difference among them (P=0.935). The incidence rate of adverse events in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 µg / kg group were 6.7%, 4.1%, and 5.5%, respectively, showing a non-significant difference among them (P=0.581). CONCLUSIONS: In patients with breast cancer and non-small cell lung cancer (NSCLC) undergoing TAC/TA chemotherapy, a single 100 µg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF at 48 hours after chemotherapy show definite therapeutic effect with a low incidence of adverse events and mild adverse reactions. Compared with the continuous daily injection of rhG-CSF 5 µg/kg/d, a single 100 µg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF has similar effect and is more advantageous in preventing chemotherapy-induced neutropenia.

[Ad-hVEGF165 reverses homocysteine-induced endothelial dysfunction by regulating nitric oxide system].

OBJECTIVE: To investigate the therapeutic effect of Ad-hVEGF165 on the endothelial cells dysfunction induced by homocysteine (Hcy) and related molecular mechanisms. METHODS: Human umbilical vein endothelial cells CRL-1730 were treated with Hcy at different concentrations (0, 0.05, 1.00 mmol/L) for 24 h. The same concentration of Hcy, Ad-Track and Ad-hVEGF165 were added to the cells in the following groups: blank group, Hcy0.05 group, Hcy1.00 group, Ad-Track group, Hcy0.05+Ad-Track group, Hcy1.00+Ad-Track group, Ad-hVEGF165 group, Hcy0.05+Ad-hVEGF165 group, Hcy1.00+ Ad-hVEGF165 group for 48 h. The mRNA and protein expressions of eNOS and DDAH2 were detected by real-time PCR and Western blot. The correlations of mRNA and protein expressions between endothelial nitric oxide synthase (eNOS) and dimethylarginine dimthylaminohydrolase (DDAH)2 were evaluated by Pearson correlation analysis. RESULTS: Compared with blank group and Ad-hVEGF165 group, the mRNA and protein expressions of eNOS were decreased in Hcy0.05 group and Hcy0.05+Ad-hVEGF165 group (both P < 0.05), and the mRNA and protein expressions of DDAH2 in cells treated with 0.05 mmol/L and 1.00 mmol/L Hcy were reduced as well (all P < 0.05). DDAH2 mRNA and protein expression are increased (all P < 0.05) in Ad-hVEGF165 group compared with the blank group and Ad-Track, Hcy0.05 + Ad-hVEGF165 and Hcy0.05 group compared with Hcy0.05+Ad-Track group, Hcy1.00+Ad-hVEGF165 and Hcy1.00 group compared with Hcy1.00+Ad-Track group. The mRNA and protein expressions of eNOS and DDAH2 were uncorrelated under the effect of Hcy (r = 0.057 and 0.449, both P > 0.05) and VEGF (r = 0.284 and 0.432, both P > 0.05). CONCLUSION: Recombinant adenovirus Ad-hVEGF165 could reverse Hcy-induced endothelial cells dysfunction via upregulating the expressions of eNOS and DDAH2.

[Lymph node metastasis and prognostic analysis of 354 cases of T1 breast cancer].

OBJECTIVE: To analyze the characteristics of lymph node metastasis and prognosis in patients with T1 breast cancer. METHODS: The clinicopathological data of 354 patients with T1 breast cancer after standard treatment from March 2007 to September 2011 were collected to analyze the relationship between the clinical characteristics of T1 breast cancer, lymph node metastasis and prognostic features. RESULTS: In the 354 patients with T1 breast cancer, 105 patients (29.7%) had lymph node metastasis, among them 73 cases (69.5%) had 1-3 lymph node metastasis, and 32 cases (30.5%) had more than 4 lymph node metastasis. The lymph node metastasis rate was 8.3% in T1a patients, 39.7% in T1b patients, and 30.4% in T1c cases (P = 0.005). Pairwise comparison showed that the difference of lymph node metastasis rate between T1a, T1b and T1c patients was statistically significant (P = 0.001 and P = 0.006, respectively). The difference of lymph node metastasis rates in T1b and T1c patients was statistically insignificant (P = 0.171). In the 354 patients of T1 breast cancer, 92 patients had vascular tumor thrombi and their lymph node metastasis rate was 71.7%, while the lymph node metastasis rate in 262 patients without vascular tumor thrombus was 14.9% (P < 0.001). The median follow-up was 49 months (range 27-81 months). 12 patients developed recurrence, and 3 patients died, one of them died of cerebrovascular accident. The 4-year disease-free survival for all patients was 96.6%, and the 4-year overall survival rate was 99.2%. CONCLUSIONS: There is a correlation between vascular tumor thrombus, tumor size and lymph node metastasis rate. The lymph node metastasis rate is lower in T1a patients and relatively higher in T1b/c patients. Compared with patients without vascular tumor thrombus, the T1 breast cancer patients with vascular tumor thrombi have a higher lymph node metastasis rate. Generally speaking, there is a still good prognosis in patients with T1 breast cancer.

Metformin enhanced the effect of pirfenidone on pulmonary fibrosis in mice.

BACKGROUND: The aim of the study is to observe the anti-inflammatory and antioxidative stress effects of metformin on bleomycin (BLM)-induced pulmonary fibrosis in mice. METHODS: Mice with BLM-induced pulmonary fibrosis were treated with pirfenidone, metformin, pirfenidone plus metformin and the NADPH oxidase 4 (NOX4) inhibitor diphenyleneiodonium chloride (DPI). Pathological changes and hydroxyproline (HPO) levels were examined in the lung tissue of mice with pulmonary fibrosis. Superoxide dismutase (SOD) activity and malonaldehyde (MDA) levels in lung tissue were determined. RESULTS: Compared with pirfenidone, pirfenidone plus metformin could reduce alveolar damage and collagen fibre deposition and alleviate BLM-induced pulmonary fibrosis. Lung HPO levels were significantly lower in the PFD + MET group than in the BLM group (p < 0.05). SOD levels in the lungs of mice were increased in the PFD + MET group than in the BLM group (p < 0.05). Metformin and pirfenidone plus metformin can reduce MDA levels (p < 0.05). Pirfenidone plus metformin could reduce HPO levels, increase SOD levels, and reduce MDA levels in the lungs of mice. There was a significant correlation between the HPO level and the Ashcroft score (r = 0.520, p < 0.001). CONCLUSION: Metformin enhanced the antifibrotic effects of pirfenidone on BLM-treated mice. Moreover, these findings provide an experimental basis for examining whether metformin can improve the antifibrotic effects of pirfenidone on patients with idiopathic pulmonary fibrosis (IPF). It has broad therapeutic prospects for patients with IPF.

Chemokine systems in oncology: From microenvironment modulation to nanocarrier innovations.

Over the past few decades, significant strides have been made in understanding the pivotal roles that chemokine networks play in tumor biology. These networks, comprising chemokines and their receptors, wield substantial influence over cancer immune regulation and therapeutic outcomes. As a result, targeting these chemokine systems has emerged as a promising avenue for cancer immunotherapy. However, therapies targeting chemokines face significant challenges in solid tumor treatment, due to the complex and fragile of the chemokine networks. A nuanced comprehension of the complicacy and functions of chemokine networks, and their impact on the tumor microenvironment, is essential for optimizing their therapeutic utility in oncology. This review elucidates the ways in which chemokine networks interact with cancer immunity and tumorigenesis. We particularly elaborate on recent innovations in manipulating these networks for cancer treatment. The review also highlights future challenges and explores potential biomaterial strategies for clinical applications.

Age-specific distributions of cytogenetic subgroups of acute myeloid leukemia: data analysis in a Chinese population.

Although some studies have reported relationships between cytogenetic subgroups, molecular markers and age in acute myeloid leukemia (AML), conclusions based on data from a Chinese population are lacking. In the present study, we evaluated 640 patients with de novo AML. The patients were divided into 8 age groups, i.e. 0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69 and ≥70 years, and were then classified into cytogenetic groups based on normal, balanced and unbalanced karyotypes.

Immunotherapy for HER-2 positive breast cancer.

Immunotherapy is a developing treatment for advanced breast cancer. Immunotherapy has clinical significance for the treatment of triple-negative breast cancers and human epidermal growth factor receptor-2 positive (HER2+) breast cancers. As a proved effective passive immunotherapy, clinical application of the monoclonal antibodies trastuzumab, pertuzumab and T-DM1 (ado-trastuzumab emtansine) has significantly improved the survival of patients with HER2+ breast cancers. Immune checkpoint inhibitors that block programmed death receptor-1 and its ligand (PD-1/PD-L1) have also shown benefits for breast cancer in various clinical trials. Adoptive T-cell immunotherapies and tumor vaccines are emerging as novel approaches to treating breast cancer, but require further study. This article reviews recent advances in immunotherapy for HER2+ breast cancers.