Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression.

Acylphosphatase 1 (ACYP1), a protein located in the mammalian cell cytoplasm, has been shown to be associated with tumor initiation and progression by functioning as a metabolism-related gene. Here we explored the potential mechanisms by which ACYP1 regulates the development of HCC and participates in the resistance to lenvatinib. ACYP1 can promote the proliferation, invasion, and migration capacities of HCC cells in vitro and in vivo. RNA sequencing reveals that ACYP1 markedly enhances the expression of genes related to aerobic glycolysis, and LDHA is identified as the downstream gene of ACYP1. Overexpression of ACYP1 upregulates LDHA levels, which then increases the malignancy potential of HCC cells. GSEA data analysis reveals the enrichment of differentially expressed genes in the MYC pathway, indicating a positive correlation between MYC and ACYP1 levels. Mechanistically, ACYP1 exerts its tumor-promoting roles by regulating the Warburg effect through activating the MYC/LDHA axis. Mass spectrometry analysis and Co-IP assays confirm that ACYP1 can bind to HSP90. The regulation of c-Myc protein expression and stability by ACYP1 is HSP90 dependent. Importantly, lenvatinib resistance is associated with ACYP1, and targeting ACYP1 remarkably decreases lenvatinib resistance and inhibits progression of HCC tumors with high ACYP1 expression when combined with lenvatinib in vitro and in vivo. These results illustrate that ACYP1 has a direct regulatory role in glycolysis and drives lenvatinib resistance and HCC progression via the ACYP1/HSP90/MYC/LDHA axis. Targeting ACYP1 could synergize with lenvatinib to treat HCC more effectively.

Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.

The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.

Clonal relationship of tet(X4)-positive Escherichia coli ST761 isolates between animals and humans.

OBJECTIVES: To characterize the relationship of tet(X4)-positive isolates from different hosts and environments. METHODS: PCR and MALDI-TOF MS were used to identify the tet(X4)-positive isolates. The MICs of 13 antimicrobial agents were determined by broth microdilution. Illumina technology was used to sequence all of the isolates. One isolate was randomly selected from Escherichia coli ST761 clones for long-read sequencing to obtain plasmid sequences. Bioinformatics analysis was used to determine the phylogeny of 46 tet(X4)-positive E. coli ST761 strains. RESULTS: A total of 12 tet(X4)-positive isolates, 8 E. coli and 4 Aeromonas simiae, were obtained from six lairages of a slaughterhouse. These isolates exhibited resistance to at least three classes of antimicrobials, including tigecycline. The majority of them, seven E. coli and three A. simiae, represent separate clonal groups. Notably, the seven E. coli isolates belonged to ST761, a common ST carrying the tet(X4) gene that has been identified in 39 isolates from animals, meat, wastewater and humans from seven Chinese provinces. All 46 tet(X4)-positive E. coli ST761 strains from various sources have a close phylogenetic relationship (0-72 SNPs), with a high nucleotide sequence similarity of resistance genes and the tet(X4)-carrying IncX1-IncFIA(HI1)-IncFIB(K) hybrid plasmid, indicating a clonal relationship of tet(X4)-positive E. coli ST761 among animals, food, the environment and humans. CONCLUSIONS: The clonal relationship of tet(X4)-positive E. coli ST761 between humans and animals poses a previously underestimated threat to public health. To the best of our knowledge, this is the first description of tet(X4)-positive A. simiae.

Total flavonoids from the dried root of Tetrastigma hemsleyanum Diels et Gilg inhibit colorectal cancer growth through PI3K/AKT/mTOR signaling pathway.

The dried root of Tetrastigma hemsleyanum Diels et Gilg is used as a traditional Chinese medicine in southern China, as a folk remedy for carcinomas and gastrointestinal diseases. The total flavonoids of T. hemsleyanum (THTF) provide its main bioactive constituents. However, the mechanisms underlying its potential activity on colorectal cancer are still unknown. Here, we investigated the antitumor effect of THTF on colorectal cancer in vitro and in vivo. It was found that THTF inhibited HCT-116 and HT-29 cell growth, with an IC50 of 105.60 and 140.80 µg/mL, respectively. THTF suppressed clonogenicity and promoted apoptosis in HCT-116. In vivo, THTF (120 mg/kg) delayed tumor growth in HCT-116 xenografts without influencing on body weight, organ pathology and indexes, and blood routine level. Mechanistically, THTF inhibited the expression of PI3K, AKT, and mTOR at the protein level and transcriptional levels. Molecular docking indicated eight compounds in THTF (kaempferol 3-rutinoside, rutinum, isoquercitrin, L-epicatechin, quercetin, astragalin, kaempferol 3-sambubioside, and catechin) strongly bound with amino acid sites of PI3K and mTOR proteins, indicating a high affinity. The results suggest that THTF delayed colorectal tumor growth by inhibiting the PI3K/AKT/mTOR pathway and might be a potential candidate for colorectal cancer prevention.

Dihydrotanshinone I Inhibits the Lung Metastasis of Breast Cancer by Suppressing Neutrophil Extracellular Traps Formation.

Breast cancer (BC) is a common female malignancy, worldwide. BC death is predominantly caused by lung metastasis. According to previous studies, Dihydrotanshinone I (DHT), a bioactive compound in Salvia miltiorrhiza Bunge (S. miltiorrhiza), has inhibitory effects on numerous cancers. Here, we investigated the anti-metastatic effect of DHT on BC, where DHT more strongly inhibited the growth of BC cells (MDA-MB-231, 4T1, MCF-7, and SKBR-3) than breast epithelial cells (MCF-10a). Additionally, DHT repressed the wound healing, invasion, and migration activities of 4T1 cells. In the 4T1 spontaneous metastasis model, DHT (20 mg/kg) blocked metastasis progression and distribution in the lung tissue by 74.9%. DHT reversed the formation of neutrophil extracellular traps (NETs) induced by phorbol 12-myristate 13-acetate, as well as ameliorated NETs-induced metastasis. Furthermore, it inhibited Ly6G+Mpo+ neutrophils infiltration and H3Cit expression in the lung tissues. RNA sequencing, western blot, and bioinformatical analysis indicated that TIMP1 could modulate DHT acting on lung metastasis inhibition. The study demonstrated a novel suppression mechanism of DHT on NETs formation to inhibit BC metastasis.

Novel fully human anti-CD47 antibodies stimulate phagocytosis and promote elimination of AML cells.

Although most patients with acute myeloid leukemia (AML) enter remission after induction chemotherapy, the risk of relapse remains considerable. Therefore, some novel therapeutic strategies are still required. This study found that the overexpression of CD47 on AML cells was at least twofold more than that on normal bone marrow (NBM) cells in 81% (17/21) of the investigated patients; no patients had lower expression level of CD47 compared with healthy donors. The study also demonstrated that blocking the CD47/SIRPα (signal regulatory protein α) signal with the established novel fully human anti-CD47 monoclonal antibodies increased the phagocytosis of AML cells by macrophages in vitro. Furthermore, in vivo experiments showed that the novel fully human anti-CD47 monoclonal antibodies could significantly prolong the survival time of mice. Overall, the novel fully human anti-CD47 antibodies could block CD47/SIRPα interaction, increase macrophage-mediated phagocytosis, and enhance the elimination of AML cells.

Cloning, characterization, and enzymatic identification of a new tryptophan decarboxylase from Ophiorrhiza pumila.

Tryptophan decarboxylase (TDC, EC 4.1.1.28) catalyzes tryptophan decarboxylation to form tryptamine through the cofactor pyridoxal-5'-phosphate (PLP), a crucial stage in the production of the terpenoid indole alkaloids like camptothecin (CPT). A new gene encoding TDC was identified from the CPT-producing plant Ophiorrhiza pumila by transcriptome analysis, termed OpTDC2. It contained a 1,536 bp open reading frame that encodes a 511 amino acid protein with a molecular mass of 57.01 kDa and an isoelectric point of 6.39. Multiple sequence alignment and phylogenetic tree analysis showed the closest similarity (85%) with the TDC from Mitragyna speciosa. Moreover, the highest expression of OpTDC2 was observed in the O. pumila root. To achieve high-efficiency expression of OpTDC2 in Escherichia coli, we fused the TF tag onto the N-terminal of the OpTDC2. Optimum enzymatic activity was observed at 45 °C, pH 8 and cofactor concentration of 0.1 mM. The catalytic reaction was strongly inhibited by metal ions of Cu2+ , Zn2+ , and Fe2+ . The l-tryptophan was particularly catalyzed compared with d-tryptophan. Besides, the Km and kcat of the OpTDC2 were 1.08 mM and 0.78 Sec-1 , respectively. The results provided information on new functional OpTDC2 that might be used in synthetic biology for the enhanced biosynthesis of CPT in O. pumila.

Presence and molecular characteristics of oxazolidinone resistance in staphylococci from household animals in rural China.

Objectives: To investigate the presence and molecular characteristics of oxazolidinone resistance genes cfr and optrA in staphylococci from household animals in rural China. Methods: Various samples were collected from household animals in 12 rural villages. Staphylococcal isolates showing florfenicol MICs ≥10 mg/L were identified and screened for the presence of cfr and/or optrA. PCR-positive isolates were characterized by antimicrobial susceptibility testing, S1 nuclease PFGE and Southern blotting. WGS data were analysed to identify the core-genome phylogenetic profile of each isolate as well as the genetic environment of cfr and/or optrA. Results: Nine optrA-positive (seven Staphylococcus sciuri and two Staphylococcus simulans) and 10 cfr-positive staphylococci were identified from eight and five villages, respectively. The gene optrA was chromosomally encoded in all nine isolates, whereas cfr was located on a plasmid in one S. sciuri and three Staphylococcus saprophyticus and in the chromosomal DNA of single Staphylococcus cohnii and Staphylococcus lentus isolates and two S. sciuri isolates. The remaining two cfr-carrying Staphylococcus haemolyticus isolates were indistinguishable by PFGE. Most optrA- or cfr-carrying staphylococci also harboured phenicol, tetracycline and/or macrolide-lincosamide-streptogramin B resistance genes. Genetic environment analysis showed that, for the first time, optrA was associated with transposon Tn6261, while cfr was adjacent to both a tnp (transposase) gene and a Tn558 transposon. Conclusions: The current study reveals for the first time the wide distribution of oxazolidinone resistance genes optrA and cfr in household animals in rural areas of China and is the first identification of optrA in S. simulans isolates.

Antibiotic use in people and pigs: a One Health survey of rural residents' knowledge, attitudes and practices in Shandong province, China.

Objectives: To evaluate rural residents' knowledge, attitudes and practices (KAP) towards antibiotic use in humans and pigs, among individuals with and without backyard pig farms living in Shandong province, China. Methods: We conducted a cross-sectional questionnaire study among residents in 12 villages, and directly observed medicines stored in households for humans and pigs. Results: In total, 769 residents participated, including 330 backyard pig farmers. Respondents had low levels of knowledge about antibiotics. A quarter of participants had bought one or more antibiotics from a pharmacy without a prescription in the previous year, and this was more common among pig farmers who had bought antibiotics for their pigs without consulting a vet (49% versus 25%, P < 0.001). Stored antibiotics for human use were found in 42% of households, and 70% of participants from these households did not know they were storing antibiotics. Thirty-one percent of backyard pig farmers were storing antibiotics for pig use. Farmers who thought it was good to store leftover antibiotics for their pigs were more likely to have stored antibiotics for pigs (41% versus 20%) and for humans (47% versus 32%; both P < 0.01). A fifth of participants thought their own actions were important for controlling antibiotic resistance. Conclusions: We found differences in the KAP of backyard pig farmers and non-pig farmers to antibiotics, and parallels between pig farmers' attitudes and behaviours towards antibiotic use in pigs and in humans. Our findings reinforce the need for context-adapted multifaceted interventions to improve antibiotic use and provide suggestions for targeting educational approaches.

Mobile colistin resistance gene mcr-5 in porcine Aeromonas hydrophila.

Objectives: To characterize the mobile colistin resistance gene mcr-5 in Aeromonas hydrophila from backyard pigs in rural areas of China. Methods: Pig faecal samples from 194 households were directly tested for the presence of mcr-5 by PCR assay and the phenotypic antimicrobial susceptibility profiles of the mcr-5-positive isolates were determined using the broth dilution method. The genomic location and transferability of mcr-5 were analysed by S1-PFGE with Southern blotting and DNA hybridization, and natural transformation, respectively. One strain isolated from an mcr-5-positive sample was subjected to WGS and the stability of the mcr-5-harbouring plasmid over successive generations was examined by subculturing. Results: One mcr-5-positive A. hydrophila isolate showing resistance, with a colistin MIC of 4 mg/L, was isolated from a backyard pig faecal sample. mcr-5 was located on a 7915 bp plasmid designated pI064-2, which could naturally transform into a colistin-susceptible A. hydrophila strain of porcine origin and mediated colistin resistance in both the original isolate and its transformants. The plasmid backbone (3790 bp) of pI064-2 showed 81% nucleotide sequence identity to the corresponding region of the ColE2-type plasmid pAsa1 from Aeromonas salmonicida, while similar replication primases are widely distributed among aeromonads, Enterobacteriaceae and Pseudomonas species. Conclusions: To the best of our knowledge, this is the first identification of the novel colistin resistance gene mcr-5 in an A. hydrophila isolate from the faeces of a backyard pig. mcr-5 is expected to be able to disseminate among different bacterial species and genera.

Comparison of vaginal microbial community structure in healthy and endometritis dairy cows by PCR-DGGE and real-time PCR.

The normal vaginal microflora provides protection against infections of the reproductive tract. Previous studies have focused on the isolation and screening of probiotic strains from the vagina of cows; however, the vaginal microflora of postpartum cows is poorly characterized. The present study was conducted to evaluate and characterize the vaginal microflora of healthy postpartum cows in relation to postpartum cows with endometritis by using PCR followed by denaturing gradient gel electrophoresis (PCR-DGGE) and Real-time PCR. The study population comprised 5 healthy cows and 5 cows with endometritis. The results indicated that the vaginal bacterial microflora of healthy postpartum cows was dominated by Lactobacillus sakei subsp. and Weissella koreensis, while there were no dominant bacterial species in the vaginal microflora of postpartum cows with endometritis. Common microorganisms such as Bacteroides spp., Fusobacterium spp., Enterococcus spp., Prevotella spp., Clostridium perfringens strains, and Escherichia coli were detected in both groups of cows by Real-time PCR. The bacterial diversity in the vagina of cows with endometritis was significantly higher than that in healthy cows. The results indicated that the vaginal microflora of cows with endometritis was more diverse and lacked dominant bacterial species as compared to that of the healthy cows, suggesting that disruption of the normal vaginal microflora may contribute to the onset of endometritis. This microbial community analysis provided information that might be used to develop probiotics to treat endometritis in cows; however, further investigation is needed.

[The Research on Measurement System and Method of Tissue Optical Parameters with Wide Spectra Based on Double-Integrating-Spheres].

The measurement of tissue optical parameters is the focusing research content of Biomedical Photonics. The optical properties of human tissue are closely related to the physiological and pathological state. In recent years, the tissue imaging diagnosis and non-invasive detection of componentsbecome the hot research topics, applying the tissue optical properties especially the absorption and scattering properties. These provide the basis for the study of optical imaging and the spectrum detection of body composition etc. The Double-Integrating-Spheres (DIS) method can measure the absorption coefficient, scattering coefficient and so on in vitro tissuesimultaneously. It has the advantages of accurate, rapid, large applicable scope. The method applya standard method for measuring the optical parameters. This paper build the wide spectrum measurement system of optical parameters based on DIS and super continuum lasers. Then we analyze the transfer function, error sources and the best measuring conditions of the system. Finally we establish the correction forward model based on BP-MCML and the inverse algorithm of the optical parameters based on L-M algorithm. The optical parameters of intralipid solution in the wavelength range of 1,100~1,400 nm are measured. The experiment results show that the improved inverse algorithm is accurate. The multiple measurements standard deviation is within 3%. Compared the results of scattering coefficient and absorption coefficient at different wavelengths to the results of other research groups, the deviation is less than 3.4%.

Halicin: A New Horizon in Antibacterial Therapy against Veterinary Pathogens.

It is crucial to discover novel antimicrobial drugs to combat resistance. This study investigated the antibacterial properties of halicin (SU3327), an AI-identified anti-diabetic drug, against 13 kinds of common clinical pathogens of animal origin, including multidrug-resistant strains. Employing minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assessments, halicin demonstrated a broad-spectrum antibacterial effect. Time-killing assays revealed its concentration-dependent bactericidal activity against Escherichia coli ATCC 25922 (E. coli ATCC 25922), Staphylococcus aureus ATCC 29213 (S. aureus ATCC 29213), and Actinobacillus pleuropneumoniae S6 (APP S6) after 4 h of treatment at concentrations above the MIC. Halicin exhibited longer post-antibiotic effects (PAEs) and sub-MIC effects (PA-SMEs) for E. coli 25922, S. aureus 29213, and APP S6 compared to ceftiofur and ciprofloxacin, the commonly used veterinary antimicrobial agents, indicating sustained antibacterial action. Additionally, the results of consecutive passaging experiments over 40 d at sub-inhibitory concentrations showed that bacteria exhibited difficulty in developing resistance to halicin. Toxicology studies confirmed that halicin exhibited low acute toxicity, being non-mutagenic, non-reproductive-toxic, and non-genotoxic. Blood biochemical results suggested that halicin has no significant impact on hematological parameters, liver function, and kidney function. Furthermore, halicin effectively treated respiratory A. pleuropneumoniae infections in murine models. These results underscore the potential of halicin as a new antibacterial agent with applications against clinically relevant pathogens in veterinary medicine.

High intestinal carriage of Clostridium perfringens in healthy individuals and ICU patients in Hangzhou, China.

Clostridium perfringens has emerged as a growing public health concern due to its ability to cause various infections and its increasing resistance to antibiotics. To assess its current epidemiology in clinical settings, we conducted a survey involving 426 healthy individuals and 273 ICU inpatients at a provincial hospital in China. Our findings revealed a high prevalence of C. perfringens in healthy individuals (45.77%, 95% CI: 41.0%-50.6%) and ICU patients (12.82%, 95% CI: 9.1%-17.4%). The identified 220 C. perfringens isolates displayed substantial resistance to erythromycin (57.9%), clindamycin (50.7%), and tetracycline (32.0%), primarily attributed to the presence of erm(Q) (54.4%), lnu(P) (13.8%), tetB(P) (83.6%), and tetA(P) (66.7%). Notably, C. perfringens isolates from this particular hospital demonstrated a high degree of sequence type diversity and phylogenic variation, suggesting that the potential risk of infection primarily arises from the bacteria's gut colonization rather than clonal transmissions within the clinical environment. This study provides an updated analysis of the current epidemiology of C. perfringens in healthy individuals and ICU patients in China and emphasizes the need to optimize intervention strategies against its public health threat. IMPORTANCE: Clostridium perfringens is a bacterium of growing public health concern due to its ability to cause infections and its increasing resistance to antibiotics. Understanding its epidemiology in clinical settings is essential for intervention strategies. This study surveyed healthy individuals and ICU inpatients in a provincial hospital in China. It found a high prevalence of C. perfringens, indicating infection risk. The isolates also showed significant antibiotic resistance. Importantly, the study revealed diverse sequence types and phylogenetic variation, suggesting infection risk from intestinal colonization rather than clonal transmission in hospitals. This analysis emphasizes the need to optimize intervention strategies against this public health threat.

MALDI-TOF MS combined with AUC method for tigecycline susceptibility testing in Escherichia coli.

Objectives: The wide spread of tet(X4) gene orthologues in the environment, food, poultry and humans is causing serious tigecycline resistance. Consequently, developing a fast and universal method to detect tigecycline resistance has become increasingly important. Methods: During 2019-2022, 116 Escherichia coli isolates were obtained from nine provinces in China. All isolates were tested for their susceptibility to antimicrobial agents by the microdilution broth method and for the tet(X4) gene by PCR. Ten tet(X4)-positive E. coli isolates were used to confirm certain conditions, including the optimal incubation time, the optimal concentration of tigecycline, and the cut-off of the relative growth (RG) value. Results: The optimal time and concentration of tigecycline for separation of susceptible and resistant isolates was 2 h and 4 mg/L, and the RG cut-off value was 0.4. We validated whether the experiment was feasible using 116 isolates of E. coli. The method yielded a susceptibility of 94.9% (95% CI: 81.4%-99.1%) and a specificity of 96.1% (95% CI: 88.3%-99.0%). Conclusions: This research has shown that this optical antimicrobial susceptibility testing method can rapidly differentiate between susceptible and resistant phenotypes in isolates of E. coli. In the same range as the current gold-standard methods, the clinical turnaround time is reduced from 48 h to 2.5 h. The above results suggest that the method has splendid specificity and operationality.

Transmission of blaNDM in Enterobacteriaceae among animals, food and human.

Despite carbapenems not being used in animals, carbapenem-resistant Enterobacterales (CRE), particularly New Delhi metallo-ß-lactamase-producing CRE (NDM-CRE), are prevalent in livestock. Concurrently, the incidence of human infections caused by NDM-CRE is rising, particularly in children. Although a positive association between livestock production and human NDM-CRE infections at the national level was identified, the evidence of direct transmission of NDM originating from livestock to humans remains largely unknown. Here, we conducted a cross-sectional study in Chengdu, Sichuan Province, to examine the prevalence of NDM-CRE in chickens and pigs along the breeding-slaughtering-retail chains, in pork in cafeterias of schools, and in colonizations and infections from children's hospital and examined the correlation of NDM-CRE among animals, foods and humans. Overall, the blaNDM increases gradually along the chicken and pig breeding (4.70%/2.0%) -slaughtering (7.60%/22.40%) -retail (65.56%/34.26%) chains. The slaughterhouse has become a hotspot for cross-contamination and amplifier of blaNDM. Notably, 63.11% of pork from the school cafeteria was positive for blaNDM. The prevalence of blaNDM in intestinal and infection samples from children's hospitals was 21.68% and 19.80%, respectively. whole genome sequencing (WGS) analysis revealed the sporadic, not large-scale, clonal spread of NDM-CRE along the chicken and pig breeding-slaughtering-retail chain, with further spreading via IncX3-blaNDM plasmid within each stage of whole chains. Clonal transmission of NDM-CRE is predominant in children's hospitals. The IncX3-blaNDM plasmid was highly prevalent among animals and humans and accounted for 57.7% of Escherichia coli and 91.3% of Klebsiella pneumoniae. Attention should be directed towards the IncX3 plasmid to control the transmission of blaNDM between animals and humans.

[Efficacy and safety of low-frequency rotary magnetic fields in the treatment of patients with advanced malignant tumors].

OBJECTIVE: To investigate the clinical efficacy and safety of low-frequency rotary magnetic fields in the treatment of patients with advanced malignant tumors. METHODS: 137 patients with advanced malignant tumors were exposed to 400 r/min, 0.4 T low-frequency rotary magnetic fields. An area including the primary tumor, local metastasis and metastatic lymph nodes was exposed daily, 2 hours per day for 30~50 days (average time of 42 days). RESULTS: All of the 137 patients completed the low-frequency rotary magnetic field treatment. There were 28 cases with complete response, 54 cases with partial response, and the clinical benefit rate was 59.9%. The tumor type, initial KPS and QOL showed statistical significance in the clinical benefit rate (P < 0.05). The median overall survival was 12 months, and the 1-year, 2-year and 3-year survival rates were 47.0%, 11.8%, 3.4%, respectively. The tumor type, initial KPS and QOL were identified by univariate log-rank test as significant prognostic factors for overall survival (P < 0.05). Multivariate analysis showed that the initial QOL was an independent prognostic factors (P = 0.037) . During the treatment, asthenia and local pain were observed in 11 patients, and 6 patients had mild tachycardia (increased 3 to 5/min) and/or temperature elevation (0.5 to 1.0°C). All above symptoms disappeared spontaneously. No treatment-related death was observed. CONCLUSIONS: Low-frequency rotary magnetic fields is an effective and safe method in the treatment of patients with advanced malignant tumors, and may prolong survival significantly.

Bioactive components and molecular mechanisms of Salvia miltiorrhiza Bunge in promoting blood circulation to remove blood stasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge (SM) is an outstanding herbal medicine with various traditional effects, especially promoting blood circulation to remove blood stasis. It has been widely used for centuries to treat blood stasis syndrome (BSS)-related diseases. BSS is one of the basic pathological syndromes of diseases such as cardiovascular and cerebrovascular diseases in traditional East Asian medicine, which is characterized by disturbance of blood circulation. However, the bioactive components and mechanisms of SM in the treatment of BSS have not been systematically reviewed. Therefore, this article outlines the anti-BSS effects of bioactive components of SM, concentrating on the molecular mechanisms. AIM OF THE REVIEW: To summarize the bioactive components of SM against BSS and highlight its potential targets and signaling pathways, hoping to provide a modern biomedical perspective to understand the efficacy of SM on enhancing blood circulation to remove blood stasis. MATERIALS AND METHODS: A comprehensive literature search was performed to retrieve articles published in the last two decades on bioactive components of SM used for BSS treatment from the online electronic medical literature database (PubMed). RESULTS: Phenolic acids and tanshinones in SM are the main bioactive components in the treatment of BSS, including but not limited to salvianolic acid B, tanshinone IIA, salvianolic acid A, cryptotanshinone, Danshensu, dihydrotanshinone, rosmarinic acid, protocatechuic aldehyde, and caffeic acid. They protect vascular endothelial cells by alleviating oxidative stress and inflammatory damage and regulating of NO/ET-1 levels. They also enhance anticoagulant and fibrinolytic capacity, inhibit platelet activation and aggregation, and dilate blood vessels. Moreover, lowering blood lipids and improving blood rheological properties may be the underlying mechanisms of their anti-BSS. More notably, these compounds play an anti-BSS role by mediating multiple signaling pathways such as Nrf2/HO-1, TLR4/MyD88/NF-κB, PI3K/Akt/eNOS, MAPKs (p38, ERK, and JNK), and Ca2+/K+ channels. CONCLUSIONS: Both phenolic acids and tanshinones in SM may act synergistically to target different signaling pathways to achieve the effect of promoting blood circulation.

Tigecycline Sensitivity Reduction in Escherichia coli Due to Widely Distributed tet(A) Variants.

Despite scattered studies that have reported mutations in the tet(A) gene potentially linked to tigecycline resistance in clinical pathogens, the detailed function and epidemiology of these tet(A) variants remains limited. In this study, we analyzed 64 Escherichia coli isolates derived from MacConkey plates supplemented with tigecycline (2 µg/mL) and identified five distinct tet(A) variants that account for reduced sensitivity to tigecycline. In contrast to varied tigecycline MICs (0.25 to 16 µg/mL) of the 64 tet(A)-variant-positive E. coli isolates, gene function analysis confirmed that the five tet(A) variants exhibited a similar capacity to reduce tigecycline sensitivity in DH5α carrying pUC19. Among the observed seven non-synonymous mutations, the V55M mutation was unequivocally validated for its positive role in conferring tigecycline resistance. Interestingly, the variability in tigecycline MICs among the E. coli strains did not correlate with tet(A) gene expression. Instead, a statistically significant reduction in intracellular tigecycline concentrations was noted in strains displaying higher MICs. Genomic analysis of 30 representative E. coli isolates revealed that tet(A) variants predominantly resided on plasmids (n = 14) and circular intermediates (n = 13). Within China, analysis of a well-characterized E. coli collection isolated from pigs and chickens in 2018 revealed the presence of eight tet(A) variants in 103 (4.2%, 95% CI: 3.4-5.0%) isolates across 13 out of 17 tested Chinese provinces or municipalities. Globally, BLASTN analysis identified 21 tet(A) variants in approximately 20.19% (49,423/244,764) of E. coli genomes in the Pathogen Detection database. These mutant tet(A) genes have been widely disseminated among E. coli isolates from humans, food animals, and the environment sectors, exhibiting a growing trend in tet(A) variants over five decades. Our findings underscore the urgency of addressing tigecycline resistance and the underestimated role of tet(A) mutations in this context.

Total flavonoids of Tetrastigma hemsleyanum Diels et Gilg inhibits colorectal tumor growth by modulating gut microbiota and metabolites.

Tetrastigma hemsleyanum Diels et Gilg is a dietary supplement in southern China. The total flavonoids of T. hemsleyanum (THTF) can be used for gastrointestinal disease treatment. Colorectal cancer (CRC) is associated with gut microbiota dysbiosis. This study was designed to investigate the effect of THTF on CRC from gut microbiota and fecal metabolomics. THTF (120 mg/kg) oral gavage reduced tumor growth and protected intestinal function (p-p65/p65, ZO-1) in HCT116 xenografts. THTF increased probiotics Bifidobacteriales, Bifidobacteriaceae, Bifidobacterium, Bifidobacterium pseudolongum, and decreased "harmful" bacteria Bacteroidota, Firmicutes, Bacteroidia, Rikenellaceae, Odoribacter, Alistipes richness. Furthermore, THTF restored abnormal fecal metabolite levels. It showed a strong correlation among gut microbiota, metabolites, and tumor weight. Finally, THTF promoted Bifidobacterium pseudolongum growth in vitro, whose cell-free supernatant further inhibited HCT116 cell proliferation and clonogenicity. Together, THTF delays CRC tumor growth by maintaining microbiota homeostasis, restoring fecal metabolites, and protecting intestinal function.