Metabolic reprogramming and interventions in angiogenesis.

BACKGROUND: Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer. AIM OF REVIEW: In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.

Development and validation of an MRI-Based nomogram to predict the effectiveness of immunotherapy for brain metastasis in patients with non-small cell lung cancer.

Introduction: The variability and unpredictability of immune checkpoint inhibitors (ICIs) in treating brain metastases (BMs) in patients with advanced non-small cell lung cancer (NSCLC) is the main concern. We assessed the utility of novel imaging biomarkers (radiomics) for discerning patients with NSCLC and BMs who would derive advantages from ICIs treatment. Methods: Data clinical outcomes and pretreatment magnetic resonance images (MRI) were collected on patients with NSCLC with BMs treated with ICIs between June 2019 and June 2022 and divided into training and test sets. Metastatic brain lesions were contoured using ITK-SNAP software, and 3748 radiomic features capturing both intra- and peritumoral texture patterns were extracted. A clinical radiomic nomogram (CRN) was built to evaluate intracranial progression-free survival, progression-free survival, and overall survival. The prognostic value of the CRN was assessed by Kaplan-Meier survival analysis and log-rank tests. Results: In the study, a total of 174 patients were included, and 122 and 52 were allocated to the training and validation sets correspondingly. The intratumoral radiomic signature, peritumoral radiomic signature, clinical signature, and CRN predicted intracranial objective response rate. Kaplan-Meier analyses showed a significantly longer intracranial progression-free survival in the low-CRN group than in the high-CRN group (p < 0.001). The CRN was also significantly associated with progression-free survival (p < 0.001) but not overall survival. Discussion: Radiomics biomarkers from pretreatment MRI images were predictive of intracranial response. Pretreatment radiomics may allow the early prediction of benefits.

Noninvasive radiomic biomarkers for predicting pseudoprogression and hyperprogression in patients with non-small cell lung cancer treated with immune checkpoint inhibition.

This study aimed to develop a computed tomography (CT)-based radiomics model capable of precisely predicting hyperprogression and pseudoprogression (PP) in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. We retrospectively analyzed 105 patients with NSCLC, from three institutions, treated with immune checkpoint inhibitors (ICIs) and categorized them into training and independent testing set. Subsequently, we processed CT scans with a series of image-preprocessing techniques, and 6008 radiomic features capturing intra- and peritumoral texture patterns were extracted. We used the least absolute shrinkage and selection operator logistic regression model to select radiomic features and construct machine learning models. To further differentiate between progressive disease (PD) and hyperprogressive disease (HPD), we developed a new radiomics model. The logistic regression (LR) model showed optimal performance in distinguishing PP from HPD, with areas under the receiver operating characteristic curve (AUC) of 0.95 (95% confidence interval [CI]: 0.91-0.99) and 0.88 (95% CI: 0.66-1) in the training and testing sets, respectively. Additionally, the support vector machine model showed optimal performance in distinguishing PD from HPD, with AUC of 0.97 (95% CI: 0.93-1) and 0.87 (95% CI: 0.72-1) in the training and testing sets, respectively. Kaplan‒Meier survival curves showed clear stratification between PP predicted by the radiomics model and true progression (HPD and PD) (hazard ratio = 0.337, 95% CI: 0.200-0.568, p < 0.01) in overall survival. Our study demonstrates that radiomic features extracted from baseline CT scans are effective in predicting PP and HPD in patients with NSCLC treated with ICIs.

Using MRI radiomics to predict the efficacy of immunotherapy for brain metastasis in patients with small cell lung cancer.

BACKGROUND: Brain metastases (BMs) are common in small cell lung cancer (SCLC), and the efficacy of immune checkpoint inhibitors (ICIs) in these patients is uncertain. In this study we aimed to develop and validate a radiomics nomogram based on magnetic resonance imaging (MRI) for intracranial efficacy prediction of ICIs in patients with BMs from SCLC. METHODS: The training and validation cohorts consisted of 101 patients from two centers. The interclass correlation coefficient (ICC), logistic univariate regression analysis, and random forest were applied to select the radiomic features, generating the radiomics score (Rad-score) through the formula. Using multivariable logistic regression analysis, a nomogram was created by the combined model. The discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. Kaplan-Meier curves were plotted based on the nomogram scores. RESULTS: Ten radiomic features were selected for calculating the Rad-score as they could differentiate the intracranial efficacy in the training (area under the curve [AUC], 0.759) and the validation cohort (AUC, 0.667). A nomogram was created by combining Rad-score, treatment lines, and neutrophil-to-lymphocyte ratio (NLR). The training cohort obtained an AUC of 0.878 for the combined model, verified in the validation cohort (AUC = 0.875). Kaplan-Meier analyses showed the nomogram was associated with progression-free survival (PFS) (p = 0.0152) and intracranial progression-free survival (iPFS) (p = 0.0052) but not overall survival (OS) (p = 0.4894). CONCLUSION: A radiomics nomogram model for predicting the intracranial efficacy of ICIs in SCLC patients with BMs can provide suggestions for exploring individual-based treatments for patients.

HSPA4 regulated glioma progression via activation of AKT signaling pathway.

Glioma is still an incurable disease with high invasiveness. Heat shock 70 kDa protein 4 (HSPA4) is a member of the HSP110 family, and is associated with the development and progression of various cancers. In the current study, we assessed the expression of HSPA4 in clinical samples, and found that HSPA4 was up-regulated in glioma tissues and correlated with tumor recurrence and grade. Survival analyses demonstrated that glioma patients with high HSPA4 expression had lower overall survival and disease-free survival times. In vitro knockdown of HSPA4 inhibited glioma cell proliferation, mediated cell cycle arrest at G2 phase and apoptosis, and reduced the migration ability. In vivo, the growth of HSPA4-knockdown xenografts was markedly suppressed compared to the tumors formed by HSPA4-positive control cells. Additionally, Gene set enrichment analyses disclosed that HSPA4 was associated with the PI3K/Akt signaling pathway. The regulatory effect of the AKT activator SC79 on cell proliferation and apoptosis was suppressed by HSPA4 knockdown, indicating that HSPA4 is capable of promoting glioma development. In summary, these data showed that HSPA4 is likely to play a pivotal role in the progression of glioma, and consequently may be a promising therapeutic target for glioma therapy.

Single­nucleotide polymorphism rs6592645 confers asthma risk through regulating LRRC32 expression.

Asthma is a complex disease, often with evident genetic predisposition; for example, the single-nucleotide polymorphism (SNP) rs7130588 was significantly associated with asthma by genome-wide association study (GWAS). Analysis of 1000 Genomes Project data suggests that there is another SNP, rs6592645, in complete linkage disequilibrium with rs7130588 and should present the same signal in GWAS. However, the causal SNP and the mechanism for the association between rs7130588 and asthma remain to be elucidated. In the presents study, results from dual-luciferase assays indicated that the A/G alleles of rs7130588 failed to present significantly different reporter gene expression. By contrast, A allele of rs6592645 presented a significant increase in relative luciferase activity than G allele, thus suggesting that rs6592645 may be a causal SNP. Using chromosome conformation capture, the enhancer region containing rs6592645 was observed to interact with promoter region of leucine-rich repeat-containing 32 (LRRC32). Gene expression quantification suggested that LRRC32 expression is significantly increased in lung tissue of patients with asthma and is dependent on the genotype of this locus, thus verifying that LRRC32 may be involved in asthma onset and that rs6592645 can regulate LRRC32 expression. Through chromatin immunoprecipitation, transcription factor 3 (TCF3) was identified to bind to rs6592645 surrounding region and the interaction between TCF3 and rs6592645 surrounding region was investigated. Results from the present study may improve our understanding of the mechanism by which the genetic variation in this locus might influence asthma susceptibility.

Application of intraoperative radiotherapy for malignant glioma.

Malignant glioma is characterized by rapid tumor cell proliferation and high recurrence risk. In terms of its treatment, the therapeutic effects of maximum resection and postoperative radiotherapy with adjuvant chemotherapy as well as many other new therapeutic techniques such as antiangiogenic therapy and immunotherapy remain poor. Glioma recurrence, especially local recurrence, is an important reason of glioma treatment failure. Intraoperative radiotherapy (IORT) enables exclusion of radiation-sensitive normal tissue from the radiation field in operation and then the application of a single high-dose precision irradiation to the residual tumor or tumor bed. IORT has great application potential in the control of local recurrence of malignant tumors. This paper thus aims to review the current status and prospects of IORT's application in malignant glioma treatment.

Intra-Abdominal Hypertension Contributes to the Development of Ventilator-Associated Pneumonia from Intestinal Bacteria.

Introduction: Ventilator-associated pneumonia (VAP) is an ICU (intensive care unit)-acquired pulmonary parenchymal infection that is complicated by mechanical ventilation and is associated with high morbidity and mortality. Klebsiella pneumoniae (KPN) is known to asymptomatically colonize the gastrointestinal tract and may increase the incidence of corresponding VAP. Our study aims were to investigate the exact origin of the carbapenem-resistant Klebsiella pneumoniae (CRKP) causing VAP in our patient. Methods: Various environmental samples, including the patient's anal swab, were collected in order to find the source of the bacteria. Minimum inhibitory concentrations (MICs) for antimicrobial agents were determined according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI); resistant genes were detected by using PCR and sequencing; clone relationships were analyzed by using multilocus-sequence typing (MLST) and pulsed field gel electrophoresis (PFGE). The IAP values were obtained via urinary catheter. Results: One CRKP strain was detected in the patient's anal swab; this strain was confirmed with the same gene type as the strain isolated from the sputum. We found that the patient's intra-abdominal pressure (IAP) was 29.41, 27.06, 24.12, and 22.66 mmHg; the IAP was either equal to or above 12 mmHg, on the operation day and the following three days. Intra-abdominal hypertension (IAH) occurred during the patient's hospitalization and was considered to be caused by the surgical procedure. Meanwhile, we found that there was a correlation between IAH and the detection of CRKP in the sputum. The findings suggested that his VAP was caused by intestinal colonial KPN, and not from the environment. Discussion: Our research illustrated that the ST11 KPC-2-producing strain colonized the intestinal tract and caused the development of VAP when the IAP was elevated. Routine screening for the intestinal carriage of CRKP, among patients in ICUs, can limit and prevent current and future outbreaks.

Crystalline Structure and Thermal Stability of an Unknown ZIF-L300 Phase.

In recent years, the synthesis, crystalline structure, and applications of zeolite imidazole frameworks (ZIFs) have attracted extensive attention. Since the ZIF-L phase was synthesized, a new phase was observed during the heating process, but its crystal structure is unknown. The unknown new phase, which was named ZIF-L300 in this study, was confirmed again. In this study, the X-ray powder diffraction technique and Rietveld refinement were used to solve the crystalline structure of the unknown ZIF-L300 phase. The results demonstrate that ZIF-L300 has the same chemical formula (ZnC8N4H10) as in ZIF-8 and belongs to a hexagonal structure with a space group of P61. The lattice parameters have been determined as follows: a = b = 8.708(7) Å, c = 24.195(19) Å, α = ß = 90°, and γ = 120°. The X-ray absorption fine structure (XAFS) technique was also used to extract the local atomic structures. The in situ X-ray diffraction (XRD) technique was used to monitor the structural evolution of the as-prepared ZIF-L in a temperature range from room temperature to 600 °C. The results show that the sample experiences a change process from the initial ZIF-L orthorhombic phase (<210 °C), to the ZIF-L300 hexagonal phase (∼300 °C), then to an amorphous phase (∼390 °C), and finally to a zincite ZnO phase (>420 °C). These sorts of structural information are helpful to the application of ZIF materials and enrich the knowledge of the thermal stability of ZIF materials.

Network pharmacology and computer-aided drug design to explored potential targets of Lianhua Qingwen and Qingfei Paidu decoction for COVID-19.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, has spread globally, affecting people's lives worldwide and hindering global development. Traditional Chinese Medicine (TCM) plays a unique role in preventing and treating COVID-19. Representative prescriptions for the COVID-19 treatment, Lianhua Qingwen (LHQW) and Qingfei Paidu Decoction (QFPD), effectively alleviate COVID-19 symptoms, delaying its progression and preventing its occurrence. Despite the extensive similarity in their therapeutic effects, the mechanisms and advantages of LHQW and QFPD in in treating mild-to-moderate COVID-19 remain elusive. To characterize the mechanisms of LHQW and QFPD in treating COVID-19, we used integrated network pharmacology and system biology to compare the LHQW and QFPD components, active compounds and their targets in Homo sapiens. LHQW and QFPD comprise 196 and 310 active compounds, some of which have identical targets. These targets are enriched in pathways associated with inflammation, immunity, apoptosis, oxidative stress, etc. However, the two TCM formulas also have specific active compounds and targets. In LHQW, arctiin, corymbosin, and aloe-emodin target neurological disease-related genes (GRM1 and GRM5), whereas in QFPD, isofucosterol, baicalein, nobiletin, oroxylin A, epiberberine, and piperlonguminine target immunity- and inflammation-related genes (mTOR and PLA2G4A). Our findings indicate that LHQW may be suitable for treating mild-to-moderate COVID-19 with nervous system symptoms. Moreover, QFPD may effectively regulate oxidative stress damage and inflammatory symptoms induced by SARS-CoV-2. These findings may provide references for the clinical application of LHQW and QFPD.

Efficacy of stereotactic body radiation therapy for locoregional recurrent pancreatic cancer after radical resection.

Objective: This study aimed to analyze the efficacy and toxicity of stereotactic body radiotherapy (SBRT) for locoregional recurrent pancreatic cancer after radical resection. Methods: Patients with locoregional recurrent pancreatic cancer after surgery treated with SBRT in our institution were retrospectively investigated from January 2010 to January 2020. Absolute neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) recorded at pretreatment were analyzed. Endpoints included overall survival (OS), progression-free survival (PFS) and cumulative incidences of local failure (LF) and metastatic failure (MF). Results: A total of 22 patients received SBRT with a median prescribed dose of 40 Gy (range of 30-50 Gy)/4 to 7 fractions. The median OS of all patients was 13.6 months (95% CI, 9.6-17.5 months). 0-1 performance status (HR 12.10, 95% CI 2.04-71.81, P=0.006) and ≤2.1 pre-SBRT NLR (HR 4.05, 95% CI 1.21-13.59, P=0.023) were significant predictors of higher OS on multivariable analysis. The median progression-free survival (PFS) of the cohort was 7.5 months (95% CI, 6.5-8.5 months). The median time to LF and MF were 15.6 months and 6.4 months, respectively. The rate of MF as a first event was higher than that of first event LF. Pain relief was observed in all patients (100%) 6 weeks after SBRT. In terms of acute toxicity, grade 1 including fatigue (6, 27.3%), anorexia (6, 27.3%), nausea (4, 18.2%) and leukopenia (4, 18.2%) was often observed. No acute toxicity of grade 4 or 5 was observed. In terms of late toxicity, no treatment-related toxicity was found during follow-up. Conclusion: This study showed that SBRT can significantly reduce pain, effectively control local tumor progression, and have acceptable toxicity for patients with locoregional recurrence after radical resection of primary pancreatic cancer. Good performance status and lower pre-SBRT NLR were associated with improved overall survival.

Analysis of Intestinal Short-Chain Fatty Acid Metabolism Profile After Probiotics and GLP-1 Treatment for Type 2 Diabetes Mellitus.

Type 2 diabetes accounts for about 90% of diabetes patients, and the incidence of diabetes is on the rise as people's lifestyles change. Compared with GLP-1 treatment, probiotic treatment can directly regulate homeostasis of the host gut microbe, and thus homeostasis of its metabolites. Currently, the regulatory role of probiotics on intestinal metabolites after treatment of type 2 diabetes mellitus remains unclear. The purpose of this study was to investigate the therapeutic effect of probiotics on type 2 diabetes mellitus and its regulatory effect on short-chain fatty acids, which are metabolites of intestinal microorganisms. I collected feces from 15 patients with diabetes before treatment and 15 patients with type 2 diabetes after treatment with GLP-1 and probiotics. The abundance of short-chain fatty acids in feces was determined by GC-MS. Results Both GLP-1 and probiotics could improve the levels of blood glucose, urine glucose and BMI in patients with type 2 diabetes. After glP-1 treatment, two short-chain fatty acids (butyric acid and valerate acid) in intestine were significantly changed. Propionic acid and isovalerate were significantly changed after probiotic treatment. At the same time, KEGG signal pathway enrichment results showed that probiotics intervention mainly achieved the purpose of treating type 2 diabetes through regulating protein and carbohydrate metabolism. Taken together, our study shows changes in intestinal short-chain fatty acids after probiotics or GLP-1 treatment of type 2 diabetes, which will provide us with new insights into the mechanism of probiotics treatment of type 2 diabetes, as well as potential intervention targets for diabetes treatment.

Evaluation of Serologic Cross-Reactivity Between Dengue Virus and SARS-CoV-2 in Patients with Acute Febrile Illness - United States and Puerto Rico, April 2020-March 2021.

The diagnosis of dengue disease, caused by the dengue virus (DENV) (a flavivirus), often requires serologic testing during acute and early convalescent phases of the disease. Some symptoms of DENV infection, such as nonspecific fever, are similar to those caused by infection with SARS-CoV-2, the virus that causes COVID-19. In studies with few COVID-19 cases, positive DENV immunoglobulin M (IgM) results were reported with various serologic tests, indicating possible cross-reactivity in these tests for DENV and SARS-CoV-2 infections (1,2). DENV antibodies can cross-react with other flaviviruses, including Zika virus. To assess the potential cross-reactivity of SARS-CoV-2, DENV, and Zika virus IgM antibodies, serum specimens from 97 patients from Puerto Rico and 12 U.S.-based patients with confirmed COVID-19 were tested using the DENV Detect IgM Capture enzyme-linked immunosorbent assay (ELISA) (InBios International).* In addition, 122 serum specimens from patients with confirmed dengue and 121 from patients with confirmed Zika virus disease (all from Puerto Rico) were tested using the SARS-CoV-2 pan-Ig Spike Protein ELISA (CDC).† Results obtained for DENV, Zika virus IgM, and SARS-CoV-2 antibodies indicated 98% test specificity and minimal levels of cross-reactivity between the two flaviviruses and SARS-CoV-2. These findings indicate that diagnoses of dengue or Zika virus diseases with the serological assays described in this report are not affected by COVID-19, nor do dengue or Zika virus diseases interfere with the diagnosis of COVID-19.

Convergent Evidence Supports TH2LCRR as a Novel Asthma Susceptibility Gene.

Asthma is a common, complex disease with apparent genetic predispositions, and previous genome-wide association studies suggest that rs1295686 within the IL13 (IL-13) gene is significantly associated with asthma. Analysis of the data provided by the 1,000 Genomes Project indicated an additional four SNPs in nearly complete linkage disequilibrium with rs1295686 in White people. However, the causal SNPs and the associated mechanism remain unclear. To investigate this issue, functional genomics approaches were utilized to analyze the functions of these SNPs. Dual-luciferase assays indicated that the functional SNP is not rs1295686 but a haplotype consisting of three other SNPs: rs1295685, rs848, and rs847. Through chromosome conformation capture, it was found that the enhancer containing the three functional SNPs interacts with the promoter of TH2LCRR (T helper type 2 locus control region associated RNA), a recently identified long noncoding RNA. RNA-seq data analysis indicated that TH2LCRR expression is significantly increased in patients with asthma and is dependent on the genotype at this locus, indicating that TH2LCRR is a novel susceptibility gene for asthma and that these SNPs confer asthma risk by regulating TH2LCRR expression. By chromatin immunoprecipitation, the related transcription factors that bind in the region surrounding these three SNPs were identified, and their interactions were investigated by functional genomics approaches. Our effort identified a novel mechanism through which genetic variations at this locus could influence asthma susceptibility.

A deep learning based automatic segmentation approach for anatomical structures in intensity modulation radiotherapy.

OBJECTIVE: To evaluate the automatic segmentation approach for organ at risk (OARs) and compare the parameters of dose volume histogram (DVH) in radiotherapy. METHODOLOGY: Thirty-three patients were selected to contour OARs using automatic segmentation approach which based on U-Net, applying them to a number of the nasopharyngeal carcinoma (NPC), breast, and rectal cancer respectively. The automatic contours were transferred to the Pinnacle System to evaluate contour accuracy and compare the DVH parameters. RESULTS: The time for manual contour was 56.5 ± 9, 23.12 ± 4.23 and 45.23 ± 2.39min for the OARs of NPC, breast and rectal cancer, and for automatic contour was 1.5 ± 0.23, 1.45 ± 0.78 and 1.8 ± 0.56 min. Automatic contours of Eye with the best Dice-similarity coefficients (DSC) of 0.907 ± 0.02 while with the poorest DSC of 0.459 ± 0.112 of Spinal Cord for NPC; And Lung with the best DSC of 0.944 ± 0.03 while with the poorest DSC of 0.709 ± 0.1 of Spinal Cord for breast; And Bladder with the best DSC of 0.91 ± 0.04 while with the poorest DSC of 0.43 ± 0.1 of Femoral heads for rectal cancer. The contours of Spinal Cord in H & N had poor results due to the division of the medulla oblongata. The contours of Femoral head, which different from what we expect, also due to manual contour result in poor DSC. CONCLUSION: The automatic contour approach based deep learning method with sufficient accuracy for research purposes. However, the value of DSC does not fully reflect the accuracy of dose distribution, but can cause dose changes due to the changes in the OARs volume and DSC from the data. Considering the significantly time-saving and good performance in partial OARs, the automatic contouring also plays a supervisory role.

Re-irradiation of multiple brain metastases using CyberKnife stereotactic radiotherapy: Case report.

INTRODUCTION: Brain metastasis (BM) is the commonest adult intracranial malignancy and many patients with brain metastases require two course radiotherapy. Re-irradiation is frequently performed in Radiotherapy (RT) departments for multiple brain metastases. PATIENT CONCERNS: We present a case of a 55-year-old male patient suffering from brain metastases, who had previously received whole-brain radiotherapy (WBRT) and first CyberKnife Stereotactic Radiotherapy (CKSRT) for metastases, presented with a recurrence of metastasis and new lesions in the brain. DIAGNOSES: An enhanced computed tomography (CT) scan of the brain revealed abnormalities with double-dosing of intravenous contrast that identified >10 lesions scattered in the whole brain. INTERVENTIONS: Re-irradiation was performed using CKSRT. The patient was treated with 30 Gy in 5 fractions for new lesions and 25 Gy in 5 fractions for lesion that were locally recurrent and close to brainstem lesions. OUTCOME: The lesions were well-controlled, and the headache of the patient was significantly relieved one month after radiotherapy. The total survival time of the patients was 17 months from the beginning of the Cyberknife treatment. CONCLUSION: The present case report demonstrates that CyberKnife therapy plays a significant role in the repeated radiotherapy for multiple metastatic brain tumors. CKSRT can be used as a salvage method in recurrent multiple brain metastases.

Ruminants reveal Eocene Asiatic palaeobiogeographical provinces as the origin of diachronous mammalian Oligocene dispersals into Europe.

Faunal provincialism between the North and South parts of Eastern Asia is shown to have been in place since the late Eocene. This provincialism structured the mammalian dispersals across Eurasia for millions of years and provides insights into both palaeonvironments and palaeoclimate zonation. In addition, this study reveals the oldest record of a crown ruminant (Iberomeryx from Shinao, China). Ecologically, as well as economically, ruminant artiodactyls are one of the most important large mammal groups today. The revision of the ruminants from the Shinao Formation, from the Caijiachong marls and Xiaerhete, resulted in two new taxa and shows that the different provinces were populated by distinct taxa living in different environments, dominated by the monsoon in the South and drier conditions in the North. Evaluating this result in a Eurasian context demonstrates that the dispersals from Asia to Europe was complex. These results confirm that there were at least two dispersal events, distinct in space and time: the Grande-Coupure from Northern and Central Asia along the North ca. 34 Mya and the Bachitherium dispersal event from the Southern province along a southerly route ca. 31 Mya.

Bacteriostatic Potential of Melatonin: Therapeutic Standing and Mechanistic Insights.

Diseases caused by pathogenic bacteria in animals (e.g., bacterial pneumonia, meningitis and sepsis) and plants (e.g., bacterial wilt, angular spot and canker) lead to high prevalence and mortality, and decomposition of plant leaves, respectively. Melatonin, an endogenous molecule, is highly pleiotropic, and accumulating evidence supports the notion that melatonin's actions in bacterial infection deserve particular attention. Here, we summarize the antibacterial effects of melatonin in vitro, in animals as well as plants, and discuss the potential mechanisms. Melatonin exerts antibacterial activities not only on classic gram-negative and -positive bacteria, but also on members of other bacterial groups, such as Mycobacterium tuberculosis. Protective actions against bacterial infections can occur at different levels. Direct actions of melatonin may occur only at very high concentrations, which is at the borderline of practical applicability. However, various indirect functions comprise activation of hosts' defense mechanisms or, in sepsis, attenuation of bacterially induced inflammation. In plants, its antibacterial functions involve the mitogen-activated protein kinase (MAPK) pathway; in animals, protection by melatonin against bacterially induced damage is associated with inhibition or activation of various signaling pathways, including key regulators such as NF-κB, STAT-1, Nrf2, NLRP3 inflammasome, MAPK and TLR-2/4. Moreover, melatonin can reduce formation of reactive oxygen and nitrogen species (ROS, RNS), promote detoxification and protect mitochondrial damage. Altogether, we propose that melatonin could be an effective approach against various pathogenic bacterial infections.

Ironing Out the Details: How Iron Orchestrates Macrophage Polarization.

Iron fine-tunes innate immune responses, including macrophage inflammation. In this review, we summarize the current understanding about the iron in dictating macrophage polarization. Mechanistically, iron orchestrates macrophage polarization through several aspects, including cellular signaling, cellular metabolism, and epigenetic regulation. Therefore, iron modulates the development and progression of multiple macrophage-associated diseases, such as cancer, atherosclerosis, and liver diseases. Collectively, this review highlights the crucial role of iron for macrophage polarization, and indicates the potential application of iron supplementation as an adjuvant therapy in different inflammatory disorders relative to the balance of macrophage polarization.