Unleashing plant synthetic capacity: navigating regulatory mechanisms for enhanced bioproduction and secondary metabolite discovery.

Plant natural products (PNPs) hold significant pharmaceutical importance. The sessile nature of plants has led to the evolution of chemical defense mechanisms over millions of years to combat environmental challenges, making it a crucial and essential defense weapon. Despite their importance, the abundance of these bioactive molecules in plants is typically low, and conventional methods are time-consuming for enhancing production. Moreover, there is a pressing need for novel drug leads, exemplified by the shortage of antibiotics and anticancer drugs. Understanding how plants respond to stress and regulate metabolism to produce these molecules presents an opportunity to explore new avenues for discovering compounds that are typically under the detection limit or not naturally produced. Additionally, this knowledge can contribute to the advancement of plant engineering, enabling the development of new chassis for the biomanufacturing of these valuable molecules. In this perspective, we explore the intricate regulation of PNP biosynthesis in plants, and discuss the biotechnology strategies that have been and can be utilized for the discovery and production enhancement of PNPs in plants.

MR-based radiomics predictive modelling of EGFR mutation and HER2 overexpression in metastatic brain adenocarcinoma: a two-centre study.

OBJECTIVES: Magnetic resonance (MR)-based radiomics features of brain metastases are utilised to predict epidermal growth factor receptor (EGFR) mutation and human epidermal growth factor receptor 2 (HER2) overexpression in adenocarcinoma, with the aim to identify the most predictive MR sequence. METHODS: A retrospective inclusion of 268 individuals with brain metastases from adenocarcinoma across two institutions was conducted. Utilising T1-weighted imaging (T1 contrast-enhanced [T1-CE]) and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequences, 1,409 radiomics features were extracted. These sequences were randomly divided into training and test sets at a 7:3 ratio. The selection of relevant features was done using the least absolute shrinkage selection operator, and the training cohort's support vector classifier model was employed to generate the predictive model. The performance of the radiomics features was evaluated using a separate test set. RESULTS: For contrast-enhanced T1-CE cohorts, the radiomics features based on 19 selected characteristics exhibited excellent discrimination. No significant differences in age, sex, and time to metastasis were observed between the groups with EGFR mutations or HER2 + and those with wild-type EGFR or HER2 (p > 0.05). Radiomics feature analysis for T1-CE revealed an area under the curve (AUC) of 0.98, classification accuracy of 0.93, sensitivity of 0.92, and specificity of 0.93 in the training cohort. In the test set, the AUC was 0.82. The 19 radiomics features for the T2-FLAIR sequence showed AUCs of 0.86 in the training set and 0.70 in the test set. CONCLUSIONS: This study developed a T1-CE signature that could serve as a non-invasive adjunctive tool to determine the presence of EGFR mutations and HER2 + status in adenocarcinoma, aiding in the direction of treatment plans. CLINICAL RELEVANCE STATEMENT: We propose radiomics features based on T1-CE brain MR sequences that are both evidence-based and non-invasive. These can be employed to guide clinical treatment planning in patients with brain metastases from adenocarcinoma.

Polygalacturonase-inhibiting proteins as an exogenously applied natural solution for prevention of postharvest fungal infections.

Polygalacturonase inhibiting proteins (PGIPs) are plant proteins involved in the inhibition of polygalacturonases (PGs), cell-wall degrading enzymes often secreted by phytopathogenic fungi. Previously, we confirmed that PGIP2 from Phaseolus vulgaris (PvPGIP2) can inhibit the growth of Aspergillus niger and Botrytis cinerea on agar plate. In this study, we further validated the feasibility of using PGIP as an environmental and ecological friendly agent to prevent fungal infection post-harvest. We found that application of either purified PGIP (full length PvPGIP2 or truncated tPvPGIP2_5-8), or PGIP-secreting Saccharomyces cerevisiae strains can effectively inhibit fungal growth and necrotic lesions on tobacco leaf. We also examined the effective amount and thermostability of PGIP when applied on plants. A concentration of 0.75 mg/mL or higher can significantly reduce the area of B. cinerea lesions. The activity of full-length PvPGIPs is not affected after incubation at various temperatures ranging from -20 to 42 °C for 24 h, while truncated tPvPGIP2_5-8 lost some efficacy after incubation at 42 °C. Furthermore, we have also examined the efficacy of PGIP on tomato fruit. When the purified PvPGIP2 proteins were applied to tomato fruit inoculated with B. cinerea at a concentration of roughly 1.0 mg/mL, disease incidence and area of disease had reduced by more than half compared to the controls without PGIP treatment. This study explores the potential of PGIPs as exogenously applied, eco-friendly fungal control agents on fruit and vegetables post-harvest.

Tumor Microenvironment Remodeling-Mediated Sequential Drug Delivery Potentiates Treatment Efficacy.

Toll-like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off-target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4, termed CA4-NPs) and an immunotherapy nanocarrier (apcitide peptide-decorated poly(l-glutamic acid)-graft-IMDQ-N3 conjugate, termed apcitide-PLG-IMDQ-N3). CA4-NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide-PLG-IMDQ-N3 could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb-IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of "-N3" to "-NH2" in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor-specific CD8+ T cells, 4T1 and CT26 tumors with a size of ≈500 mm3 are eradicated without recurrence in mouse models.

IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia.

Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age. We established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse. Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1ß mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M delivery was an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.

Adenosinergic metabolism pathway: an emerging target for improving outcomes of solid organ transplantation.

Extracellular nucleotides are widely recognized as crucial modulators of immune responses in peripheral tissues. Adenosine triphosphate (ATP) and adenosine are key components of extracellular nucleotides, the balance of which contributes to immune homeostasis. Under tissue injury, ATP exerts its pro-inflammatory function, while the adenosinergic pathway rapidly degrades ATP to immunosuppressive adenosine, thus inhibiting excessive and uncontrolled inflammatory responses. Previous reviews have explored the immunoregulatory role of extracellular adenosine in various pathological conditions, especially inflammation and malignancy. However, current knowledge regarding adenosine and adenosinergic metabolism in the context of solid organ transplantation remains fragmented. In this review, we summarize the latest information on adenosine metabolism and the mechanisms by which it suppresses the effector function of immune cells, as well as highlight the protective role of adenosine in all stages of solid organ transplantation, including reducing ischemia reperfusion injury during organ procurement, alleviating rejection, and promoting graft regeneration after transplantation. Finally, we discuss the potential for future clinical translation of adenosinergic pathway in solid organ transplantation.

A latent class analysis of resilience and its association with patient-reported symptoms in patients with esophageal cancer after esophagectomy.

Purpose: To identify the latent classes of resilience in patients with esophageal cancer after esophagectomy and develop a deeper understanding of the association between these classes and patient-reported symptoms. Background: China accounts for more than half of the global burden of esophageal cancer, and patients with esophageal cancer experience numerous symptoms that affect their quality of life and prognosis. Given that resilience is a key element that alleviates the progression of symptoms, it may represent a potential means of to enhancing cancer patients' physical and psychological well-being. Methods: The study was implemented in the thoracic surgery departments of three tertiary hospitals in eastern China. The participants were patients who were still hospitalized after esophagectomy. Data were gathered by self-report questionnaires, and a latent class analysis was utilized to identify different categories of resilience among the patients. Results: A total of 226 patients were recruited. The three classes of resilience identified included high strength and striving (53.5%), medium resilience but weak self-recovery (35.9%), and minimal tenacity and external support (10.6%). Patients with low income (OR = 12.540, p = 0.004) were more likely to be in the minimal tenacity and external support class. Patients without comorbidities (OR = 2.413, p = 0.013) and aged 66-70 years (OR = 4.272, p < 0.001) were more likely to be in the high strength and striving class. The patient-reported symptoms and symptom-related interference of patients after esophagectomy varied considerably among the three categories of resilience. Conclusion: Accurate interventions should be devised and executed according to the features of each type of resilience in patients after esophagectomy to maximize intervention efficacy. These findings highlight the important role of precision nursing.

The mediating role of cognitive emotion regulation in the relationship between self-concealment and quality of life among breast cancer chemotherapy patients.

PURPOSE: This study aimed to explore whether self-concealment (SC) affects the quality of life (QOL), and whether cognitive emotion regulation (CER) mediates the relationship between SC and QOL among breast cancer chemotherapy patients. METHODS: This cross-sectional study was conducted among 228 breast cancer chemotherapy patients from November 2021 to March 2022 in Anhui Province, China. Data were collected using the Self-Concealment Scale, Cognitive Emotion Regulation Questionnaire, and Short Form 36 Questionnaire. Descriptive statistics, independent-sample t test, one-way analysis of variance, and structural equation modeling were used to explore associations among SC, CER, and QOL. RESULTS: QOL levels differed significantly by participant age, monthly per capita household income and home location. SC was negatively correlated with QOL. SSC was negatively correlated with adaptive-CER strategies and positively correlated with maladaptive-CER strategies. Adaptive-CER strategies were positively correlated with QOL. Maladaptive-CER strategies were negatively correlated with QOL. CER fully mediated the association between SC and QOL in breast cancer chemotherapy patients. CONCLUSION: Nursing staff should help breast cancer chemotherapy patients reduce the use of maladaptive-CER strategies in the care of patients in the future. Helping patients reduce SC is more conductive to improving the QOL of breast cancer chemotherapy patients.

The STROMICS genome study: deep whole-genome sequencing and analysis of 10K Chinese patients with ischemic stroke reveal complex genetic and phenotypic interplay.

Ischemic stroke is a leading cause of global mortality and long-term disability. However, there is a paucity of whole-genome sequencing studies on ischemic stroke, resulting in limited knowledge of the interplay between genomic and phenotypic variations among affected patients. Here, we outline the STROMICS design and present the first whole-genome analysis on ischemic stroke by deeply sequencing and analyzing 10,241 stroke patients from China. We identified 135.59 million variants, > 42% of which were novel. Notable disparities in allele frequency were observed between Chinese and other populations for 89 variants associated with stroke risk and 10 variants linked to response to stroke medications. We investigated the population structure of the participants, generating a map of genetic selection consisting of 31 adaptive signals. The adaption of the MTHFR rs1801133-G allele, which links to genetically evaluated VB9 (folate acid) in southern Chinese patients, suggests a gene-specific folate supplement strategy. Through genome-wide association analysis of 18 stroke-related traits, we discovered 10 novel genetic-phenotypic associations and extensive cross-trait pleiotropy at 6 lipid-trait loci of therapeutic relevance. Additionally, we found that the set of loss-of-function and cysteine-altering variants present in the causal gene NOTCH3 for the autosomal dominant stroke disorder CADASIL displayed a broad neuro-imaging spectrum. These findings deepen our understanding of the relationship between the population and individual genetic layout and clinical phenotype among stroke patients, and provide a foundation for future efforts to utilize human genetic knowledge to investigate mechanisms underlying ischemic stroke outcomes, discover novel therapeutic targets, and advance precision medicine.

Identification of a Prunus MAX1 homolog as a unique strigol synthase.

Strigol is the first identified and one of the most important strigolactones (SLs), but the biosynthetic pathway remains elusive. We functionally identified a strigol synthase (cytochrome P450 711A enzyme) in the Prunus genus through rapid gene screening in a set of SL-producing microbial consortia, and confirmed its unique catalytic activity (catalyzing multistep oxidation) through substrate feeding experiments and mutant analysis. We also reconstructed the biosynthetic pathway of strigol in Nicotiana benthamiana and reported the total biosynthesis of strigol in the Escherichia coli-yeast consortium, from the simple sugar xylose, which paves the way for large-scale production of strigol. As proof of concept, strigol and orobanchol were detected in Prunus persica root extrudes. This demonstrated a successful prediction of metabolites produced in plants through gene function identification, highlighting the importance of deciphering the sequence-function correlation of plant biosynthetic enzymes to more accurately predicate plant metabolites without metabolic analysis. This finding revealed the evolutionary and functional diversity of CYP711A (MAX1) in SL biosynthesis, which can synthesize different stereo-configurations of SLs (strigol- or orobanchol-type). This work again emphasizes the importance of microbial bioproduction platform as an efficient and handy tool to functionally identify plant metabolism.

Patient-derived models facilitate precision medicine in liver cancer by remodeling cell-matrix interaction.

Liver cancer is an aggressive tumor originating in the liver with a dismal prognosis. Current evidence suggests that liver cancer is the fifth most prevalent cancer worldwide and the second most deadly type of malignancy. Tumor heterogeneity accounts for the differences in drug responses among patients, emphasizing the importance of precision medicine. Patient-derived models of cancer are widely used preclinical models to study precision medicine since they preserve tumor heterogeneity ex vivo in the study of many cancers. Patient-derived models preserving cell-cell and cell-matrix interactions better recapitulate in vivo conditions, including patient-derived xenografts (PDXs), induced pluripotent stem cells (iPSCs), precision-cut liver slices (PCLSs), patient-derived organoids (PDOs), and patient-derived tumor spheroids (PDTSs). In this review, we provide a comprehensive overview of the different modalities used to establish preclinical models for precision medicine in liver cancer.

RAGE-TLR4 Crosstalk Is the Key Mechanism by Which High Glucose Enhances the Lipopolysaccharide-Induced Inflammatory Response in Primary Bovine Alveolar Macrophages.

The receptor of advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) are important receptors for inflammatory responses induced by high glucose (HG) and lipopolysaccharide (LPS) and show crosstalk phenomena in inflammatory responses. However, it is unknown whether RAGE and TLR4 can influence each other's expression through a crosstalk mechanism and whether the RAGE-TLR4 crosstalk related to the molecular mechanism of HG enhances the LPS-induced inflammatory response. In this study, the implications of LPS with multiple concentrations (0, 1, 5, and 10 µg/mL) at various treatment times (0, 3, 6, 12, and 24 h) in primary bovine alveolar macrophages (BAMs) were explored. The results showed that a 5 µg/mL LPS treatment at 12 h had the most significant increment on the pro-inflammatory cytokine interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor (TNF)-α levels in BAMs (p < 0.05) and that the levels of TLR4, RAGE, MyD88, and NF-κB p65 mRNA and protein expression were upregulated (p < 0.05). Then, the effect of LPS (5 µg/mL) and HG (25.5 mM) co-treatment in BAMs was explored. The results further showed that HG significantly enhanced the release of IL-1ß, IL-6, and TNF-α caused by LPS in the supernatant (p < 0.01) and significantly increased the levels of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression (p < 0.01). Pretreatment with FPS-ZM1 and TAK-242, the inhibitors of RAGE and TLR4, significantly alleviated the HG + LPS-induced increment of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression in the presence of HG and LPS (p < 0.01). This study showed that RAGE and TLR4 affect each other's expression through crosstalk during the combined usage of HG and LPS and synergistically activate the MyD88/NF-κB signaling pathway to promote the release of pro-inflammatory cytokines in BAMs.

Investigation of the Effect of Rice Bran Content on the Antioxidant Capacity and Related Molecular Conformations of Plant-Based Simulated Meat Based on Raman Spectroscopy.

At present, plant-based simulated meat is attracting more and more attention as a meat substitute. This study discusses the possibility of partial substitution of rice bran (RB) for soybean protein isolate (SPI) in preparing plant-based simulated meat. RB was added to SPI at 0%, 5%, 10%, 15%, and 20% to prepare RB-SPI plant-based simulated meat by the high moisture extrusion technique. RB-SPI plant-based simulated meat revealed greater polyphenol content and preferable antioxidant capacity (DPPH radical scavenging capacity, ABTS scavenging ability, and FRAP antioxidant capacity) compared to SPI plant-based simulated meat. The aromatic amino acids (tryptophan and tyrosine) of RB-SPI plant-based simulated meats tend to be masked first, and then the hydrophobic groups are exposed as RB content increases and the polarity of the surrounding environment increases due to the change in the disulfide conformation of RB-SPI plant-based simulated meats from a stable gauche-gauche-gauche conformation to a trans-gauche-trans conformation.

A depression network caused by brain tumours.

To systematically analyse and discuss whether suppressive heterogeneous brain tumours (BTs) belong to a common brain network and provide a theoretical basis for identifying BT patients with a high risk of depression and select therapeutic targets for clinical treatment. The PubMed database was systematically searched to obtain relevant case reports, and lesion locations were manually traced to standardised brain templates according to ITK-SNAP descriptive literature. Resting-state functional magnetic resonance imaging data sets were collected from 1,000 healthy adults aged 18-35 years. Each lesion location or functional connectivity area of the lesion network. Connectivity analysis was performed in an MN152 space, and Fisher z-transformation was applied to normalise the distribution of each value in the functional connectivity correlation map, and T maps of each tumour location network were calculated with the T score of individual voxels. This T score indicates the statistical significance of voxelwise connectivity at each tumour location. The lesion networks were thresholded at T = 7, creating binarised maps of brain regions connecting tumour locations, overlaying network maps to identify tumour-sensitive hubs and also assessing specific hubs with other conditional controls. A total of 18 patients describing depression following focal BTs were included. Of these cases, it was reported that depression-related tumours were unevenly distributed in the brain: 89% (16/18) were positively correlated with the left striatum, and the peak of the left striatum lesion network continuously overlapped. The depression-related tumour location was consistent with the tumour suppressor network (89%). These results suggest that sensitive hubs are aligned with specific networks, and specific hubs are aligned with sensitive networks. Brain tumour-related depression differs from acute lesion-related depression and may be related to the mapping of tumours to depression-related brain networks. It can provide an observational basis for the neuroanatomical basis of BT-related depression and a theoretical basis for identifying patients with BTs at high risk of depression and their subsequent clinical diagnosis and treatment.

Novel application of the traditional lipid ratios as strong risk predictors of nonsmall-cell lung cancer risk in a Chinese population.

Dyslipidemia has been associated with cancer risk, yet the relationship between lipid ratios and nonsmall-cell lung cancer (NSCLC) is still unclear. This study aimed to explore the value of lipid ratios, including total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) and triglyceride/HDL-C (TG/HDL-C) as predictors of NSCLC in a Chinese population. Adult patients with histologically confirmed NSCLC, without a previous history of cancer, concomitant disease associated with lipid metabolism disorders, or usage of lipid-lowering drugs, were enrolled from a single center. Controls without NSCLC, matched for age and sex, were enrolled from the same Center. Lipid profile including TC, TG, HDL-C were measured in all participants. TC/HDL-C and TG/HDL-C were calculated based on the levels of TC, TG, HDL-C. Seven hundred eighty-two NSCLC cases and 599 controls were enrolled. NSCLC patients had significantly higher TG/HDL-C and TC/HDL-C levels than those in the control. After controlling for confounding factors, TG/HDL-C (OR = 4.489, 95% CI: 2.463-6.035, P < .001) and TC/HDL-C (OR = 2.396, 95% CI: 2.086-2.752, P = .001) were independently associated with NSCLC risk. The incidence of NSCLC was increased with rising tertiles of TG/HDL-C and TC/HDL-C. Moreover, patients with TNM II-IV stage NSCLC had higher TG/HDL-C and TC/HDL-C than those in TNM I and Tis stage. TG/HDL-C and TC/HDL-C are positively correlated with NSCLC risk and TG/HDL-C is more predictive than TC/HDL-C in predicting the risk of NSCLC. The highest AUC was that of TG/HDL (0.898), at a cutoff point of 0.62, with 83.6% sensitivity and 83.5% specificity.

A red-light activatable and mitochondrion-targeting PtIV complex to overcome drug resistance.

The therapeutic effects of platinum anticancer drugs are commonly whittled away by drug resistance, which is associated with drug efflux and the nucleotide excision repair (NER) pathway. Activation of drugs in a spatiotemporally controllable manner in the mitochondria of cancer cells is a very promising strategy to alleviate these problems. In this work, PtIV-PS2, a cisplatin-based PtIV prodrug, was designed to release cisplatin inside the mitochondria on red light exposure. This PtIV complex could be effectively reduced to PtII species under irradiation. PtIV-PS2 very effectively accumulates in the mitochondria of cancer cells through active transport. After photoactivation, PtIV-PS2 showed higher cytotoxicity than cisplatin in the cisplatin-resistant carcinoma cells and the amount of Pt in genomic DNA was elevated. Moreover, PtIV-PS2 decreased the cellular mitochondrial membrane potential (MMP) and the cellular content of ATP. This work developed a promising window for the design of controllably activated and mitochondrion-targeting PtIV prodrugs to overcome drug resistance of chemotherapy.

The protective role of mesencephalic astrocyte-derived neurotrophic factor in endoplasmic reticulum stress in RT4-D6P2T schwannoma sells with the S63del MPZ mutation.

BACKGROUND: Endoplasmic reticulum stress (ERS) occurred in S63del mutant CMT1B mice model, and few drugs has been studied. Mesencephalic astrocyte-derived neurotrophic factor (MANF) can inhibit ERS. This study aimed at investigating the effect of MANF on ERS of RT4-D6P2T schwannoma cells with S63del MPZ Mutation. METHODS: Experimental grouping: blank control group, blank control + MANF group, lentivirus group, lentivirus + MANF group, S63del MPZ group, S63del MPZ + MANF group. CCK8 and Annexin-FITC/PI were used to detect cell proliferation and apoptosis. JC-1 was used to detect ΔΨm. MANF, GRP78 and CHOP mRNA and protein were detected by using RT-qPCR, western blotting and immunofluorescence. ER-Tracker and mito-tracker were used to observe the morphology of endoplasmic reticulum (ER) and mitochondria. RESULTS: Cell proliferation decreased (p < 0.001) and apoptosis increased (p < 0.001) in S63del MPZ group; cell proliferation increased (p = 0.005) and apoptosis decreased (p < 0.001) in S63del MPZ + MANF group. ΔΨm decreased (p < 0.001), MANF, GRP78, CHOP, ATF6, P-PERK/PERK, P-IRE1/IRE1, Bax and Caspase3 increased (p < 0.001) and Bcl2 decreased (p < 0.001) in S63del MPZ group. MANF, GRP78, CHOP, ATF6, P-PERK/PERK, P-IRE1/IRE1, Bax and Caspase3 decreased (p < 0.001) and Bcl2 increased (p < 0.001) in S63del MPZ group. CONCLUSIONS: ERS occurred in RT4-D6P2T cells with S63del MPZ mutation, and MANF exerted protective effect in RT4-D6P2T cells with S63del MPZ mutation.

Mechanism of extracellular space changes in cryptococcal brain granuloma revealed by MRI tracer.

Purpose: This study aimed to investigate the changes in extracellular space (ECS) in cryptococcal brain granuloma and its pathological mechanism. Materials and methods: The animal model of cryptococcal brain granuloma was established by injecting 1 × 106 CFU/ml of Cryptococcus neoformans type A suspension into the caudate nucleus of Sprague-Dawley rats with stereotactic technology. The infection in the brain was observed by conventional MRI scanning on days 14, 21, and 28 of modeling. The tracer-based MRI with a gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a magnetic tracer was performed on the rats with cryptococcal granuloma and the rats in the control group. The parameters of ECS in each area of cryptococcal brain granuloma were measured. The parameters of ECS in the two groups were compared by independent sample t-test, and the changes in ECS and its mechanism were analyzed. Results: Up to 28 days of modeling, the success rate of establishing the brain cryptococcal granuloma model with 1 × 106 CFU/ml Cryptococcus neoformans suspension was 60%. In the internal area of cryptococcal granuloma, the effective diffusion coefficient D* was significantly higher than that of the control group (t = 2.76, P < 0.05), and the same trend showed in the volume ratio α (t = 3.71, P < 0.05), the clearance rate constant k (t = 3.137, P < 0.05), and the tracer half-life T1/2 (t = 3.837, P < 0.05). The tortuosity λ decreased compared with the control group (t = -2.70, P < 0.05). At the edge of the cryptococcal granuloma, the D* and α decreased, while the λ increased compared with the control group (D*:t = -6.05, P < 0.05; α: t = -4.988, P < 0.05; λ: t = 6.222, P < 0.05). Conclusion: The internal area of the lesion demonstrated a quicker, broader, and more extended distribution of the tracer, while the edge of the lesion exhibited a slower and narrower distribution. MRI tracer method can monitor morphological and functional changes of ECS in pathological conditions and provide a theoretical basis for the treatment via ECS.

Resistin, a Novel Host Defense Peptide of Innate Immunity.

Resistin, a cysteine-rich protein, expressed in adipocytes, was initially proposed as a link between obesity and diabetes in mice. In humans, resistin is considered to be a pro-inflammatory molecule expressed in immune cells, which plays a regulatory role in many chronic inflammatory diseases, metabolic diseases, infectious diseases, and cancers. However, increasing evidence shows that resistin functions as a host defense peptide of innate immunity, in terms of its wide-spectrum anti-microbial activity, modulation of immunity, and limitation of microbial product-induced inflammation. To date, the understanding of resistin participating in host defense mechanism is still limited. The review aims to summarize current knowledge about the biological properties, functions, and related mechanisms of resistin in host defense, which provides new insights into the pleiotropic biological function of resistin and yields promising strategies for developing new antimicrobial therapeutic agents.