Short-chain fatty acids: bridges between diet, gut microbiota, and health.

In recent years, gut microbiota has become a hot topic in the fields of medicine and life sciences. Short-chain fatty acids (SCFAs), the main metabolites of gut microbiota produced by microbial fermentation of dietary fiber, play a vital role in healthy and ill hosts. SCFAs regulate the process of metabolism, immune, and inflammation and have therapeutic effects on gastrointestinal and neurological disorders, as well as antitumor properties. This review summarized the production, distribution, and molecular mechanism of SCFAs, as well as their mechanisms of action in healthy and ill hosts. In addition, we also emphasized the negative effects of SCFAs, aiming to provide the public with a more comprehensive understanding of SCFAs.

Immune Checkpoint Neuropilins as Novel Biomarkers and Therapeutic Targets for Pancreatic Cancer.

The traditional immune checkpoint blockade therapy benefits some patients with cancer, but elicits no response in certain cancers, such as pancreatic adenocarcinoma (PAAD); thus, novel checkpoints and effective targets are required. Here, we found that there was a higher Neuropilin (NRP) expression in tumor tissues as novel immune checkpoints, which was associated with poor prognosis and pessimistic responses to immune checkpoint blockade therapy. In the tumor microenvironment of PAAD samples, NRPs were widely expressed in tumor, immune and stromal cells. The relationship of NRPs with tumor immunological features in PAAD and pan-cancer was evaluated using bioinformatics methods; it was positively correlated with the infiltration of myeloid immune cells and the expression of most immune checkpoint genes. Bioinformatics analysis, in vitro and in vivo experiments suggested that NRPs exhibit potential immune-related and immune-independent pro-tumor effects. NRPs, especially NRP1, are attractive biomarkers and therapeutic targets for cancers, particularly PAAD.

Renal-hepatic-pancreatic dysplasia-1 with a novel NPHP3 genotype: a case report and review of the literature.

BACKGROUND: Renal-hepatic-pancreatic dysplasia type 1 (RHPD1) is a rare sporadic and autosomal recessive disorder with unknown incidence. RHPD1 is caused by biallelic pathogenic variants in NPHP3, which encode nephrocystin, an important component of the ciliary protein complex. CASE PRESENTATION: In this case report, we describe a male newborn who was confirmed by ultrasound to have renal enlargement with multiple cysts, pancreatic enlargement with cysts, and increased liver echogenicity, leading to the clinical diagnosis of RHPD. In addition, a compound heterozygous pathogenic variant, namely, NPHP3 c.1761G > A (p. W587*) and the c.69delC (p. Gly24Ala24*11) variant, was detected by WES. The patient was clinically and genetically diagnosed with RHPD1. At 34 h of life, the infant died of respiratory insufficiency. CONCLUSION: This is the first published case of RHPD1 in China. This study broadens the known range of RHPD1 due to NPHP3 pathogenic variants.

The Role and Mechanism of Autophagy in Pancreatic Cancer: An Update Review.

Pancreatic cancer, with high morbidity and mortality rates, is one of the most malignant tumors worldwide. Despite extensive research, the prognosis remains poor. Autophagy, a lysosomal-mediated, highly conserved degradation process that removes abnormal proteins and damaged organelles from the body, is upregulated in pancreatic ductal adenocarcinoma. Based on differences in the tumor microenvironment and tumor stage, the functions of autophagy in the pathophysiology and treatment of pancreatic cancer differ. In the initial phase, autophagy inhibits the transformation of precancerous lesions to cancer. However, in the progressive stage, autophagy promotes tumor growth. Autophagy is also one of the main mechanisms of drug resistance during treatment. Here, we describe the role of autophagy in pancreatic cancer progression and discuss relevant treatment strategies for this disease.

Gut Microbiome-Mediated Alteration of Immunity, Inflammation, and Metabolism Involved in the Regulation of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of end-stage liver disease, leading to a rapidly growing global public health burden. The term "gut microbiome (GM)" refers to the approximately 100 trillion microbial cells that inhabit the host's gastrointestinal tract. There is increasing evidence that GM is involved in the pathogenesis of NAFLD and may be a potential target for intervention. To explore GM-based strategies for precise diagnosis and treatment of NAFLD, great efforts have been made to develop a comprehensive and in-depth understanding of the host-microbe interaction. This review evaluates this interaction critically, mainly considering the intricate regulation of the metabolism, immunity, and inflammatory status during the evolution of the disease pathogenesis, revealing roles for the GM in NAFLD by examining advances in potential mechanisms, diagnostics, and modulation strategies. Synopsis: Considering the intricate metabolic and immune/inflammatory homeostasis regulation, we evaluate the latest understanding of the host-microbe interaction and reveal roles for the gastrointestinal microbiome in NAFLD. Strategies targeting the gastrointestinal microbiome for the diagnosis and treatment of NAFLD are proposed.

Granulocyte-macrophage colony-stimulating factor protects mice against hepatocellular carcinoma by ameliorating intestinal dysbiosis and attenuating inflammation.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. The gut microbiota can help maintain healthy metabolism and immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical factor in promoting health and homeostasis; it promotes intestinal immunity, stimulates bone marrow precursors to generate macrophage colonies, and enhances the antibacterial and antitumor activity of circulating monocytes. As such, GM-CSF may protect against HCC development by regulating immunity as well as intestinal microecology. AIM: To investigate the impact of GM-CSF on the gut microbiome and metabolic characteristics of HCC. METHODS: Thirty-six male BALB/c nude mice were divided into three groups: Control (n = 10), HCC (n = 13), and HCC + GM-CSF (GM-CSF overexpression, n = 13). We utilized HCC cells to establish orthotopic transplantation tumor models of HCC with normal and over-expressing GM-CSF. Liver injury, immune inflammatory function and intestinal barrier function were evaluated. The fecal microbiome and metabolome were studied using 16S rRNA absolute quantification sequencing and gas chromatography-mass spectrometry. RESULTS: GM-CSF overexpression significantly affected the gut microbiome of mice with HCC and resulted in a high abundance of organisms of the genera Roseburia, Blautia and Butyricimonass, along with a significant reduction in Prevotella, Parabacteroides, Anaerotruncus, Streptococcus, Clostridium, and Mucispirillum. Likewise, GM-CSF overexpression resulted in a substantial increase in fecal biotin and oleic acid levels, along with a prominent decrease in the fecal succinic acid, adenosine, fumaric acid, lipoic acid, and maleic acid levels. Correlation analysis revealed that the intestinal microbiota and fecal metabolites induced by GM-CSF were primarily involved in pathways related to reducing the inflammatory response, biotin metabolism, and intestinal barrier dysfunction. CONCLUSION: GM-CSF can protect against HCC development by regulating immunity and modulating the abundance of specific intestinal microorganisms and their metabolites. This study provides new insights into the therapeutic approaches for HCC.

NRP1 is a Prognostic Factor and Promotes the Growth and Migration of Cells in Intrahepatic Cholangiocarcinoma.

BACKGROUND: Neuropilin-1 (NRP-1) participates in cancer cell proliferation and metastasis as a multifunctional co-receptor by interacting with multiple signaling pathways. However, few studies have addressed the precise function and prognosis analysis of NRP1 in intrahepatic cholangiocarcinoma (ICC). We aimed to study the correlations between NRP1 and clinicopathological characteristics and NRP1 effect on ICC cell line functions. METHODS: NRP1 mRNA and its protein levels in human ICC tissues and cell lines were detected by IHC, qRT-PCR, and WB method. Transwell, wound healing, and CCK-8 assays were performed to verify the effects of NRP1 knockdown and overexpression on cell migration and proliferation capability. RESULTS: NRP1 proteins and mRNA levels increased in ICC tissues compared to those in paired adjacent non-tumor tissues. High NRP1 expression of ICC tissues was related to poor prognosis. NRP1 expression level was expected to be an independent prognosticator for overall survival and cumulative tumor recurrence, and was closely related to tumor number (P=0.047). Knockdown of NRP1 inhibited cell proliferation and migration capability of RBE cells in vitro, and NRP1 overexpression in 9810 cells accelerated proliferation and migration. Additionally, NRP1 may promote cell proliferation and migration in ICC via the FAK/PI3-K/AKT pathway. CONCLUSION: As an oncogene, NRP1 may function as a candidate target and prognostic biomarker of value for ICC therapy.

Intestinal Flora as a Potential Strategy to Fight SARS-CoV-2 Infection.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly worldwide, seriously endangering human health. In addition to the typical symptoms of pulmonary infection, patients with COVID-19 have been reported to have gastrointestinal symptoms and/or intestinal flora dysbiosis. It is known that a healthy intestinal flora is closely related to the maintenance of pulmonary and systemic health by regulating the host immune homeostasis. Role of the "gut-lung axis" has also been well-articulated. This review provides a novel suggestion that intestinal flora may be one of the mediators of the gastrointestinal responses and abnormal immune responses in hosts caused by SARS-CoV-2; improving the composition of intestinal flora and the proportion of its metabolites through probiotics, and personalized diet could be a potential strategy to prevent and treat COVID-19. More clinical and evidence-based medical trials may be initiated to determine the strategy.

Neuropilin1 silencing impairs the proliferation and migration of cells in pancreatic cancer.

BACKGROUND: Neuropilin1 (NRP1) participates in cancer cell proliferation, migration, and metastasis as a multifunctional co-receptor by interacting with multiple signal pathways, but few studies have addressed the precise function of NRP1 in pancreatic cancer (PACA) cells. We aimed to study whether NRP1 gene silencing involved in the proliferation and migration of PACA cells in vitro. METHODS: A lentiviral vector expressing NRP1 shRNA was constructed and transfected into human PACA cells (CFPAC-1 and PANC-1). The expression of NRP1 protein and mRNA was detected by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) assay, respectively. CCK-8 assay, wound healing assay, and transwell assay were conducted to examine the effect of NRP1 silencing on cells proliferation and migration capability. RESULTS: Results of qRT-PCR and Western blot showed successfully established, stably transfected shRNA-NRP1 cells in PACA cells. The proliferation capacity of PACA cells in NRP1 shRNA group was lower significantly than that in the negative control (NC) group (P < .05). The invasion and migration capability of PACA cells in NRP1 shRNA group was lower significantly than that in the NC group (P < .01). CONCLUSIONS: NRP1-shRNA lentiviral interference vectors can effectively decrease NRP1 gene expression in PACA cells, thereby inhibiting cells proliferation and migration, which provides a basis for finding a valuable therapeutic target for PACA therapy.

[Parameter sensitivity of simulating net primary productivity of Larix olgensis forest based on BIOME-BGC model].

Model based on vegetation ecophysiological process contains many parameters, and reasonable parameter values will greatly improve simulation ability. Sensitivity analysis, as an important method to screen out the sensitive parameters, can comprehensively analyze how model parameters affect the simulation results. In this paper, we conducted parameter sensitivity analysis of BIOME-BGC model with a case study of simulating net primary productivity (NPP) of Larix olgensis forest in Wangqing, Jilin Province. First, with the contrastive analysis between field measurement data and the simulation results, we tested the BIOME-BGC model' s capability of simulating the NPP of L. olgensis forest. Then, Morris and EFAST sensitivity methods were used to screen the sensitive parameters that had strong influence on NPP. On this basis, we also quantitatively estimated the sensitivity of the screened parameters, and calculated the global, the first-order and the second-order sensitivity indices. The results showed that the BIOME-BGC model could well simulate the NPP of L. olgensis forest in the sample plot. The Morris sensitivity method provided a reliable parameter sensitivity analysis result under the condition of a relatively small sample size. The EFAST sensitivity method could quantitatively measure the impact of simulation result of a single parameter as well as the interaction between the parameters in BIOME-BGC model. The influential sensitive parameters for L. olgensis forest NPP were new stem carbon to new leaf carbon allocation and leaf carbon to nitrogen ratio, the effect of their interaction was significantly greater than the other parameter' teraction effect.

Investigation of dentin hardness in roots exhibiting the butterfly effect.

INTRODUCTION: Most vertical root fractures occur in root canal treated teeth, and they usually run in a buccolingual direction. The butterfly effect is an optical phenomenon seen in some sections of tooth roots. The aim was to investigate the microhardness of dentin in mesiodistal and buccolingual cross sections of roots exhibiting the effect. METHODS: Thirty extracted single-rooted teeth were allocated according to patient age: group 1, 15-24 years; group 2, 25-44 years; and group 3, 45 years and older. Roots were embedded in acrylic and cut into ten 1-mm-thick cross sections. Sections were viewed under a light microscope and coded (1 or 2) according to presence or absence of the butterfly effect. A root scored 20 when all levels featured the butterfly appearance. The 2 teeth with the highest score from each group and 2 control teeth with the minimum score (10) were selected. Two adjacent, consecutive cross sections were chosen from the middle of the roots. Vickers microhardness testing was carried out on the dentin walls. RESULTS: Mean hardness scores were highest mesiodistally (83.7 kgf/mm(2)) and lowest buccolingually (56.4 kgf/mm(2)), a significant difference (P = .028). This trend was found across all age groups. CONCLUSIONS: Root sections with the butterfly effect are harder mesiodistally. This might explain the high prevalence of vertical root fractures that run buccolingually.

[Influence of fruit size of Camellia meiocarpa on growth of oil tea weevil, Curculio chinensis (Coleoptera: Curculionidae)].

The relationship between mature larval mass of oil tea weevil (Curculio chinensis) and fruit volume of its host plant oil tea (Camellia meiocarpa) was fitted with Logistic equation in order to understand the restriction of host fruit size on large larval growth and development of the weevil. The results showed that the larval mass increased with the increasing host fruit volume, which was in good conformity with the Logistic model. The weevil larval growth followed the principle of diminishing marginal utility, and it could be divided into two periods, the fast-growing period (<3.216 cm3, one larva per fruit; <4.747 cm3, two larvae per fruit ) and the asymptotic growing period (>3.216 cm3, one larva per fruit; >4.747 cm3, two larvae per fruit). The minimum fruit size threshold was 1500 cm3 for one larva per fruit, and 2.539 cm3 for two larvae per fruit. The temporal pattern that the mature larvae exited from their host fruits was established, the number of larvae escaping from their host fruits decreased daily after the fruit collection, and the larval escaping peak largely appeared from 6:00 to 10:00 AM with 43.9% of total escaping number, and especially from 7:00 to 8:00 AM with 21.1% of total escaping number. The bigger the larvae, the earlier exited from their host fruits. The restriction of fruit size on growth and development of oil tea weevil was observed, and it should be a behavioral adaptation strategy to increase the offspring' s fitness for the parental weevil adults to oviposit on the bigger fruits.

CHL1 is involved in human breast tumorigenesis and progression.

Neural cell adhesion molecules (CAM) play important roles in the development and regeneration of the nervous system. The L1 family of CAMs is comprised of L1, Close Homolog of L1 (CHL1, L1CAM2), NrCAM, and Neurofascin, which are structurally related trans-membrane proteins in vertebrates. Although the L1CAM has been demonstrated play important role in carcinogenesis and progression, the function of CHL1 in human breast cancer is limited. Here, we found that CHL1 is down-regulated in human breast cancer and related to lower grade. Furthermore, overexpression of CHL1 suppresses proliferation and invasion in MDA-MB-231 cells and knockdown of CHL1 expression results in increased proliferation and invasion in MCF7 cells in vitro. Finally, CHL1 deficiency promotes tumor formation in vivo. Our results may provide a strategy for blocking breast carcinogenesis and progression.

Molecular clone and expression of a NAD+-dependent glycerol-3-phosphate dehydrogenase isozyme gene from the halotolerant alga Dunaliella salina.

Glycerol is an important osmotically compatible solute in Dunaliella. Glycerol-3-phosphate dehydrogenase (G3PDH) is a key enzyme in the pathway of glycerol synthesis, which converts dihydroxyacetone phosphate (DHAP) to glycerol-3-phosphate. Generally, the glycerol-DHAP cycle pathway, which is driven by G3PDH, is considered as the rate-limiting enzyme to regulate the glycerol level under osmotic shocks. Considering the peculiarity in osmoregulation, the cDNA of a NAD(+)-dependent G3PDH was isolated from D. salina using RACE and RT-PCR approaches in this study. Results indicated that the length of the cDNA sequence of G3PDH was 2,100 bp encoding a 699 amino acid deduced polypeptide whose computational molecular weight was 76.6 kDa. Conserved domain analysis revealed that the G3PDH protein has two independent functional domains, SerB and G3PDH domains. It was predicted that the G3PDH was a nonsecretory protein and may be located in the chloroplast of D. salina. Phylogenetic analysis demonstrated that the D. salina G3PDH had a closer relationship with the G3PDHs from the Dunaliella genus than with those from other species. In addition, the cDNA was subsequently subcloned in the pET-32a(+) vector and was transformed into E. coli strain BL21 (DE3), a expression protein with 100 kDa was identified, which was consistent with the theoretical value.

A natural functionally graded biocomposite coating--human enamel.

Human enamel has been found to be a coating with excellent mechanical performance, and has undergone extensive investigation and discussion. However, most of the reported studies consider the enamel as a homogeneous anisotropic biocomposite. The current study illustrated the graded properties of the biocomposite from its functional load-bearing direction. Within the thickness of the enamel, from the outer surface towards the enamel-dentin junction (EDJ), the elastic modulus (E(x)) and hardness (H(x)) of enamel exist in an exponential relationship with normalized thickness (x) as E(x)=111.64x(0.18) (R(2)=0.94) and H(x)=4.41x(0.16) (R(2)=0.87) GPa, respectively. Moreover, the creep ability of enamel increases towards the EDJ. The graded properties of the biocomposite can be explained by both microstructural and compositional changes along the thickness of the material towards the EDJ. Finite element analysis indicates that the graded properties of enamel have important roles in reducing the enamel-dentin interface stresses and maintaining the integrity of the multilayer tooth structure. The results provide a new angle to understand the excellent mechanical behaviour of the multilayer tooth structure and may inspire the development of new functionally graded materials and coating structures.

An evaluation of dental operative simulation materials.

The study was to evaluate the performance of different materials used in dental operative simulation and compare them with those of natural teeth. Three typical phantom teeth materials were compared with extracted permanent teeth by a nanoindentation system and evaluated by students and registered dentists on the drilling sensation of the materials. Moreover, the tool life (machinability) of new cylindrical diamond burs on cutting the sample materials was tested and the burs were observed. Although student and dentist evaluations were scattered and inconclusive, it was found that elastic modulus (E) and hardness (H) were not the main factors in determining the drilling sensation of the materials. The sensation of drilling is a reflection of cutting force and power consumption.An ideal material for dental simulation should be able to generate similar drilling resistance to that of natural tooth, which is the machinability of the material.

A comparison of pressure generated by cordless gingival displacement techniques.

STATEMENT OF PROBLEM: Handling properties of cordless gingival displacement materials is not well understood, resulting in incorrect use. Insufficient displacement of the gingival margin may result in a poor impression. PURPOSE: This study investigated the pressure generated by a cordless displacement paste with respect to different techniques. MATERIAL AND METHODS: Two chambers with dimensions of 5 × 5 × 2 mm were made from Type IV stone and silicone material to simulate a rigid and elastic environment. A pressure gage was embedded into the wall of the chamber, and a paste material (Expasyl) was injected into the different chambers. The final pressures generated by the Expasyl were recorded by Chart 5 software and Power Lab system. This was repeated by using a displacement cord (KnitTrax) as a control for the study. The different loading methods for the Expasyl material were compared with 1-way ANOVA (α=.05). RESULTS: The mean pressure generated during placement of the Expasyl paste material in the silicone chamber was 143 kPa, which is significantly lower (P=.001) than the pressure generated by the KnitTrax cord (5396 kPa). Manipulating Expasyl after placement resulted in a pressure reduction of 73% in the stone chamber and 29% in the silicone chamber. CONCLUSIONS: Pressure generated by Expasyl is minimal compared to the cord system. Pressure is generated during the injection of the Expasyl, and subsequent manipulation reduced the final pressure. Handheld and motorized delivery guns produce similar pressure, but the motorized gun was found to have a more constant pressure delivery.

Development of a dental model hardener.

The paper presents a novel method of strengthening dental gypsum materials by infiltrating with a low-viscosity autopolymerising monomer. Gypsum specimens were infiltrated with diluted butyl-cyanoacrylate monomer at different concentrations. Nanoindentation was employed to measure their hardness and elastic modulus. A standard single-edge-notched beam (SENB) method was used to measure fracture toughness. Biaxial strength was measured using a universal test machine with a piston-on-ring jig. Scanning Electron Microscopy (SEM) and affiliated energy dispersive X-ray spectroscopy (EDX) were used to observe the fracture topography and the depth of infiltration. Infiltration and autopolymerisation of the cyanoacrylate improved the biaxial strength and fracture toughness of the gypsum by around 39% and around 30%, respectively. The hardness and elastic modulus for the treated specimens were also higher, albeit slightly. The proposed method provides a convenient way to strengthen and repair dental gypsum models in situ.