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.

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.

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.

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.

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.

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.

Expression of three sHSP genes involved in heat pretreatment-induced chilling tolerance in banana fruit.

BACKGROUND: Banana fruit is highly susceptible to chilling injury. In previous research it was shown that heat pretreatment of banana fruit at 38 °C for 3 days before storage at a chilling temperature of 8 °C for 12 days prevented increases in visible chilling injury index, electrolyte leakage and malondialdehyde content and also decreases in lightness and chroma, indicating that heat pretreatment could effectively alleviate chilling injury of banana fruit. However, little is known about the role of small heat shock proteins (sHSPs) in postharvest chilling tolerance of banana fruit. In the present study, three cytosolic sHSP expression profiles in peel and pulp tissues of banana fruit during heat pretreatment and subsequent chilled storage (8 °C) were investigated in relation to heat pretreatment-induced chilling tolerance. RESULTS: Three full-length cDNAs of cytosolic sHSP genes, including two class I sHSP (CI sHSP) and one class II sHSP (CII sHSP) cDNAs, named Ma-CI sHSP1, Ma-CI sHSP2 and Ma-CII sHSP3 respectively, were isolated and characterised from harvested banana fruit. Accumulation of Ma-CI sHSP1 mRNA transcripts in peel and pulp tissues and Ma-CII sHSP3 mRNA transcripts in peel tissue increased during heat pretreatment. Expression of all three Ma-sHSP genes in peel and pulp tissues was induced during subsequent chilled storage. Furthermore, Ma-CI sHSP1 and Ma-CII sHSP3 mRNA transcripts in pulp tissue and Ma-CI sHSP2 mRNA transcripts in peel and pulp tissues were obviously enhanced by heat pretreatment at days 6 and 9 of subsequent chilled storage. CONCLUSION: These results suggested that heat pretreatment enhanced the expression of Ma-sHSPs, which might be involved in heat pretreatment-induced chilling tolerance of banana fruit.

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.

A novel polymer infiltrated ceramic for dental simulation.

Simulation of tooth preparation using rotary cutting instruments is viewed as beneficial and essential in dental training. Various types of materials have been used for simulation systems in dental preclinical training. However, the phantom tooth materials used for simulation have not changed significantly for decades and they are acknowledged to be different from natural teeth. This study investigated the mechanical properties and microstructure of a widely used phantom tooth material and compared them with a novel, polymer infiltrated, ceramic. It was concluded that the polymer infiltrated ceramic has mechanical properties more similar to natural teeth than current phantom tooth materials, suggesting that it might be a good candidate material for phantom teeth for trainees to acquire initial tactile sense for tooth preparation.

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.

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.

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.

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.

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.

Role of phenylalanine ammonia-lyase in heat pretreatment-induced chilling tolerance in banana fruit.

Increasing evidence suggests that phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) is associated with low temperature stress in plant tissues. Banana fruit are highly susceptible to chilling injury. However, little is known about the role of PAL (i.e. gene expression, protein level and activity) in fruit chilling. In this work, the involvement of PAL induced by heat treatment (38 degrees C for 3 days) prior to storage (8 degrees C) in chilling tolerance was investigated. The PAL inhibitor 2-aminoindan-2-phosphonic acid (AIP) was also used to further study the role of PAL in the chilling tolerance. The results showed that mRNA transcripts (MaPAL1 and MaPAL2) and PAL protein levels increased during storage at chilling temperature. Heat treatment prior to storage alleviated chilling injury and enhanced PAL activity, protein amount and MaPAL1 and MaPAL2 transcript levels. The increases in parameters of PAL upon heat pretreatment were all inhibited by AIP treatment, which resulted in aggravation of chilling injury. Thus, these findings indicate that the induction of PAL by heat pretreatment was regulated at both the transcriptional and the translational levels and that PAL may play a role in heat pretreatment-induced chilling tolerance of banana fruit.

Micromechanical evaluation of mineralized multilayers.

The biomechanical stability of osseointegrated implants is of particular importance, especially the stability which is achieved from structural manipulation at the interface between the implant surface and the bone tissues. Nanoscale beta-tricalcium phosphate-immobilized titanium was prepared by discharge into a physiological buffered saline solution. Compared with hydroxyapatite, it has been shown to be effective in generating a bone-like chemical structure on the surface by cooperative interaction between osteoblastic cells and the beta-tricalcium phosphate. The present study, after cell cultivation, investigates the nanostructures and biomechanical property differences of a mineralized layer formed on two samples of nano-calcium phosphate-immobilized titanium. A scanning probe microscope study revealed that the mineralized tissue formed on the beta-tricalcium phosphate samples after 1 week of cell culture showed significantly higher roughness, compared with hydroxyapatite samples. Nanoindentation micromechanical evaluation of the in vitro generated multilayered structures exhibited thicker bone-like mineralized layers on the beta-tricalcium phosphate samples. A successful modification of titanium implants through the cooperative interaction between osteoblastic cells and nano beta-tricalcium phosphate is anticipated.

Mechanical behaviour of porous hydroxyapatite.

The aim of the study was to investigate the role of microstructure and porosity on the mechanical behaviour of sintered hydroxyapatite. Hydroxyapatite disks with four different porosities were used in this investigation. With a nanoindentation system, elastic modulus, hardness, contact stress-strain relationship, energy absorption and indentation creep behaviour were investigated. The elastic modulus and hardness of hydroxyapatite exhibited an exponential relationship (e(-bP)) with the porosity P, which is similar to Rice's finding with the minimum solid area model. High porosity samples showed more substantial inelastic behaviour, including higher energy absorption, no linear elastic region in the contact stress-strain curve and some indentation creep behaviour. We conclude that porous microstructure endows hydroxyapatite with inelastic deformation properties, which are important in a material for bone substitution usage.

The effect of zoledronic acid on the intrinsic material properties of healing bone: an indentation study.

BACKGROUND: Bisphosphonates are commonly used for the treatment of osteoporosis and have recently been shown to increase bone mineral parameters and strength in endochondral fracture repair. There is concern, however, that BPs may negatively affect bone material properties. METHODS: Nanoindentation was performed on femoral fracture samples of rats that had undergone closed fracture healing for six weeks to determine hardness and elastic modulus. The rats had received either intravenous saline or a single intravenous dose of zoledronic acid at zero, one or two weeks post fracture (n = 3 per group). FINDINGS: The mean elastic modulus and hardness of mineralised tissue in control calluses were mean 16.4 GPa (S.D. 2.3) and mean 0.65 GPa(S.D. 0.1), respectively. There was no significant change in these parameters with zoledronic acid treatment. INTERPRETATION: The results from this preliminary data suggest that single dose zoledronic acid treatment in fracture healing may not adversely affect the intrinsic properties of callus bone tissue. Single dose bisphosphonate may be a viable treatment for augmenting fracture repair without negatively affecting the material properties.

[Docetaxel and capecitabine combination chemotherapy for patients with anthracycline-resistant metastatic breast cancer].

OBJECTIVE: To evaluate the efficacy and safety of docetaxel and capecitabine combination chemotherapy (DC regimen) for patients with anthracycline-resistant metastatic breast cancer. METHODS: Thirty-two patients with anthracycline-resistant metastatic breast cancer were treated with a docetaxel and capecitabine combination regimen. All patients received oral administration of capecitabine at a dose of 1250 mg/m(2) twice daily, within 30 min after meal on D1 to D14, and intravenous infusion of docetaxel at a dose of 75 mg/m(2) on D1. The regimen was repeated every 3 weeks. RESULTS: A total of 126 cycles of DC regimen were administered in the 32 cases, with a median of 4 cycles. The overall response rate was 46.9%. Among the 32 patients, there were complete response in 1, partial response in 14, stable disease in 11 and progressive disease in 6 cases. The median time to progression (TTP) was 5.6 months. The one-year survival rate was 56.3%. The effective cases in different metastatic organs were: 8 cases in the lung, 6 cases in the liver, 3 cases in the soft tissue and 3 cases in the lymph nodes. The common adverse reactions were myelosuppression, hand-foot syndrome, nausea and vomiting. Neutropenia was observed in 84.4% of the patients. Two patients developed degree IV myelosuppression. CONCLUSION: The combination chemotherapy regimen of docetaxel plus capecitabine is well-tolerated and effective for anthracycline-resistant metastatic breast cancer.