Piperine induces autophagy of colon cancer cells: Dual modulation of AKT/mTOR signaling pathway and ROS production.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy and poses a significant clinical challenge. Piperine, an alkaloid molecule extracted from Piper nigrum and Piper longum, has emerged as a promising anticancer agent. However, the molecular mechanisms of piperine' antitumor effects in CRC need to be further elucidated. METHODS: Human colorectal cancer cells were treated with piperine in vitro. CCK-8 and clone formation assays were adopted to detect cell viability. The accumulation of autophagosomes was assessed by Western blotting and immunofluorescence. Apoptosis and reactive oxygen species (ROS) levels were analyzed by flow. In vivo, a xenograft tumor mouse model was constructed using CT26 cells. RESULTS: Piperine inhibited CRC cell viability and suppressed tumor weight and volume in a mouse model. Additionally, piperine treatment induced the accumulation of autophagosomes in CRC cells. This effect was attributed to the inhibition of the AKT/mTOR pathway and the accumulation of ROS. activation of AKT or clearance of ROS attenuated piperine-mediated tumor suppression. CONCLUSION: This study shows that piperine induces autophagy-dependent cell death in CRC cells by increasing ROS production and inhibiting Akt/mTOR signaling.

SIRT1 promotes glucolipid metabolic conversion to facilitate tumor development in colorectal carcinoma.

Background: Fatty acid oxidation (FAO) is a major alternate energy metabolism pathway in tumor cells subjected to metabolic stress caused by glucose deficiency during rapid progression. However, the mechanism of metabolic reprogramming between glycolysis and FAO in tumor cells is unknown. Therefore, identifying the metabolic glucolipid conversion hub in tumor cells is crucial. Methods: We used single-cell RNA sequencing (scRNA-Seq), RNA sequencing (RNA-Seq), The Cancer Genome Atlas (TCGA), and chromatin immunoprecipitation sequencing (ChIP-Seq) to predict the critical regulator and mechanism of metabolic glucolipid conversion in colorectal cancer (CRC) tumor cells. We used Seahorse metabolic analysis, immunoblotting, immunofluorescence, and immunohistochemical (IHC) technology to verify the prediction and mechanism of this regulator in cancer cell lines, a nude mouse xenograft model, and clinical CRC samples. Results: We demonstrated that sirtuin-1 (SIRT1) was upregulated in CRC cells in response to glucose deprivation and oxidative stress. SIRT1 was also a hub of metabolic glucolipid conversion. SIRT1 upregulation deacetylated ß-catenin, translocated it from the nucleus to the cytoplasm, attenuated glycolysis, and was positively correlated with fatty acid oxidation (FAO). Clinical analysis of SIRT1 expression in tumor tissues showed the SIRT1High profile was associated with poor prognosis in CRC patients. SIRT1 interference therapy significantly suppressed tumors in the mouse xenograft model. Conclusions: In hostile, glucose-deficient TMEs, SIRT1 is upregulated, and CRC cells transform the Warburg phenotype to FAO. SIRT1 indicates the frequency of glucolipid transformation and rapid tumor progression and is a promising therapeutic target of CRC.

Cranial capacity measurement for modern Chinese adults based on 3D reconstruction.

OBJECTIVES: To determine the average modern adult cranial capacity in China, and assess the gender differences and trends in order to establish normal reference values and provide theoretical basis for individualized treatment in clinical practice. METHODS: We conducted a cross-sectional study between January 2019 to June 2020. Thin-slice (0.9 mm) CT scans of 309 males and 238 females from China were obtained, and classified into the 18-32, 33-47, 48-62, 63-77 and 78-92 years age groups. Three-dimensional reconstruction was performed using mimics software to obtain the cranial capacity for statistical analysis. RESULTS: The average cranial capacity of men was 1497.12±120.70 cm3 and that of women was 1326.24±95.72 cm3. The average cranial capacity of men was larger than that of women in all age groups. In addition, cranial capacity across the different age groups showed significant differences among both men and women. CONCLUSION: The average cranial capacity of modern Chinese male is larger that of females, and both sexes show a tendency to an increase in the intracranial volume over the past few decades. Our findings provide important data for establishing normal reference values for cranial capacity of modern Chinese adults and theoretical basis for individualized treatment of certain cranial diseases with increased intracranial pressure.

Enhancement of the antioxidant abilities of lignin and lignin-carbohydrate complex from wheat straw by moderate depolymerization via LiCl/DMSO solvent catalysis.

A facile and environmentally-friendly strategy for increasing antioxidant activity is a crucial issue for value-added lignin and lignin-carbohydrate complex (LCC) as alternative antioxidants. However, the antioxidant activities of lignin and LCC by the traditional solid-liquid extraction (SLE) methods were restricted by the relatively lower solubility induced from high molecular weight (Mw), and the less functional groups including, phenolic hydroxyl and carboxyl. To improve the antioxidantion of lignin and LCC, lithium chloride/dimethyl sulfoxide (LiCl/DMSO) solvent fractionation (LDSF) was conducted to increase the functional groups and reduce Mw, in which LiCl/DMSO acted triple roles as solvent, acid, and metal chloride catalyst for the depolymerization reaction synchronously. The ß-O-4' linkages were cleaved to release the phenolic hydroxyl, resulting in decreasing Mw; the hydroxyl of the side-chain of lignin was oxidized into carboxyl. Thus, the lignin (LD-RL) and LCC (LD-LCC) samples from LDSF had a higher syringyl (S)/guaiacyl (G) ratio, phenolic hydroxyl, and carboxyl contents, but less Mw than control groups from SLE. Consequently, they presented more excellent scavenging rates toward DPPH and ABTS radicals, up to 90%. This work provided panoramic perspectives and basics of the green and convenient approach to isolate and modify lignin and LCC for great antioxidantion with LDSF.

Efficient isolation of organosolv lignin-carbohydrate complexes (LCC) with high antioxidative activity via introducing LiCl/DMSO dissolving.

Lignin-carbohydrate complexes (LCC) have shown great potential as biocompatible antioxidants. But it is difficult to isolate LCC efficiently from lignocellulose by traditional Solid-Liquid Extraction method (SLE), which is blamed to the innate bioimpedance caused by the complex supramolecular structure of the lignocellulose, and a great mass transferring resistance between the extracting solution and solid lignocellulose. To release these restrictions above and improve the efficiency of LCC isolation, a modified isolating method named Liquid-Liquid Extraction (LLE) was proposed, in which ball-milled wheat stalk was dissolved in lithium chloride/dimethyl sulfoxide (LiCl/DMSO) solution, then regenerated by dioxane aqueous to extract LL-LCCs. The effect of the LLE on the LCC isolating was evaluated and results showed that both the total yield and antioxidant activity of LL-LCCs were higher than that of control group. It proved the dissolution of wheat stalk in LiCl/DMSO solution could reduce the mass transfer resistance during the extraction. Due to the catalyzation of LiCl as Lewis acid, LL-LCCs had lower molecular weight but more phenolic hydroxyl groups and higher S/G ratios. These factors of LL-LCCs resulted in greater free-radical scavenging ability than control sample. The modified isolation protocol could facilitate the isolation and utilization of LCCs as a free-radical scavenger.

Sirtuin-1/Mitochondrial Ribosomal Protein S5 Axis Enhances the Metabolic Flexibility of Liver Cancer Stem Cells.

Metabolic reprogramming endows cancer cells with the ability to adjust metabolic pathways to support heterogeneously biological processes. However, it is not known how the reprogrammed activities are implemented during differentiation of cancer stem cells (CSCs). In this study, we demonstrated that liver CSCs relied on the enhanced mitochondrial function to maintain stemness properties, which is different from aerobic glycolysis playing main roles in the differentiated non-CSCs. We found that liver CSCs exhibit increased mitochondrial respiratory capacity and that complex-I of mitochondria was necessary for stemness properties of liver CSCs through regulation of mitochondrial respiration. Bioinformatics analysis reveals that mitochondrial ribosomal protein S5 (MRPS5) is closely related with the function of complex-I. Further experiments confirmed that MRPS5 promoted the production of nicotinamide adenine dinucleotide (NAD+ ), which is necessary for enhanced mitochondrial function in liver CSCs. MRPS5 played a critical role for liver CSCs to maintain stemness properties and to participate in tumor progression. Mechanistically, the acetylation status of MRPS5 is directly regulated by NAD+ dependent deacetylase sirtuin-1 (SIRT1), which is abundant in liver CSCs and decreased during differentiation. Deacetylated MRPS5 locates in mitochondria to promote the function complex-I and the generation of NAD+ to enhance mitochondrial respiration. Conversely, the acetylated MRPS5 gathered in nuclei leads to increased expression of glycolytic proteins and promotion of the Warburg Effect. Therefore, liver CSCs transform mitochondrial-dependent energy supply to a Warburg phenotype by the dual function of MRPS5. Clinical analysis of SIRT1 and MRPS5 expression in tumor tissues showed the SIRT1High /Cytoplasmic-MRPS5High profile was associated with patients with hepatocellular carcinoma with poor prognosis. Conclusion: SIRT1/MRPS5 axis participates in metabolic reprogramming to facilitate tumor progression and may serve as a promising therapeutic target of liver cancer.

Fabrication of thermo-sensitive lignocellulose hydrogels with switchable hydrophilicity and hydrophobicity through an SIPN strategy.

Herein, thermo-sensitive lignocellulose hydrogels with varying lignin contents were fabricated with N-isopropylacrylamide (NIPAAm) by a semi-interpenetrating polymer network (SIPN) strategy using a LiCl/DMSO solvent system. Soda lignin mixed with the lignocellulose/LiCl/DMSO solution was also used to prepare the composite hydrogels, and the influence of the existential state of lignin on the hydrogel properties was analyzed objectively. The SIPN hydrogels exhibited more favorable mechanical properties due to the physical entanglement of poly-NIPAAm and lignocellulose. The presence of externally added lignin in the composite hydrogels is beneficial for mechanical improvement. Both the mechanical properties and the morphologies of the SIPN hydrogels can be tuned by varying the existential state and content of lignin. Furthermore, the prepared SIPN hydrogels showed rapid conversion from being hydrophilic at 20 °C to being hydrophobic at 45 °C. All SIPN hydrogels exhibited obvious oil absorbency in an oil/water mixture at 45 °C. Moreover, the different lignin existential states in the hydrogels resulted in different lower critical solution temperatures (LCST). This study provides a feasible route to produce reinforced thermo-sensitive hydrogels and develops a method for tailoring the morphology and the absorption properties of hydrogels by controlling the existential state and content of lignin.

[Evaluation of intraductal papillary mucinous neoplasms of the pancreas on MDCT and MRI].

OBJECTIVE: The purpose of our study was to evaluate the predictive factors of the presence of invasive carcinoma associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas on MDCT and MRI. METHODS: Preoperative MDCT or/and MRI of 27 consecutive patients (19 men, 8 women, mean age 61.3 years) who had undergone surgical resection and had a pathological diagnosis of IPMN were retrospectively assessed. The type of ductal involvement, solid appearance of the lesion, location, tumor size of branch duct type and combined type lesions, maximum diameter of the tumor, caliber of the main pancreatic duct and the extent of the common bile duct dilatation were assessed on CT and MRI and correlated with the pathological findings of the invasive carcinoma. Two abdominal radiologists reviewed all the images, and when discrepancies of the findings were found, the consensus was reached by discussion. RESULTS: Pathological analysis revealed carcinoma in situ in two patients and invasive carcinoma in 19 patients arising from the IPMN. The type of ductal involvement (P = 0.038), a solid mass (P = 0.003) and the common bile duct dilatation ( ≥ 15 mm, P = 0.004) were correlated with the presence of associated invasive carcinoma. For the finding of solid and cystic mass in predicting invasive IPMN, the sensitivity was 66.7% (8/12) and specificity was 100.0% (8/8), and for bile duct diameter ≥ 15 mm, the sensitivity was 47.4% (9/19) and specificity was 100.0% (8/8). However, no association was found between the location of the lesion and associated invasive carcinoma. The caliber of the main pancreatic duct of patients with associated invasive carcinoma was significantly larger than that in the cases without invasive carcinoma (8.07 ± 2.23 mm vs. 4.86 ± 1.86 mm, P = 0.002). When using the main pancreatic duct dilatation ≥ 4 mm as the threshold, the sensitivity and specificity in predicting invasive IPMN were 94.7% (18/19) and 37.5% (3/8), respectively. For the branch duct type and combined type, the size of the tumor with associated invasive carcinoma was significantly larger than these without invasive carcinoma (41.35 ± 12.58) mm vs. (23.76 ± 8.06) mm (P = 0.003). When the maximum diameter was ≥ 40 mm, the sensitivity and specificity in predicting invasive IPMN were 50.0% (6/12) and 87.5% (7/8), respectively. CONCLUSIONS: The findings of CT and MRI are helpful to predict invasive carcinoma associated with IPMN, which may play an important role in the preoperative evaluation, surgical planning and predicting the prognosis of IPMN.