Metabolite secretions of Lactobacillus plantarum YYC-3 may inhibit colon cancer cell metastasis by suppressing the VEGF-MMP2/9 signaling pathway.

BACKGROUND: Colorectal cancer (CRC) is a major clinical challenge, and the gut microbiome plays important roles in the occurrence and metastasis of CRC. Lactobacillus and their metabolites are thought to be able to suppress the growth of CRC cells. However, the antimetastatic mechanism of Lactobacillus or their metabolites toward CRC cells is not clear. Therefore, the aim of this study was to assess the inhibitory mechanism of cell-free supernatants (CFSs) of L. rhamnosus GG, L. casei M3, and L. plantarum YYC-3 on metastasis of CRC cells. RESULTS: YYC-3 CFS showed the highest inhibitory effect on CRC cell growth, invasion and migration, and inhibited MMP2, MMP9, and VEGFA gene and protein expression, and protein secretion. Furthermore, it suppressed the activities of MMPs by gelatin zymography. Moreover, the effective compounds in these CFSs were analyzed by Q Exactive Focus liquid chromatography-mass spectrometry. CONCLUSIONS: Our results showed that metabolite secretions of YYC-3 may inhibited cell metastasis by downregulating the VEGF/MMPs signaling pathway. These data suggest that treatment of CRC cells with metabolites from L. plantarum YYC-3 may reduce colon cancer metastasis.

Vitamin K1 Inhibition of Renal Crystal Formation through Matrix Gla Protein in the Kidney.

BACKGROUND AND OBJECTIVES: Vitamin K (VK) plays a major role in modifying the binding of calcium in bones and blood vessels. Understanding the effect of VK on crystal formation in the kidney would contribute to advancing the treatment and prevention of kidney stones. METHODS: Rats were treated with vitamin K1 (VK1) for 8 weeks. VK1 levels were detected and crystal formation were observed. HK2 cells were exposed to calcium oxalate monohydrate crystals. Apoptosis and cell viability were detected. Crystal deposition was analyzed using atomic absorption assay. The adenovirus vectors expressing matrix Gla protein (MGP) and siMGP were constructed to elucidate the effect and mechanism of VK1 on crystal formation. MGP expression in vivo and in vitro was analyzed by Western blot. The mRNA levels of monocyte chemoattractant protein-1 (MCP-1) and collagen I was measured by semiquantitative RT-PCR. RESULTS: The concentrations of VK1 in whole blood and kidney tissues rose under treatment with VK1. Crystal formation was inhibited from the second to the 6th week, the frequency and quality of crystal formation decreased significantly, and the location of crystal formation was limited to a greater extent in the rats treated by VK1 compared to the control group. Warfarin treatment in the crystals-exposed HK2 cells significantly increased the number of crystals adhering to cells and the number of apoptotic cells and reduced cell viability. VK1 treatment reversed warfarin's above influence. VK1 inhibited the upregulations of MCP-1 and collagen I in kidney tissues under crystal load. VK1 treatment increased MGP expression in vivo and in vitro, and MGP is necessary for VK1 to play a role in crystal deposition in cells. CONCLUSIONS: VK1 treatment can inhibit the formation of renal crystals in vivo. VK1 increases MGP expression and functions through MGP to reduce crystal deposition in cells and provide cell protection. Our findings suggest that VK1 treatment could be a potential strategy for the treatment and prevention of nephrolithiasis.

Cholesterol depletion induced by RNA interference targeting DHCR24 protects cells from liposome-induced cytotoxicity.

Existing evidence has demonstrated liposomes as the gene transporter induce the cytotoxicity during the transfection process through several known pathways. In the present study, we investigated the possibility of siRNAs targeting 3-ß-hydroxysterol △-24-reductase (DHCR24), which encodes an enzyme catalyzing the last step of cholesterol biosynthesis, to suppress the liposome cytotoxicity induced by lipid-based transfection reagent in the neuroblastoma cell line N2A. We found that the siRNAs targeting DHCR24 mRNA protect cells from the liposome-induced cell death, probably through the effect of siDHCR24s on the reduction of the cellular cholesterol and decrease in the generation of reactive oxygen species (ROS). This suggests that siRNAs targeting DHCR24 or other methods that reduce the intracellular cholesterol levels might be a good strategy for avoiding the cytotoxicity of liposomes, without impairing its efficiency of gene-delivering.

Comparison of phospholipid composition and microstructure of milk fat globules contained in human milk and infant formulae.

Phospholipids play key roles in infant nutrition and cognitive development. It is hypothesized that infant formula (IF) has lower phospholipid species, content and milk fat globule (MFG) structural integrity than human milk (HM). Herein, we performed qualitative and quantitative analyses of phospholipids in six classes of IF and HM using ultra-performance liquid chromatography with mass spectrometry. The contents of phosphatidylethanolamine (15.81 ± 7.20 mg/L) and sphingomyelin (35.84 ± 15.56 mg/L) in IF were significantly lower than those in HM (30.74 ± 17.38 mg/L, 45.53 ± 16.04 mg/L, respectively). Among the six IF classes, cow's milk-based IF had the highest number of phospholipid species, and IF containing milk fat globular membrane had the highest phospholipid content. The size, zeta potential, and amount of MFGs in IF were significantly lower than those in HM. These results may prove useful for designing better IF that mimic HM.

The effect of low-dose chemotherapy on the tumor microenvironment and its antitumor activity combined with anti-PD-1 antibody.

Aim: This study aimed to explore the effects of low-dose chemotherapy in the tumor microenvironment (TME) on a gastric cancer xenograft and its antitumor activity combined with the anti-PD-1 antibody. Materials & methods: Mice with gastric cancer were divided into four groups. The body weight and tumor volume of the mice were recorded. The TME was analyzed using flow cytometry. Results: Low-dose paclitaxel increased the PD-L1 expression level and the number of CD8+ T cells, but not the CD4+ T and myeloid-derived suppressor cells or PD-1+ CD8+ T cells in the TME. Low-dose 5-fluorouracil reduced the number of myeloid-derived suppressor cells and PD-1+ CD8+ T cells, but the PD-L1 expression level and the number of CD4+ T and CD8+ T cells did not change in the TME. The anti-PD-1 antibody inhibited tumor growth, but the combination therapy did not show superior antitumor activity. Conclusion: Low-dose chemotherapy altered the TME but failed to improve the responses to the anti-PD-1 antibody.

The anti-PD-1 antibody shows potential as an anticancer therapy for tumors, including gastric cancer. However, the antitumor effect of the anti-PD-1 antibody alone is unsatisfactory. The tumor microenvironment (TME) is an environment in which a tumor develops and survives. The TME comprises heterogeneous molecules and cell types, including immune cells, endothelial cells and fibroblasts, besides cancer cells. This study aimed to explore the effects of low-dose chemotherapy on the TME and its antitumor effect when combined with anti-PD-1 antibody. The TME was analyzed using the flow cytometry method. Although low-dose paclitaxel and low-dose 5-fluorouracil changed the TME, both failed to enhance the antitumor activity when combined with the anti-PD-1 antibody.

A cohort study of vitamins contents in human milk from maternal-infant factors.

Human milk vitamin content is an important indicator to evaluate the nutritional composition of human milk. This paper investigates the influence of maternal and infant factors on the dynamics of human milk vitamin content. A total of 147 mother-infant pairs from 3 different cities (north-south distribution) in China were selected and 9 major vitamins were measured in 332 human milk samples. The three vitamins (vitamin A, ß-carotene, and pantothenic acid) showed significant downward trends with lactation period (| r | > 0.3, p < 0.05). The lactation period factor could explain the negative variation of vitamin A (21.2%) and pantothenic acid (9.5%). The factors of lactation period and oils intake could jointly explain variations of ß-carotene (11.8%). (Registration number: NCT02658500).

Three urban areas of China: a cohort study of maternal-infant factors and HM protein components.

This work studies the concentrations of proteins in human milk (HM) at different lactation periods and explores the influence of maternal-infant factors on the dynamics of HM proteins in a Chinese cohort. The cohort contained 153 mother-infant pairs, and 12 main proteins of 376 HM samples were analyzed. The result showed that physiological factors (age and pre-pregnancy BMI), demographic factors (education and occupation), endogenous factors (cesarean section), and exogenous factors (lactation period and area) could explain the dynamics of HM proteins, including the total protein, true protein, whey protein, ß-casein, lactoferrin, IgA, and IgM (R2 > 0.3). Factor analysis explained the dynamic changes in the IgM content by the highest degree of 49.5%. This study aimed to find the mother-infant factors that affected the dynamic changes in HM proteins, in order to optimize HM proteins and improve the long- and short-term health of infants (registration number: NCT02658500).

Retrospective analysis of adjuvant intraperitoneal chemotherapy effect prognosis of resectable gastric cancer.

OBJECTIVE: This study evaluated the efficacy and safety of adjuvant intraperitoneal perfusion chemotherapy (IPC) in resectable gastric cancer through retrospective analysis. METHODS: Three hundred and sixty T2-4bN0-3M0 resectable gastric cancer patients were included in this study. One hundred and eighty-four patients used systemic chemotherapy combined with IPC (IP+ group) and 176 systemic chemotherapy only (IP- group). RESULTS: With a median of 49.9 months of follow-up, the 5-year overall survival in IP+ patients was significantly better than in IP- patients (60.4 vs. 42.9%; p = 0.001), and the average progression-free survival in IP+ patients was significantly longer than in IP- patients (60.5 vs. 46.2 months; p = 0.001). Relapse rates of peritoneal carcinomatosis, celiac lymph node and hepatic metastasis in the IP+ patients were significantly lower than in the IP- patients. Patients with curative resection, a histological type other than mucinous adenocarcinoma and signet ring cell carcinoma, low and undifferentiated tumor grade, lymph node metastasis, and T3 and T4a benefited from adjuvant IPC. The toxicities were the same except for more patients with leukopenia in the IP+ group (p = 0.001). The number of cycles of IPC and the time of IPC start after surgery had an impact on overall and disease-free survival. CONCLUSION: Adjuvant IPC for resectable gastric cancer gave encouraging results and large multicenter prospective randomized controlled studies are warranted.

Characterization of SSU5C promoter of a rbcS gene from duckweed (Lemna gibba).

Photosynthesis-associated nuclear genes are able to respond to multiple environmental and developmental signals. Studies have shown that light signals coordinate with hormone signaling pathways to control photomorphogenesis. A small subunit of ribulose-1,5 bisphosphate carboxylase/oxygenase (rbcS) gene promoter was cloned from duckweed (Lemna gibba). Sequence analysis revealed this promoter is different from the previously reported rbcs promoters and is named SSU5C. Analysis of T1 transgenic tobacco plants with a reporter gene under the control of the SSU5C promoter revealed that this promoter is tissue-specific and is positively regulated by red light. Promoter deletion analysis confirmed a region from position -152 to -49 relative to the start of transcription containing boxes X, Y and Z, and is identified to be critical for phytochrome responses. Further functional analysis of constructs of box-X, Y, Z, which was respectively fused to the basal SSU5C promoter, defined boxes X, Y and Z alone are able to direct phytochrome-regulated expression, indicating that boxes Y and Z are different from those of the SSU5B promoters in L. gibba. This promoter may be used for plant gene expression in a tissue-specific manner.

A Network Pharmacology Study to Uncover the Multiple Molecular Mechanism of the Chinese Patent Medicine Toujiequwen Granules in the Treatment of Corona Virus Disease 2019 (COVID-19).

Since the outbreak of the novel corona virus disease 2019 (COVID-19) at the end of 2019, specific antiviral drugs have been lacking. A Chinese patent medicine Toujiequwen granules has been promoted in the treatment of COVID-19. The present study was designed to reveal the molecular mechanism of Toujiequwen granules against COVID-19. A network pharmacological method was applied to screen the main active ingredients of Toujiequwen granules. Network analysis of 149 active ingredients and 330 drug targets showed the most active ingredient interacting with many drug targets is quercetin. Drug targets most affected by the active ingredients were PTGS2, PTGS1, and DPP4. Drug target disease enrichment analysis showed drug targets were significantly enriched in cardiovascular diseases and digestive tract diseases. An "active ingredient-target-disease" network showed that 57 active ingredients from Toujiequwen granules interacted with 15 key targets of COVID-19. There were 53 ingredients that could act on DPP4, suggesting that DPP4 may become a potential new key target for the treatment of COVID-19. GO analysis results showed that key targets were mainly enriched in the cellular response to lipopolysaccharide, cytokine activity and other functions. KEGG analysis showed they were mainly concentrated in viral protein interaction with cytokine and cytokine receptors and endocrine resistance pathway. The evidence suggests that Toujiequwen granules might play an effective role by improving the symptoms of underlying diseases in patients with COVID-19 and multi-target interventions against multiple signaling pathways related to the pathogenesis of COVID-19.

Suppression of neuronal cholesterol biosynthesis impairs brain functions through insulin-like growth factor I-Akt signaling.

Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-ß hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid ß and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.

3ß-Hydroxysteroid-Δ24 Reductase (DHCR24) Protects Pancreatic ß Cells from Endoplasmic Reticulum Stress-Induced Apoptosis by Scavenging Excessive Intracellular Reactive Oxygen Species.

There is accumulating evidence showing that apoptosis induced by endoplasmic reticulum (ER) stress plays a key role in pancreatic ß cell dysfunction and insulin resistance. 3ß-Hydroxysteroid-Δ24 Reductase (DHCR24) is a multifunctional enzyme located in the endoplasmic reticulum (ER), which has been previously shown to protect neuronal cells from ER stress-induced apoptosis. However, the role of DHCR24 in type 2 diabetes is only incompletely understood so far. In the present study, we induced ER stress by tunicamycin (TM) treatment and showed that infection of MIN6 cells with Ad-DHCR24-myc rendered these cells resistant to caspase-3-mediated apoptosis induced by TM, while cells transfected with siRNAs targeting DHCR24 were more sensitive to TM. Western blot analysis showed that TM treatment induced upregulation of Bip protein levels in both cells infected with Ad-LacZ (the control group) and Ad-DHCR24-myc, indicating substantial ER stress. Cells infected with Ad-LacZ exhibited a rapid and strong activation of ATF6 and p38, peaking at 3 h after TM exposure. Conversely, cells infected with Ad-DHCR24-myc showed a higher and more sustained activation of ATF6 and Bip than control cells. DHCR24 overexpression also inhibited the generation of intracellular reactive oxygen species (ROS) induced by ER stress and protected cells from apoptosis caused by treatment with both cholesterol and hydrogen peroxide. In summary, these data demonstrate, for the first time, that DHCR24 protects pancreatic ß cells from apoptosis induced by ER stress.

Stable Colonization of Orally Administered Lactobacillus casei SY13 Alters the Gut Microbiota.

The gut microbiota plays an important role in intestinal health. Probiotics such as Lactobacillus are known to regulate gut microbes and prevent diseases. However, most of them are unable to colonize their stability in hosts' intestinal tracts. In this study, we investigated the ability of Lactobacillus casei SY13 (SY13) to colonize the intestinal tract of BALB/c mice, after its oral administration for a short-term (once for a day) and long-term (once daily for 27 days) duration. Furthermore, we also evaluated the influence of its administration on the gut microbial structure and diversity in mice. Male BALB/c mice were gavaged with 108 colony-forming units (CFU) of SY13, and TaqMan-MGB probe and Illumina MiSeq sequencing were performed to assess the colonization ability and bacterial community structure in the cecum contents. The results showed that long-term treatment with SY13 enhanced its ability to form a colony in the intestine tract in contrast to the short-term treatment group, whose colony was retained for only 3 days. Oral administration of SY13 also significantly enhanced the gut microbial diversity. Short-term treatment with SY13 (SSY13) elevated Firmicutes and diminished Bacteroidetes phyla compared with long-term treatment (LSY13) and controls. The findings laid the foundation for the study of probiotic colonization ability and improvement of microbiota for the prevention of gut diseases.

Probiotic strain Lactobacillus plantarum YYC-3 prevents colon cancer in mice by regulating the tumour microenvironment.

The gut microbiota plays important roles in chronic inflammation and colon cancer. Lactobacillus is a gut-resident probiotic with benefits to host health. We recently identified Lactobacillus plantarum strain YYC-3 with strong inhibition against two colon cancer cell lines (HT-29 and Caco2). However, the inhibitory effect of YYC-3 against colon cancer in vivo has not been verified. Thus, in the present study, we explored the probiotic function of strain YYC-3 and its cell-free supernatant (YYCS) respectively in the APCMin/+ mouse model of colon cancer during tumour development and growth, and the underlying anti-cancer mechanism. Treatment of both strain YYC-3 and the YYCS prevented the occurrence of colon tumours and mucosal damage in APCMin/+ mice fed a high-fat diet, although YYC-3 had a stronger anti-cancer effect. The mechanism involved modulation of the immune system and downregulated expression of the inflammatory cytokines interleukin (IL)-6, IL-17 F, and IL-22, along with reduced infiltration of inflammatory cells. Moreover, YYC-3 suppressed activation of the NF-κB and Wnt signalling pathways, and restored the altered gut microbiota composition to closely match that of wild-type mice. These results lay a theoretical foundation for application of YYC-3 in colon cancer prevention.

Cetuximab Maintenance Therapy in Patients with Unresectable Wild-Type RAS and BRAF Metastatic Colorectal Cancer: A Single-Institute Prospective Study.

INTRODUCTION: Cetuximab plus FOLFIRI (leucovorin, fluorouracil, and irinotecan) is the preferred first-line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC). To counter chemotherapy-induced side effects, use of maintenance therapy is suggested. Therefore, we evaluated the efficacy and safety of cetuximab maintenance therapy in patients after effective completion of first-line induction therapy. METHODS: This prospective study enrolled untreated patients with mCRC RBWT who received first-line cetuximab plus FOLFIRI therapy. Following this, patients with treatment response either entered observation (stop treatment) or maintenance treatment 1 (cetuximab plus irinotecan) groups. After 6-12 cycles of maintenance treatment 1, patients entered maintenance treatment 2 (cetuximab only). If a patient progressed on maintenance 2, cetuximab plus FOLFIRI was reintroduced. The primary end point was failure-free survival (FFS), whereas the secondary end points included disease control rate (DCR), objective remission rate (ORR), and progression-free survival (PFS). Safety events were also evaluated. RESULTS: Among 79 enrolled patients, 72 completed first-line treatment effectively (DCR 91.1%, ORR 63.9%) and 44 entered maintenance 1 [median PFS 1 (mPFS, maintenance 1) 6.1 months, 95% confidence interval (CI) 6.0-6.2; DCR 56.8%; ORR 22.7%]. Of them, 21 entered maintenance treatment 2 (mPFS2 8.7 months, 95% CI 3.3-14.1; DCR 28.6%; ORR 4.8%). Median FFS (mFFS) was significantly longer in the maintenance 1 group compared with the observation group [12.7 vs. 3.0 months; hazard ratio (HR) 0.202, 95% CI 0.111-0.369; P < 0.001]. Overall, mFFS was 19.0 and 9.3 months in maintenance and observation groups, respectively (HR 0.211, 95% CI 0.117-0.380; P < 0.001). Rash acneiform, mucositis, and asthenia were commonly observed adverse events during maintenance treatment. CONCLUSION: Maintenance treatment with cetuximab after first-line therapy significantly improved FFS, with an acceptable safety profile in untreated patients with mCRC RBWT. TRIAL REGISTRATION: Retrospectively registered, 2019/10/02, Chinese Clinical Trial Registry, ChiCTR number 1900026360.

Heterologous expression of human paraoxonases in Pseudomonas aeruginosa inhibits biofilm formation and decreases antibiotic resistance.

Quorum sensing (QS) regulates virulence and biofilm formation in Pseudomonas aeruginosa and other medically relevant bacteria. Human paraoxonases (hPONs) are a family of closely related enzymes with multiple functions, including inactivation of the QS signal molecule in P. aeruginosa. However, there is no direct evidence to show the functions of hPONs on biofilm formation and antibiotic resistance in P. aeruginosa. In the present study, hPONs (hPON1, hPON2, and hPON3) genes were respectively cloned into the pMEKm12 shuttle vector and transformed into P. aeruginosa strain PAO1. Expression of the three recombinant proteins was confirmed by Western blotting, and growth of the recombinant strains was not affected by the hPONs gene expression. Biofilm formation and antibiotics resistance of the hPONs recombinant strains were analyzed. Our results showed that biofilm formation was significantly inhibited in all of the three hPONs recombinant strains. Interestingly, this inhibition can be reverted by addition of the corresponding hPONs polyclonal antibodies in the culture media, further indicating that the inhibition of biofilm formation was due to hPONs protein expression. In addition, we also demonstrated that hPONs expression decreased resistance of P. aeruginosa to gentamicin and ceftazidima, two antibiotics clinically used for the treatment of P. aeruginosa infection.

Expression of baculovirus anti-apoptotic p35 gene in tobacco enhances tolerance to abiotic stress.

Expression of baculovirus anti-apoptotic p35 gene in plants on biotic stress responses has been well studied but its function on abiotic stress has not been documented. In the present study, the p35 gene from Autographa californica multiple nucleopolyhedrovirus (AcMNPV) was expressed in tobacco. A detached leaf assay was used to test tolerance of p35 transgenic plants to various abiotic stress responses. Expression of p35 gene in tobacco gave tolerance to treatment with methanol and H2O2 and also delayed leaf senescence under starvation in the dark. Germination of T(0) seeds on NaCl-containing medium also demonstrated to increase salt tolerance.

Retrospective study on efficacy of a paclitaxel combined with a leucovorin and fluorouracil regimen for advanced gastric cancer.

PURPOSE: To investigate the efficacy of paclitaxel combined with a leucovorin and 5-fluorouracil regimen (PLF regimen; q2w) as neoadjuvant chemotherapy (NCT) for advanced gastric cancer. METHODS: A total of 183 patients with advanced gastric cancer who underwent 3 cycles of PLF regimen chemotherapy before surgery and received surgery 2 weeks after chemotherapy were enrolled as a treatment group. A total of 184 patients with advanced gastric cancer and no NCT during the same period were enrolled as the controls and treated with surgery. Both groups underwent a D2 radical gastrectomy and the standard postoperative adjuvant chemotherapy. RESULTS: In the NCT group, there were 19 cases of complete remission, 86 cases of partial remission, 72 cases of stable disease, and 6 cases of progressive disease, with an overall response rate of 57.4%. The R0 resection rate was higher than in the control group (85.2% vs 61.4%, p < .05). In the NCT group, 12 cases of esophagogastric cancer (20.7%) showed complete remission and 32 cases (55.2%) showed partial remission, while 7 cases of distal gastric cancer (5.6%) showed complete remission and 54 cases (43.2%) showed partial remission. Pathologic complete remission was higher for esophagogastric cancer than for distal gastric cancer (20.7% vs 3.2%, p < .05). Differences were found between the NCT and control groups in terms of 1-year, 3-year, and 5-year overall and disease-free survival. CONCLUSION: The PLF regimen showed good tolerability and a high response rate, especially for esophagogastric cancer. This regimen reduced the tumor size, lowered the tumor stage, and improved the R0 resection rate and survival rate.

Computer-Assisted Drug Virtual Screening Based on the Natural Product Databases.

BACKGROUND: Computer-assisted drug virtual screening models the process of drug screening through computer simulation technology, by docking small molecules in some of the databases to a certain protein target. There are many kinds of small molecules databases available for drug screening, including natural product databases. METHODS: Plants have been used as a source of medication for millennia. About 80% of drugs were either natural products or related analogues by 1990, and many natural products are biologically active and have favorable absorption, distribution, metabolization, excretion, and toxicology. RESULTS: In this paper, we review the natural product databases' contributions to drug discovery based on virtual screening, focusing particularly on the introductions of plant natural products, microorganism natural product, Traditional Chinese medicine databases, as well as natural product toxicity prediction databases. CONCLUSION: We highlight the applications of these databases in many fields of virtual screening, and attempt to forecast the importance of the natural product database in next-generation drug discovery.

A Proteomic Network Approach across the Kidney Stone Disease Reveals Endoplasmic Reticulum Stress and Crystal-Cell Interaction in the Kidney.

Crystal-cell interactions are a vital step toward kidney stone formation. However, its mechanisms remained unclear. Here, a protein-protein interaction (PPI) network analysis of a kidney stone revealed that the proteins were enriched in a posttranslational protein modification process in the endoplasmic reticulum (ER). The in vitro study showed that the markers of ER stress, including Bip and CHOP, were upregulated, PERK and ATF6 were activated, and XBP-1 mRNA was spliced. An ER stress-specific protein, caspase-12, was activated in the apoptotic cells induced by calcium oxalate monohydrate (COM) crystals. The treatment with tunicamycin, an ER stress inducer, promoted the crystal-cell adhesion assayed by atomic absorption, reduced cell viability assayed by MTT, and downregulated the expression of proteins involved in the crystal formations. The treatment with salubrinal, an ER stress inhibitor, reversed the above effects for both tunicamycin and COM crystals. The aforementioned main observations were supported by in vivo study. These data demonstrated that ER stress was an essentially biological process of crystal-cell interactions. Our findings suggest that blocking ER stress may become a potential approach to preventing a kidney stone.