Metabologenomics and network pharmacology to understand the molecular mechanism of cancer research

In this editorial I comment on the article“Network pharmacological and molecular docking study of the effect of Liu-Wei-Bu-Qi capsule on lung cancer”published in the recent issue of the World Journal of Clinical Cases 2023 November 6;11(31):7593-7609.Almost all living forms are able to manufacture particular chemicals-metabolites that enable them to differentiate themselves from one another and to overcome the unique obstacles they encounter in their natural habitats.Numerous methods for chemical warfare,communication,nutrition acquisition,and stress prevention are made possible by these specialized metabolites.Metabolomics is a popular technique for collecting direct mea-surements of metabolic activity from many biological systems.However,con-fusing metabolite identification is a typical issue,and biochemical interpretation is frequently constrained by imprecise and erroneous genome-based estimates of enzyme activity.Metabolite annotation and gene integration uses a biochemical reaction network to obtain a metabolite-gene association so called metabologe-nomics.This network uses an approach that emphasizes metabolite-gene consensus via biochemical processes.Combining metabolomics and genomics data is beneficial.Furthermore,computer networking proposes that using meta-bolomics data may improve annotations in sequenced species and provide testable hypotheses for specific biochemical processes.CONCLUSION The genome and metabolites of biological organisms are not fully characterized with current technologies.However,increasing high-throughput metabolomics and genomics data provide promising generation of paired data sets to understand the molecular mechanism of biochemical processes as well as determining targets for pharmaceutical drug design.Contemporary network infrastructures to integrate omics analysis can provide molecular mechanism of biochemical pathways.Furthermore,clinical data may be integrated to gene expression–metabolite expression by system genetics approach.Calculating pair-wise correlations and weighted correlation network analysis provide the basis of this integration[11-13].The occurrence of strong correlations between classified metabolites and co-expression transcripts implies either various roles of metabolites or linkages between metabolic pathways and the immune system.

Pancreatic acinar cell carcinoma: A review on molecular profiling of patient tumors

Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4,BRAF,BRCA2,TP53,RB1,MEN1,JAK-1,BRCA-1,BRCA-2,and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore,molecular profiling of PACC should be an option for patients with refractory PACC.

Forkhead box protein P1, a key player in neuronal development?

Forkhead box protein P1（FOXP1）is a transcription factor belonging to the forkhead box（FOX）proteins,a family of transcriptional regulators sharing a highly conserved forkhead DNA-binding domain（Bacon and Rappold,2012）.Previous reports have proposed a role for FOXP1 in functionally regulating the central nervous system（CNS）,while mutations in FOXP1 have been implicated in cognitive abnormalities（Bacon and Rappold, 2012）.

Green spermatozoa illuminate a 30-year-old model： sperm-egg adhesion involves intra-acrosomal proteins

Fertilisation in mammals involves many synchronized steps including spermegg adhesion. Prior to sperm-oolemma fusion, spermatozoa need to undergo the acrosome reaction （AR） or exocytosis. The universal belief, for many years, has been that the AR was initiated upon binding to the zona pellucida （ZP）. As such acrosomal proteins were not thought to be involved in the primary contact with the ZP. These proteins were only suggested to be biologically relevant once the sperm were attached to the ZP and during subsequent events. However,

Circulating levels of hydroxylated bradykinin function as an indicator of tissue HIF-1a expression

The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.

EpiMap: Fine-tuning integrative epigenomics maps to understand complex human regulatory genomic circuitry

In a recent paper published in Nature,Boix et al.1 developed an integrated platform on epigenomic maps that represents a significant updated resource in human regulatory circuitry as related to specific organ tissues and cells,as well as specific disease traits.The EpiMap(for epigenome integration across multiple annotation projects)is a highly valuable compendium comprising 10,000 epigenomic maps across 833 biospecimens and 33 tissue categories.The distinct biospecimens expanding coverage to life development(embryonic to adult)and different sample types including complex organ tissues as well as primary cells,and established normal and tumor cell lines.The biospecimen analysis provides a comprehensive view of human genome circuitry making EpiMap a remarkable platform for epigenomic landscapes assessment to the investigator.

Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease

Background:Family studies support a genetic predisposition to inflammatory bowel diseases(IBD),but known genetic variants only partially explain the disease heritability.Families withmultiple affected individuals potentially harbour rare and highimpact causal variants.Long regions of homozygosity due to recent inbreedingmay increase the risk of individuals bearing homozygous loss-of-function variants.This study aimed to identify rare and homozygous genetic variants contributing to IBD.Methods:Four families with known consanguinity and multiple cases of IBD were recruited.In a family-specific analysis,we utilised homozygosity mapping complemented by whole-exome sequencing.Results:We detected a single region of homozygosity shared by Crohn’s disease cases from a family of Druze ancestry,spanning 2.6Mb containing the NOD2 gene.Whole-exome sequencing did not identify any potentially damaging variants within the region,suggesting that non-coding variation may be involved.In addition,affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1,WHAMM,DENND3,and C5.Conclusion:This study examined the potential contribution of rare,high-impact homozygous variants in consanguineous families with IBD.While the analysis was not designed to achieve statistical significance,our findings highlight genes or loci that warrant further research.Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn’s disease.

Lipoid Proteinosis Due to Homozygous Deletion Mutation(c.735delTG)in the ECM1 Gene Presents with Seizures and Hoarseness but No Skin Involvement

Histopathology The histopathological features of bowenoid papulosis(BP)are hyperkeratosis,focal keratosis,acanthosis,and cellular atypia of the epidermis characterized by hyperchromatic nuclei,prominent nucleoli,mitotic figures,epidermal multinucleated giant cells,and dyskeratotic cells.1 Slight or moderate perinuclear vacuole formation is occasionally observed.Histopathologically,BP shows similar but generally milder changes compared with Bowen's disease.Dilated capillaries and perivascular diffuse infiltration of lymphocytes can be observed in the upper dermis.The most characteristic finding of BP is an occasional transformation of bowenoid atypia to benign proliferation as time progresses,especially during the course of spontaneous regression.1 Parakeratosis,acanthosis,scattered cellular atypia of the epidermis,dyskeratotic cells,dilated capillaries,and perivascular diffuse infiltration of lymphocytes,all of which are typical histopathological features of BP,were observed in our patient(Fig.1).