HPV-associated cervicovaginal microbiome and host metabolome characteristics.

BACKGROUND: Cervicovaginal microbiome plays an important role in the persistence of HPV infection and subsequent disease development. However, cervicovaginal microbiota varied cross populations with different habits and regions. Identification of population-specific biomarkers from cervicovaginal microbiota and host metabolome axis may support early detection or surveillance of HPV-induced cervical disease at all sites. Therefore, in the present study, to identify HPV-specific biomarkers, cervicovaginal secretion and serum samples from HPV-infected patients (HPV group, n = 25) and normal controls (normal group, n = 17) in Xichang, China were collected for microbiome (16S rRNA gene sequencing) and metabolome (UHPLC-MS/MS) analysis, respectively. RESULTS: The results showed that key altered metabolites of 9,10-DiHOME, α-linolenic acid, ethylparaben, glycocholic acid, pipecolic acid, and 9,12,13-trihydroxy-10(E),15(Z)-octadecadienoic acid, correlating with Sneathia (Sneathia_amnii), Lactobacillus (Lactobacillus_iners), Atopobium, Mycoplasma, and Gardnerella, may be potential biomarkers of HPV infection. CONCLUSION: The results of current study would help to reveal the association of changes in cervicovaginal microbiota and serum metabolome with HPV infections.

Role of miRNAs in macrophage-mediated kidney injury.

Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.

eIF6 Promotes Gastric Cancer Proliferation and Invasion by Regulating Cell Cycle.

OBJECTIVE: To investigate the role and function of eIF6 in gastric cancer (GC). METHODS: The expression level of eIF6 in GC tissues and normal tissues was detected in different high-throughput sequencing cohorts. Survival analysis, gene differential analysis, and enrichment analysis were performed in the TCGA cohort. Biological networks centered on eIF6 were constructed through two different databases. Immunohistochemistry (IHC) and Western blot were used to detect protein expression of eIF6, and qRT-PCR was used to detect eIF6 mRNA expression. The correlation between the expression of eIF6 in GC tissues and clinicopathological parameters of GC was analyzed. siRNA knockout of eIF6 was used to study the proliferation, migration, and invasion. The effects of eIF6 on cell cycle and Cyclin B1 were detected by flow cytometry and Western blot. RESULTS: eIF6 was significantly overexpressed in GC tissues and predicted poor prognosis. In addition, 113 differentially expressed genes were detected in cancer-related biological pathways and functions by differential analysis. Biological networks revealed interactions of genes and proteins with eIF6. The expression intensity of eIF6 in cancer tissues was higher than that in adjacent tissues (P = 0.0001), confirming the up-regulation of eIF6 expression in GC tissues. The expression level of eIF6 was statistically significant with pTNM stage (P = 0.006). siRNA knockout of eIF6 significantly reduced the proliferation, colony formation, migration, and invasion ability of GC cells. Silencing of eIF6 also inhibited the cell cycle of GC cells in G2/M phase and decreased the expression level of CyclinB1. CONCLUSION: Our study suggests that eIF6 is up-regulated in GC and may promote the proliferation, migration, and invasion of GC by regulating cell cycle.

Chemical profiling and quality evaluation of Liuweizhiji Gegen-Sangshen oral liquid by UPLC-Q-TOF-MS and HPLC-diode array detector fingerprinting.

INTRODUCTION: Liuweizhiji Gegen-Sangshen (LGS) oral liquid is a Chinese patent medicine that is widely used for the prevention and treatment of alcoholic liver disease in clinical practice. However, the chemical complexity of LGS has not yet been investigated. OBJECTIVE: The aim of this study was to rapidly identify chemical constituents of LGS and establish a quality control method based on fingerprint and quantitative analysis. METHODOLOGY: A comprehensive strategy was used by combining qualitative analysis by ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and fingerprint analysis by high-performance liquid chromatography with diode array detection (HPLC-DAD). RESULTS: A total of 162 chemical components in LGS, including 91 flavonoids, 31 organic acids, and 20 phenolic compounds, were identified or preliminarily characterized in both positive and negative ion modes based on the UPLC-Q-TOF-MS results. Of these, 37 were confirmed with the reference standards. In fingerprint analysis, 23 peaks were chosen as common peaks and used to evaluate the similarity of different batches of LGS. Subsequently, a rapid quantification method was optimized and validated for the simultaneous determination of multiple chemical markers in LGS. The validated quantitative method was successfully used to analyze different batches of LGS samples. CONCLUSION: The proposed comprehensive strategy combining HPLC-DAD fingerprinting and multi-component quantification demonstrated satisfactory results with high efficiency, accuracy, and reliability. This can be used as a reference for the overall quality consistency evaluation of Chinese patent medicines.

Anoikis resistance--protagonists of breast cancer cells survive and metastasize after ECM detachment.

Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive. Video Abstract.

CD3ζ as a novel predictive biomarker of PD-1 inhibitor resistance in melanoma.

Malignant melanoma is the most lethal form of skin cancer, and its incidence rates are increasing in Europe, America, and Oceania countries. Despite immune checkpoint inhibitors, such as PD-1 inhibitors, have been shown to have significant therapeutic effects on malignant melanoma, many patients are unresponsive to these treatments, even emerged resistance. There is an urgent need to discover novel biomarkers that might distinguish resistant patients from responders. In this study, we used a series of bioinformatics analyses and experimental validation. The GSE65041 was used for differential expression analysis. Kaplan-Meier was used to assess the prognostic value. ESTIMATE, ssGSEA, EPIC, TIMER, quanTiseq and MCPcounter for estimation of immune infiltration in the tumor microenvironment. We eventually identified that CD3ζ was significantly down-regulated in IHC PD-L1(-) melanoma patients. Low level of CD3ζ expression possessed a poor prognosis. CD3ζ low expression population is significantly associated with lower immune infiltration. In vivo experiment, CD3ζ expression was significantly down-regulated in mice melanoma after intradermally injected with B16-F10R cells. Compared to their wildtype counterparts, melanoma resistant mice treated with nivolumab showed significant reductions in tumor volume and weight when adding CD3ζ. In vitro experiment, the addition of CD3ζ increased nivolumab effection on inhibiting B16-F10R cell viability. Our findings indicated that CD3ζ could be a novel predictive biomarker of PD-1 inhibitor resistance in melanoma.

Immunomodulatory Mechanism and Potential Application of Dental Pulp-Derived Stem Cells in Immune-Mediated Diseases.

Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) derived from dental pulp tissue, which have high self-renewal ability and multi-lineage differentiation potential. With the discovery of the immunoregulatory ability of stem cells, DPSCs have attracted much attention because they have similar or even better immunomodulatory effects than MSCs from other sources. DPSCs and their exosomes can exert an immunomodulatory ability by acting on target immune cells to regulate cytokines. DPSCs can also migrate to the lesion site to differentiate into target cells to repair the injured tissue, and play an important role in tissue regeneration. The aim of this review is to summarize the molecular mechanism and target cells of the immunomodulatory effects of DPSCs, and the latest advances in preclinical research in the treatment of various immune-mediated diseases, providing new reflections for their clinical application. DPSCs may be a promising source of stem cells for the treatment of immune-mediated diseases.

Synthesis of Oleanolic Acid-Dithiocarbamate Conjugates and Evaluation of Their Broad-Spectrum Antitumor Activities.

Efficient and mild synthetic routes for bioactive natural product derivatives are of current interest for drug discovery. Herein, on the basis of the pharmacophore hybrid strategy, we report a two-step protocol to obtain a series of structurally novel oleanolic acid (OA)-dithiocarbamate conjugates in mild conditions with high yields. Moreover, biological evaluations indicated that representative compound 3e exhibited the most potent and broad-spectrum antiproliferative effects against Panc1, A549, Hep3B, Huh-7, HT-29, and Hela cells with low cytotoxicity on normal cells. In terms of the IC50 values, these OA-dithiocarbamate conjugates were up to 30-fold more potent than the natural product OA. These compounds may be promising hit compounds for the development of novel anti-cancer drugs.

Dopamine receptor D1 signaling stimulates lipolysis and browning of white adipocytes.

Adipocytes express several kinds of catecholamine receptors, including adrenergic receptors, and dopamine receptors. Signaling pathways mediated by catecholamine receptors, such as ß3-adrenergic receptor pathway, can induce body energy expenditure via activating thermogenesis of adipose tissue. However, the roles of adipose dopamine receptors on adipocytes are still unclear. Here, we investigate the role of dopamine receptor D1 (DRD1) on adipocytes. To this end, we use DRD1 agonist Fenoldopam and antagonist SCH23390 to stimulate and inhibit DRD1 signaling, respectively. We found that, compared with control group mice, Fenoldopam-treated and SCH23390-treated high-fat-diet (HFD)-fed mice showed smaller and bigger white adipose tissue/adipocyte sizes, respectively. Meanwhile, activating of DRD1 signaling enhanced intracellular levels of cAMP, phosphorylation levels of protein kinase A substrates, and hormone-sensitive lipase, a key enzyme for lipolysis in mature 3T3-L1 adipocytes and white adipose tissue of HFD-fed mice. As a result, the levels of free fatty acid or glycerol were increased, indicating stimulation of lipolysis by DRD1 activation. Moreover, activating DRD1 can induce the browning of adipocytes, as indicated by enhanced phosphorylation of P38 MAP kinase, increased expression of beige cell markers (PGC-1α, UCP-1, and CD81), mitochondrion content, and expression of ß-oxidation related genes. All of these effects were reduced after treating with SCH23390 both in vitro and in HFD-fed mice. Collectively, our study indicated that DRD1 signaling stimulates lipolysis and browning of white adipocytes in vitro and in vivo. Understanding the functions of DRD1 on human adipocytes and adipose tissues will help us to design novel strategies to treat obesity.

Polyphenols as Lung Cancer Chemopreventive Agents by Targeting microRNAs.

Lung cancer is the second leading cause of cancer-related death worldwide. In recent decades, investigators have found that microRNAs, a group of non-coding RNAs, are abnormally expressed in lung cancer, and play important roles in the initiation and progression of lung cancer. These microRNAs have been used as biomarkers and potential therapeutic targets of lung cancer. Polyphenols are natural and bioactive chemicals that are synthesized by plants, and have promising anticancer effects against several kinds of cancer, including lung cancer. Recent studies identified that polyphenols exert their anticancer effects by regulating the expression levels of microRNAs in lung cancer. Targeting microRNAs using polyphenols may provide a novel strategy for the prevention and treatment of lung cancer. In this review, we reviewed the effects of polyphenols on oncogenic and tumor-suppressive microRNAs in lung cancer. We also reviewed and discussed the potential clinical application of polyphenol-regulated microRNAs in lung cancer treatment.

The distinct roles of exosomes in tumor-stroma crosstalk within gastric tumor microenvironment.

Gastric cancer (GC) development is a complex process displaying polytropic cell and molecular landscape within gastric tumor microenvironment (TME). Stromal cells in TME, including fibroblasts, endothelial cells, mesenchymal stem cells, and various immune cells, support tumor growth, metastasis, and recurrence, functioning as the soil for gastric tumorigenesis. Importantly, exosomes secreted by either stromal cells or tumor cells during tumor-stroma crosstalk perform as crucial transporter of agents including RNAs and proteins for cell-cell communication in GC pathogenesis. Therefore, given the distinct roles of exosomes secreted by various cell types in GC TME, increasing evidence has indicated that exosomes present as new biomarkers for GC diagnosis and prognosis and shed light on novel approaches for GC treatment.

Identification of a distinct luminal subgroup diagnosing and stratifying early stage prostate cancer by tissue-based single-cell RNA sequencing.

BACKGROUND: The highly intra-tumoral heterogeneity and complex cell origination of prostate cancer greatly limits the utility of traditional bulk RNA sequencing in finding better biomarker for disease diagnosis and stratification. Tissue specimens based single-cell RNA sequencing holds great promise for identification of novel biomarkers. However, this technique has yet been used in the study of prostate cancer heterogeneity. METHODS: Cell types and the corresponding marker genes were identified by single-cell RNA sequencing. Malignant states of different clusters were evaluated by copy number variation analysis and differentially expressed genes of pseudo-bulks sequencing. Diagnosis and stratification of prostate cancer was estimated by receiver operating characteristic curves of marker genes. Expression characteristics of marker genes were verified by immunostaining. RESULTS: Fifteen cell groups including three luminal clusters with different expression profiles were identified in prostate cancer tissues. The luminal cluster with the highest copy number variation level and marker genes enriched in prostate cancer-related metabolic processes was considered the malignant cluster. This cluster contained a distinct subgroup with high expression level of prostate cancer biomarkers and a strong distinguishing ability of normal and cancerous prostates across different pathology grading. In addition, we identified another marker gene, Hepsin (HPN), with a 0.930 area under the curve score distinguishing normal tissue from prostate cancer lesion. This finding was further validated by immunostaining of HPN in prostate cancer tissue array. CONCLUSION: Our findings provide a valuable resource for interpreting tumor heterogeneity in prostate cancer, and a novel candidate marker for prostate cancer management.

Thyroid disruption and developmental toxicity caused by triphenyltin (TPT) in zebrafish embryos/larvae.

The adverse effects of triphenyltin (TPT) on aquatic systems have attracted much attention because TPT is widely used and prevalent in aquatic environments. Here, zebrafish embryos/larvae were exposed to TPT (0, 0.039, 0.39, and 3.9 nM; 0, 15, 150 and 1500 ng/L) for 7 or 14 days to determine its toxic effects on the hypothalamic-pituitary-thyroid (HPT) axis. The results showed that whole-body total T4 and T3 levels were significantly decreased, which was accompanied by the significant upregulation of the expression of the dio1, dio2 and ugt1ab genes after exposure to TPT for 7 and 14 days. Genes related to thyroid hormone synthesis (crh, tshß, nis, tpo and tg) were upregulated at both 7 and 14 days after TPT exposure. This might have been due to the positive feedback regulation of the HPT axis, which is caused by a decrease in thyroid hormone in the whole body in zebrafish. In addition, the survival rates and body lengths were reduced after treatment with TPT for 7 and 14 days. This indicated that TPT caused adverse effect on the development of zebrafish embryos/larvae. In summary, the results suggested that TPT caused thyroid disruption and developmental toxicity in zebrafish larvae.

Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer - A comprehensive review from chemotherapy to immunotherapy.

Breast cancer is the most frequently occurring cancer in women. Chemotherapy in combination with immunotherapy has been used to treat breast cancer. Atezolizumab targeting the protein programmed cell death-ligand (PD-L1) in combination with paclitaxel was recently approved by the Food and Drug Administration (FDA) for Triple-Negative Breast Cancer (TNBC), the most incurable type of breast cancer. However, the use of such drugs is restricted by genotype and is effective only for those TNBC patients expressing PD-L1. In addition, resistance to chemotherapy with drugs such as lapatinib, geftinib, and tamoxifen can develop. In this review, we address chemoresistance in breast cancer and discuss Akt as the master regulator of drug resistance and several oncogenic mechanisms in breast cancer. Akt not only directly interacts with the mitogen-activated protein (MAP) kinase signaling pathway to affect PD-L1 expression, but also has crosstalk with Notch and Wnt/ß-catenin signaling pathways involved in cell migration and breast cancer stem cell integrity. In this review, we discuss the effects of tyrosine kinase inhibitors on Akt activation as well as the mechanism of Akt signaling in drug resistance. Akt also has a crucial role in mitochondrial metabolism and migrates into mitochondria to remodel breast cancer cell metabolism while also functioning in responses to hypoxic conditions. The Akt inhibitors ipatasertib, capivasertib, uprosertib, and MK-2206 not only suppress cancer cell proliferation and metastasis, but may also inhibit cytokine regulation and PD-L1 expression. Ipatasertib and uprosertib are undergoing clinical investigation to treat TNBC. Inhibition of Akt and its regulators can be used to control breast cancer progression and also immunosuppression, while discovery of additional compounds that target Akt and its modulators could provide solutions to resistance to chemotherapy and immunotherapy.

Natural killer cells as a double-edged sword in cancer immunotherapy: A comprehensive review from cytokine therapy to adoptive cell immunotherapy.

Natural killer (NK) cells are immune cells which are able to kill tumor and virus-infected cells and play an important role in both innate immunity and acquired immunity. Tumor immunotherapy is an emerging model of tumor treatment in the clinic. It is a re-emerging type of anticancer immunotherapy with the purpose of killing tumor cells by modulating the body's immune function and enhancing the antitumor immunity in tumor microenvironment. At present, many immune cells including lymphokine-activated killer cells, NK cells, cytokine-induced killer cells, and dendritic cells are involved in tumor immunotherapy studies. NK cells, which lyse tumor cells without prior stimulation, has become a research hotspot in cancer immunotherapy for clinical application. In this article, we discussed the surface receptors of NK cells and the anticancer function of NK cells. We also reviewed the biological characteristics and the current research status of NK cells, their clinical application in cancer immunotherapy and its future perspectives.

Glyoxalase 1 gene improves the antistress capacity and reduces the immune inflammatory response.

BACKGROUND: Fish immunity is not only affected by the innate immune pathways but is also triggered by stress. Transport and loading stress can induce oxidative stress and further activate the immune inflammatory response, which cause tissue damage and sudden death. Multiple genes take part in this process and some of these genes play a vital role in regulation of the immune inflammatory response and sudden death. Currently, the key genes regulating the immune inflammatory response and the sudden death caused by stress in Coilia nasus are unknown. RESULTS: In this study, we studied the effects of the Glo1 gene on stress, antioxidant expression, and immune-mediated apoptosis in C. nasus. The full-length gene is 4356 bp, containing six exons and five introns. Southern blotting indicated that Glo1 is a single-copy gene in the C. nasus genome. We found two single-nucleotide polymorphisms (SNPs) in the Glo1 coding region, which affect the three-dimensional structure of Glo1 protein. An association analysis results revealed that the two SNPs are associated with stress tolerance. Moreover, Glo1 mRNA and protein expression of the heterozygous genotype was significantly higher than that of the homozygous genotype. Na+ and sorbitol also significantly enhanced Glo1 mRNA and protein expression, improved the fish's antioxidant capacity, and reduced the immune inflammatory response, thus sharply reducing the mortality caused by stress. CONCLUSIONS: Glo1 plays a potential role in the stress response, antioxidant capacity, and immune-mediated apoptosis in C. nasus.

The molecular landscape of histone lysine methyltransferases and demethylases in non-small cell lung cancer.

Background: Lung cancer is one of the most common malignant tumors. Histone methylation was reported to regulate the expression of a variety of genes in cancer. However, comprehensive understanding of the expression profiles of histone methyltransferases and demethylases in lung cancer is still lacking. Methods: We analyzed the expression profile of methyltransferases and demethylases in non-small cell lung cancer (NSCLC) using TCGA and cBioportal databases. The mutation, expression level, association with survival and clinical parameters of histone methyltransferases and demethylases were determined. Results: We found overall upregulation of histone regulators in NSCLC. Mutation and copy number alteration of histone methylation related genes both exist in NSCLC. The expression of certain histone methylation related genes were significantly associated with overall survival and clinical attributes. Conclusions: Our result suggests that alteration of histone methylation is strongly involved in NSCLC. Some histone methylation related genes might serve as potential prognosis predictor or therapeutic target for NSCLC. The significance of some histone methylation related genes was contrary to the literature and awaits further validation.

CD4+ T cells in obesity and obesity-associated diseases.

Over the past few decades, obesity has been recognized as low-grade chronic inflammatory disease and was contributed to systemic metabolic diseases such as type 2 diabetes (T2D). Accumulating evidence indicates that adipose tissue (AT) inflammation is a key event in the pathogenesis of obesity and obesity-associated diseases. While AT-resident immune cells play important roles in maintaining AT homeostasis, obesity changes their numbers and activities, which were accompanied by the activation of inflammatory responses. Recent investigations emphasized the contributions of adaptive immune cells, especially CD4+ T cells, in controlling immune-AT crosstalk in the progression of obesity and obesity-associated disorders. In this review, we focus on the current understandings of the roles of CD4+ T cells in obesity and obesity-associated diseases, and the effects of adipocytes as antigen presenting cells on regulating CD4+ T cell activity.

EZH2 coupled with HOTAIR to silence MicroRNA-34a by the induction of heterochromatin formation in human pancreatic ductal adenocarcinoma.

MicroRNA-34a (miR-34a) is frequently downregulated in pancreatic ductal adenocarcinoma (PDAC) cells, however, the silencing mechanism remains unclear. Enhancer of zeste homolog 2 (EZH2) is overexpressed in PDAC, and our previous miRNA profiling showed that inhibition of EZH2 in PDAC cells led to the re-expression of a group of tumor suppressor miRNAs including miR-34a. Here, we studied the effect of ectopic EZH2 expression to the silencing of miR-34a, and identified HOTAIR as an interacting partner to induce heterochromatin formation during miR-34a repression. We identified EZH2 as a major player in silencing miR-34a. Inhibition of EZH2 upregulated miR-34a expression in PDAC cells, while EZH2 overexpression in human pancreatic ductal epithelial (HPDE) cells repressed miR-34a expression and decreased the miR-34a promoter activity. We then showed that HOTAIR played a critical role in EZH2-mediated repression of miR-34a, as knockdown of HOTAIR attenuated the miR-34a inhibition effect in EZH2-overexpressing HPDE cells. HOTAIR physically interacted with miR-34a promoter, and the EZH2-interacting region located at 5' HOTAIR RNA was essential in repressing miR-34a and promoting cell proliferation. More importantly, we showed that the interaction between EZH2 and HOTAIR underlay the silencing of miR-34a through induction of heterochromatin formation. We first showed that manipulation of EZH2 level interfered the occupancy of heterochromatin markers H3K9me2, heterochromatin associated protein 1α and 1γ in PDAC cells. In turn, we showed that knockdown of HOTAIR reduced the occupancy of EZH2 at miR-34a promoter. The identification of HOTAIR-guided miR-34a silencing opened a new avenue in miR-34a-oriented therapy against PDAC.

The involvement of regulatory non-coding RNAs in sepsis: a systematic review.

BACKGROUND: Sepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis. METHODS: We searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words ("microRNA", "long non-coding RNA", "circular RNA", "sepsis" and/or "septic shock") from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool. RESULTS: Observational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common. CONCLUSIONS: Although non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful.