Metastatic progression of female breast and colon cancer represents a major cause of mortality in women. Spontaneous/acquired resistance to conventional and targeted chemo-endocrine therapy is associated with the emergence of drug-resistant tumor-initiating cancer stem cell populations. The cancer-initiating premalignant stem cells exhibit activation of select cancer cell signaling pathways and undergo epithelial–mesenchymal transition, leading to the evolution of a metastatic phenotype. The development of reliable cancer stem cell models provides valuable experimental approaches to identify novel testable therapeutic alternatives for therapy-resistant cancer. Drug-resistant stem cell models for molecular subtypes of clinical breast cancer and for genetically predisposed colon cancer are developed by selecting epithelial cells that survive in the presence of cytostatic concentrations of relevant therapeutic agents. These putative stem cells are characterized by the expression status of select cellular and molecular stem cell markers. The stem cell models are utilized as experimental approaches to examine the stem-cell-targeted growth inhibitory efficacy of naturally occurring dietary phytochemicals. The present review provides a systematic discussion on (i) conceptual and experimental aspects relevant to the chemo-endocrine therapy of breast and colon cancer, (ii) molecular/cellular aspects of cancer stem cells and (iii) potential stem-cell-targeting lead compounds as testable alternatives against the progression of therapy-resistant breast and colon cancer. Progression of female breast and colon cancer to advanced-stage metastatic disease represents a major cause of mortality in the female population. The American Cancer Society projects combined new cases at 333,230 and cancer-related deaths at 68,060 in 2022 . ConventLong-term treatment with these pharmacological agents is commonly associated with systemic toxicity, spontaneous/acquired tumor resistance and the emergence of therapy-resistant cancer stem cell populations. These major limitations associated with conventional chemo-endocrine therapy and small-molecule-based targeted therapy emphasize an unmet need to identify testable therapeutic alternatives against therapy-resistant breast and colon cancers. Natural products such as dietary phytochemicals, micro-nutrients and nutritional herbs have documented cancer-preventive efficacy on epithelial organ site cancers of the breast and colon, in part via targeting cancer stem cells ,4. TheseMIN/+ model, a lack of ER-α and ER-β accelerates the formation of colon cancer  pyrene (BP), dimethyl hydrazine (DMH) and azoxy-methane (AOM), and metabolism-independent direct-acting methyl nitroso urea (MNU) and N-methyl-N-nitroso-guanidine (MNNG) ,31,32,33The parental cell lines developed from human breast carcinoma and from genetically predisposed mice exhibit hyper-proliferation, as evidenced by decreased population doubling time, increased saturation density, accelerated cell cycle progression and downregulated cellular apoptosis.The data presented in The non-tumorigenic epithelial cells initiated for carcinogenesis by either chemical carcinogens, viruses or oncogenes exhibit AI growth in vitro and tumor formation in vivo. The tumorigenic status of the epithelial cells is confirmed by the in vivo tumor formation of transplanted cells. Thus, in the cell culture models, AI growth represents an in vitro surrogate endpoint marker for in vivo tumorigenic transformation that is indicative of a quantifiable risk of developing cancer ,35,36,37The data presented in Several mechanistic assays that have been optimized for the parental cell lines and also for stem cells are widely used in preclinical cancer research. The assays for parental cell lines involve monitoring cell cycle progression, cellular apoptosis and the expression status of relevant regulatory molecules at genomic and proteomic levels. In the mechanistic assays for stem cells, tumor spheroid (TS) formation represents a commonly used biological marker. In addition, flow-cytometry-based assays have facilitated the quantitation of the expression status of additional stem cell markers. The quantitative immunofluorescence assay is optimized to measure the relative cellular uptake of antibodies specific for cell surface markers and for nuclear transcription factors. The cell surface markers include clusters of differentiation CD44 and CD133, while the molecular markers include nuclear transcription factors octamer-binding transcription factor-4 (OCT-4), Kruppel-like factor-4, (Klf-4), sex-determining region box Y-2 (SOX-2), cellular myc (c-myc) and homeobox transcription factor (NANOG) ,29,38,39Conventional chemo-endocrine therapy for breast cancer includes the use of multi-drug cytotoxic chemotherapeutics containing doxorubicin, 5-fluro-uracil, cisplatin, paclitaxel, selective estrogen receptor modulators (SERM) such as tamoxifen, selective estrogen receptor degraders (SERD) such as fulvestrant, aromatase inhibitors such as letrozole and exemestane and cyclin-dependent kinase inhibitors such as palbociclib and ribociclib. For colon cancer, multi-drug combinations of 5-fluro-uracil+ irinotecan and 5-fluoro-uracil + oxaliplatin and non-steroidal anti-inflammatory drugs such as sulindac and celecoxib are used ,27.Some of these clinically relevant agents for breast and colon cancer are utilized to select the resistant phenotypes, as summarized in Therapy-resistant cancer-initiating stem cells are characterized by the expression of select nuclear transcription factors, some of which are also documented to be crucial for the maintenance of drug-resistant stem cells and induced pluripotent stem cells. These stem-cell-specific transcription factors include OCT-4, Klf-4, SOX-2 and c-myc ,39. The 90 concentrations are used in experiments. TS formation represents a sensitive and specific cellular marker for stem cells. The data presented in The drug-resistant stem cells maintained in the presence of TAM, LAP and DOX at their respective predetermined ICThe data presented in 90 concentrations for experiments. The data presented in MIN COL cells, a model for FAP. The TS number is increased in the SUL-R phenotype. The data presented in The drug-resistant stem cells are maintained in the presence of SUL and 5-FU at their respective predetermined IC1/1638N COL cells, a model for HNPCC. The 5-FU-R stem cells exhibit increased expression of the stem cell markers relative to the 5-FU-S cells [The data presented in -S cells .Transgenic animal models expressing RAS, Myc and HER-2 oncogenes in the mammary epithelium develop mammary cancer. Stable expression of these oncogenes in non-tumorigenic mammary epithelial cells induces tumorigenic transformation ,35,36,37MIN/+ model has been utilized to examine the combinatorial chemo-preventive efficacy of pharmacological agents and natural products [Genetically predisposed mice exhibit germline mutations in the tumor suppressor gene Apc and in DNA mismatch repair genes Mlh1, Msh2 and Msh6. These genetic defects in mice lead to the formation of intestinal adenoma. The 850products ,28,29.Naturally occurring dietary agents have documented preventive efficacy in transgenic models expressing RAS, Myc and HER-2 oncogenes in the mammary epithelium and leading to the formation of premalignant lesions such as ductal carcinoma in situ and lobular carcinoma in situ for breast cancer ,31,32,331 phase of the cell cycle and the inhibition of phosphorylated HER-2 expression. Induction of cellular apoptosis is associated with the downregulation of BCL-2 and upregulation of BAX [Naturally occurring phytochemicals such as polyphenols, isoflavones and terpenoids induce anti-proliferative and pro-apoptotic effects via distinct mechanisms in 184-B5/HER cells, a model for HER-2-enriched breast cancer. Mechanistically, growth inhibition is associated with the arrest of cells in the Gn of BAX .Chinese herbs, many of them nutritional in nature, have been traditionally used for the management of general health concerns and also for estrogen-related health issues, including breast diseases in women ,42. ThesSmall molecules targeting programed cell death protein-1, programed death ligand-1, poly ADP-ribose polymerase and antibody–drug conjugates represent novel agents selective for several actionable molecular targets .Recently published evidence suggests that Chinese nutritional herbs and constituent active components ,41,42, dThe data presented in MIN COL model for familial adenomatous polyposis (FAP) syndrome, independent treatment with mechanistically distinct pharmacological agents and naturally occurring dietary compounds as single agents inhibits the growth of colonic epithelial cells. For example, the pharmacological compounds difluoro-methylornithine, sulindac and celecoxib function as selective inhibitors of ornithine decarboxylase and of cyclooxygenases, respectively. The naturally occurring tea polyphenol epigallocatechin gallate predominantly affects EGFR signaling. Collectively, these agents function as potent inhibitors of the Wnt/APC/β-catenin signaling cascade via the expression of select downstream target genes. Treatment with low-dose combinations of these agents results in a greater reduction in AI colony number, relative to treatment with individual single agents. The superior efficacy of the combinatorial treatment is predominantly due to synergistic interactions via distinct mechanisms [In the 850chanisms ,28,29. Ichanisms .In traditional Chinese medicine, nutritional herbs have also been used for the treatment of colon cancer. Extracts prepared from the roots, leaves, fruits and seeds of the herbs function as potent immunomodulatory and anti-inflammatory agents . In a coPseudo ginseng (PC), Radix salviae (RS), Radix paeoniae (RP) and Morinda officinalis (MO). The data presented in MIN COL model.For these experiments, the cells were treated with predetermined maximum cytostatic concentrations of non-fractionated aqueous extracts prepared from the nutritional herbs MIN COL model.Several natural products, including polyphenols, terpenes and N-3 PUFA, exhibit inhibitory effects in colon cancer models. For these experiments, the cells are treated with natural products at their respective predetermined maximum cytostatic concentrations. The data presented in MIN COL cells, a model for FAP.For these experiments, the cells are treated with the natural products CUR, the bioactive agent from turmeric, and ATRA, a vitamin A derivative, at their respective predetermined maximum cytostatic concentrations. The data presented in The multi-step progression of breast and colon cancers is profoundly influenced by a complex interaction of dietary, endocrine and environmental factors. These aspects present formidable challenges for the selection of appropriate therapeutic options. In addition, the emergence of drug-resistant cancer stem cells facilitates the metastatic progression of the disease. MIN/+ animal model for FAP syndrome, the evidence of the stem-cell-targeted growth-inhibitory effects of natural products provides a proof of concept that naturally occurring compounds may represent testable therapeutic alternatives for therapy-resistant breast and colon cancer. Collectively, this evidence provides a basis for expanding the present research for its potential clinical relevance.This review discusses the conceptual, phenomenological and mechanistic evidence for cancer stem cell models developed from epithelial cell lines derived from human breast carcinoma and from colonic epithelial cell lines derived from female mice genetically predisposed to intestinal carcinogenesis. These models exhibit relevance to molecular subtypes of clinical breast and colon subtypes. Based on the evidence for the in vivo combinatorial efficacy of pharmacological agents and natural products in the 850The premalignant cancer-initiating stem cells are endowed with resistance to chemotherapy and EMT. These chemo-resistant, EMT-positive cells progress to the metastatic phenotype, which is capable of invading distant metastatic sites ,52,53,54It is notable that the LAP-R, SUL-R and 5-FU-R phenotypes represent relevant models of premalignant cancer-initiating stem cells for HER-2-enriched, FAP and HNPCC cancer subtypes, respectively. Collectively, these stem cell models provide valuable experimental approaches for the genomic, transcriptomic, proteomic and metabolomic analysis of molecular mechanisms that are relevant to the progression of the target premalignant cells to the invasive cancer phenotype.Breast-carcinoma-derived immortalized cell lines and spontaneously immortalized colonic epithelial cell lines express telomerase enzyme, which represents a specific and sensitive marker for the immortalized phenotype. Synthetic small molecules and naturally occurring phytochemicals that function as telomerase inhibitors may also represent novel testable alternatives .In the estrogen receptor (ER) expressing the Luminal A breast cancer subtype, the ER functions as a ligand-regulated transcription factor. The ER isoforms α and β are responsible for distinct positive and negative growth regulatory functions ,9,10,11.The experimental evidence discussed in the present review is derived predominantly from preclinical animal models in vivo, and from established epithelial cell lines in vitro. Collectively, these aspects represent important research directions for future investigations. However, it needs to be recognized that experiments on cancer stem cell models that are derived from established cell lines depend on extrapolation for their clinical relevance. These approaches have provided valuable mechanistic data. However, the potential clinical translatability of these data is strongly dependent on extrapolation.In an effort to reduce the need for extrapolation, future investigations on patient-derived tumor samples may be of considerable importance. These investigations may include ex vivo models developed from patient-derived tumor xenografts , patient


Accumulating evidence supports that prostate cancer stem-like cells (PCSCs) play significant roles in therapy resistance and metastasis of prostate cancer. Many studies also show that nitric oxide (NO) synthesized by NO synthases can function to promote tumor progression. However, the exact roles of NOSs and NO signaling in the growth regulation of PCSCs and castration-resistant prostate cancer (CRPC) are still not fully understood.The regulatory functions of NOS-NO signaling were evaluated in prostate cancer cells, especially in PCSCs enriched by 3D spheroid culture and CD133/CD44 cell sorting. The molecular mechanisms of NOS-NO signaling in PCSCs growth regulation and tumor metastasis were investigated in PCSCs and mice orthotopic prostate tumor model.Endothelial NOS (eNOS) exhibited a significant upregulation in high-grade prostate cancer and metastatic CRPC. Xenograft models of CRPC exhibited notable increased eNOS expression and higher intracellular NO levels. PCSCs isolated from various models displayed significant enhanced eNOS-NO signaling. Functional analyses demonstrated that increased eNOS expression could promote in vivo tumorigenicity and metastatic potential of prostate cancer cells. Characterization of eNOS-NO involved downstream pathway which confirmed that enhanced eNOS signaling could promote the growth of PCSCs and antiandrogen-resistant prostate cancer cells via an activated downstream NO-sGC-cGMP-PKG effector signaling pathway. Interestingly, eNOS expression could be co-targeted by nuclear receptor ERRα and transcription factor ERG in prostate cancer cells and PCSCs.TMPRSS2:ERG fusion gene.Enhanced eNOS-NO signaling could function to promote the growth of PCSCs and also the development of metastatic CRPC. Besides eNOS-NO as potential targets, targeting its upstream regulators (ERRα and ERG) of eNOS-NO signaling could also be the therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the The online version contains supplementary material available at 10.1186/s13287-022-02864-6. It is well recognized that many cancers, including prostate cancer, contain heterogeneous populations of transformed cells, with difference in their growth features and clinical behaviors. Accumulating evidence shows that within cancers, there is a small subpopulation of highly tumorigenic cancer cells designated as cancer stem-like cells , thus named largely due to their stemness features, such as expression of stem cells-associated transcription factors, high self-renewal capacity and phenotypic plasticity . ExperimStudies in prostate cancer validate that prostate cancer stem-like cells (PCSCs) can be indeed isolated from various sources, including prostate cancer cell lines and patient-derived tumor xenografts, using different methodologies . EmerginNOS1), inducible (iNOS/NOS2) and endothelial (eNOS/NOS3). The effects of NO on tumor growth can be dichotomous or context-dependent, depending on the activities and expressions of NOSs, NO concentration and duration of exposure, and cellular sensitivity to NO   than CD133−/CD44− cells  as compared to their parental LNCaP cells  and membrane antigens  ] and mesenchymal marker CDH2 (N-cadherin) as compared to their corresponding cells grown under adherent 2D culture condition, with their further expressions in 3D-cultured spheroids formed by eNOS-overexpressed cells  in LNCaP-eNOS cells when grown in non-adherent 3D culture condition. These results suggest that enhancement of eNOS-NO signaling could maintain the stemness of PCSCs and induce the EMT process in PCSCs. In vitro wound healing assay showed that eNOS overexpression could remarkably promote, whereas its knockdown could suppress, the migration capacity of PC-3 M cells, a highly metastatic subline of PC-3  in prostate cancer, and the EMT process is shown to be closely associated with cancer stemness or PCSC growth , 44. To To evaluate the functional significance of eNOS-NO signaling in the growth regulation of PCSCs, we next determined the growth impact of either knockdown or overexpression of eNOS and also pharmacological suppression of eNOS activity on the non-adherent 3D culture growth capacity (stemness feature) of prostate cancer cells. Studies showed that shRNA-mediated knockdown of eNOS induced no significant growth impact on the adherent 2D cultures of DU145  to be significantly regulated by the activated eNOS-NO signaling. Expression analysis confirmed that HES6 and F2RL1 showed reduced expressions in LNCaP-sheNOS cells but exhibited significant higher expressions in PSCS-enriched 3D-cultured spheroids as compared to their corresponding adherent 2D-cultured cells. Contrarily, KDM3A was repressed by the activated eNOS-NO signaling in PSCS-enriched 3D-cultured spheroids (unpublished data). In all, our present study and also others indicate that activation of NOS-NO signaling or increased intracellular NO production is a common feature of CSCs originated from different cancer types and also its increased level is critical to their growth and maintenance.We further characterized that the enhanced eNOS-NO signaling could significantly promote the growth of PCSCs regardless of their AR expression status, and also antiandrogen-resistant prostate cancer cells via the activation of downstream NO-sGC-cGMP-PKG signaling pathway, as evidenced by pharmacological inhibition of effectors in this signaling pathway. Moreover, our findings also showed that pharmacological blockage of individual signaling effectors of eNOS-NO-sGC-cGMP-PKG pathway or knockdown of eNOS could impair the stemness (spheroid growth capacity) of PCSCs and also inhibit the in vivo orthotopic tumor growth of prostate cancer cells, suggesting that targeting eNOS-NO-sGC-cGMP-PKG signaling may have therapeutic potential in PCSC targeting and also management of advanced prostate cancer. Accumulating studies show that increased NO production as a result of upregulation of iNOS or eNOS can promote the stemness phenotypes of cancer cells derived from various tumor sources or experimental models, including glioma , 49, livThe consequent functional impact of enhanced eNOS-NO signaling in PCSCs is still unclear. Previously, we have demonstrated that increased eNOS expression and NO production can contribute to antiandrogen-resistant growth of prostate cancer cells via a mechanism of suppression of AR transactivation and also activation of protein kinase Akt . Our preIn addition to CSCs, NO derived from other cell types, including tumor-associated macrophages (TAMs), tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and endothelial cells have been demonstrated to be involved in the cancer development . Lung TATMPRSS2:ERG fusion gene, to activate the eNOS-NO signaling in PCSCs  could also be the PCSC-directed therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the Additional file 1. Supplementary Figures S1-S5 and Supplementary Tables S1 and S2.


The reduction in right hemispheric PC-PHG LPS was significantly correlated with negative symptom improvement at the end of the stimulation . Our findings suggest that in-phase theta-tACS can modulate theta-band large-scale functional connectivity pertaining to negative symptoms. Considering the failure of right hemispheric PC-PHG functional connectivity to predict improvement in negative symptoms at one-week follow-up, future studies should investigate whether it can serve as a surrogate of treatment response to theta-tACS.EEG studies indicated that schizophrenia patients had increased resting-state theta-band functional connectivity, which was associated with negative symptoms. We recently published the first study showing that theta (6 Hz) transcranial alternating current stimulation (tACS) over left prefrontal and parietal cortices during a working memory task for accentuating frontoparietal theta-band synchronization (in-phase theta-tACS) reduced negative symptoms in schizophrenia patients. Here, we hypothesized that in-phase theta-tACS can modulate theta-band large-scale networks connectivity in schizophrenia patients. In this randomized, double-blind, sham-controlled trial, patients received twice-daily, 2 mA, 20-min sessions of in-phase theta-tACS for 5 consecutive weekdays (n = 18) or a sham stimulation (n = 18). Resting-state electroencephalography data were collected at baseline, end of stimulation, and at one-week follow-up. Exact low resolution electromagnetic tomography (eLORETA) was used to compute intra-cortical activity. Lagged phase synchronization (LPS) was used to measure whole-brain source-based functional connectivity across 84 cortical regions at theta frequency (5–7 Hz). EEG data from 35 patients were analyzed. We found that in-phase theta-tACS significantly reduced the LPS between the posterior cingulate (PC) and the parahippocampal gyrus (PHG) in the right hemisphere only at the end of stimulation relative to sham ( Schizophrenia is a chronic, debilitating mental illness. Its core components include positive symptoms, negative symptoms, and cognitive deficits. Primary negative symptoms  account for a large part of poor functional outcomes and long-term disability in patients with schizophrenia . EfficacRecent research indicates that transcranial electrical stimulation (tES) is a representative non-invasive brain stimulation method that may serve as an effective therapy in counteracting negative symptoms . Common Functional magnetic resonance imaging (fMRI) studies identified working memory (WM) related activities in a widely distributed neural network involving the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (mPFC), insula, hippocampus, posterior parietal cortex (PPC), and occipito-temporal cortex . Data frResearch indicates that a fundamental pathophysiological feature of schizophrenia consists of a functional disconnection syndrome, in which neural oscillations at the theta frequency are robustly implicated . For exaMotivated by the above-mentioned findings, suggesting long-range EEG phase synchronization in a narrow theta band of 5–7 Hz as an underlying neural mechanism of WM related activities , this stClinicalTrials.gov (accessed on 15 February 2023), ID: NCT04545294; The present study is a double-blind, randomized, sham-controlled trial, approved by the ethics committee of Tri-Service General Hospital, Taipei, Taiwan and registered . A study coordinator not involved in the trial created 5-digit random numbers and assigned the randomization numbers to the participants to maintain blinding integrity . The par®  was used to simulate the numerical computation of the electric field of the current montage  with a sampling frequency of 4000 Hz, an analogue-digital precision of 24 bits, and an analogous bandpass filter (0–1200 Hz). Patients were seated comfortably in a recliner in a light and sound-attenuated room. They were instructed not to drink caffeinated beverages one hour prior to, and alcohol 24 h prior to EEG recording to avoid caffeine- or alcohol-induced changes in the EEG stream. The ground electrode was placed at Fpz. The horizontal electrooculogram (HEOG) was recorded by two electrodes placed at 1 cm from the outer canthi of both eyes. Two electrodes were placed above and below the left eye, respectively, to record the blinks and vertical electrooculogram (VEOG). The impedance of each electrode was checked to remain below 5 kΩ. Before starting the EEG recording, the patients performed 3-min calibration tasks to estimate the influence of horizontal/vertical movements and blink artifacts on EEG, which was processed and stored in the Neuro Prax® EEG system built-in software providing fully automatic correction of real-time EEG artifacts caused by blinking and eye or body movement during the subsequent EEG recording (Resting-state EEG (rsEEG) was collected at baseline, end of stimulation, and one-week follow-up, using a 32-channel EEG cap  with Ag/AgCl sintered ring electrodes placed according to the international 10–20 system and referenced to the tip of the nose, together with Neuro Praxecording . rsEEG wecording . ConsideAll source imaging was performed with the exact low-resolution brain electromagnetic tomography (eLORETA), a linear inverse solution used to compute the standardized current density or distribution of current density across voxels in the brain by localizing and reconstructing the intracerebral electrical sources underlying the scalp-recorded activity  in a reahttp://www.talairach.org/ (accessed on 15 February 2023)” [In this study, whole-brain EEG source-based functional connectivity analyses were performed by the ‘‘whole-brain Brodmann areas (BAs)’’ approach, using the anatomical definitions of 84 BAs provided by eLORETA software package and based on the Talairach Daemon “y 2023)” . Standary 2023)” . A valuet-tests were used to compare the between-group differences at post-baseline visits. The SnPM analysis tool includes a correction for multiple comparisons. The statistical analyses of between-group changes in theta-band (5–7 Hz) electrical source estimation and source functional connectivity from baseline to post-baseline visits were conducted using t-tests that were corrected for multiple comparisons using a non-parametric permutation procedure (5000 randomizations). Spearman rank correlations were used to analyze the relationships between the significant changes in EEG-based source functional connectivity from baseline to post-baseline visits and treatment response to in-phase theta-tACS. Statistical significance for the results was set at p < 0.05 (two-tailed) and the false discovery rate (FDR) was used for multiple comparisons corrections.Statistical analyses were performed using either IBM SPSS Statistics 21.0 software  or the implemented statistical eLORETA nonparametric mapping (SnPM) tool . Repeatep = 0.0027). Post-hoc analyses showed significant between-group differences at all post-baseline assessments  or a sham stimulation (n = 18)  greater than the t-value threshold for statistical significance returned 1 and those less than the threshold returned 0 in the map -tACS improves negative symptoms of schizophrenia through modulating theta-band (5–7 Hz) EEG source-based large-scale functional network connectivity. Recent research showed that a single session of online in-phase theta (6 Hz)-tACS with a low current intensity (1 mA) did not result in any significant change in resting-state EEG scalp-level theta-band connectivity between prefrontal and parietal areas in healthy individuals . There wEvidence indicates that patients with schizophrenia showed increased EEG-based resting-state functional connectivity at lower frequencies  compared to the healthy controls, especially higher right fronto-parietal connectivity and higher connectivity between central and parietal areas in the theta band , the incOur study demonstrated that adjunct 10 sessions of in-phase theta (6 Hz)-tACS during a working memory task resulted in theta-band (5–7 Hz) interregional de-synchronization between two nodes in the posterior part of DMN  at the end of stimulation along with an improvement in negative symptoms. Furthermore, the reduction in resting-state theta-band connectivity within the above network over time was positively correlated with negative symptom improvement at the end of stimulation, thus supporting the value of right hemispheric PC-PHG LPS as a surrogate biomarker for the clinical efficacy of online in-phase theta-tACS in treating negative symptoms of schizophrenia.A large number of fMRI/DTI studies indicate that functional hyperconnectivity within the DMN may be the most common finding in comparisons of schizophrenia patients with healthy individuals ,31 and sThe DMN can be separated into two subsystems , tightly linked by functional hubs also known as a midline core  . The dorOur results suggest a potential relationship between theta-tACS inducing a decrease in right hemispheric PC-PHG functional connectivity in the theta frequency (5–7 Hz) and improvements in negative symptoms, suggesting that theta-band long-range functional hyper-connectivity may be a neural signature of negative symptoms of schizophrenia, and theta-tACS controlled negative symptoms by effectively regulating the PC-PHG connectivity within DMN. It should be noted that a recent fMRI study indicated that hyperconnectivity within the DMN nodes, i.e., the functional connectivity between angular gyrus (AG) and middle temporal gyrus (MTG), was further enhanced in medication-resistant schizophrenia patients receiving a regular course of bitemporal electroconvulsive therapy (ECT) combined with antipsychotics for 4 weeks, as compared to those receiving only antipsychotics, suggesting that ECT did not reverse the original state of hyperconnectivity within the DMN, but provoked a compensatory increase in DMN connectivity . In addiA previous study used magnetoencephalography (MEG) to investigate resting-state brain oscillation and the DMN based on a source space in different frequency bands  and found that the spatial distribution of DMN activity in the alpha frequency was similar to that reported in fMRI studies, and schizophrenia patients had an increased resting activity of the posterior hub of DMN , predominantly in the theta band . It is kOur study has a few limitations. First, EEG directly measures fast neural network dynamics with high temporal resolution (ms) for investigating the high temporal dynamics of the whole-brain network functional connectivity but it is limited by its ability to detect sources of electrical activity in deep structures  that were reported to have aberrant connectivity in schizophrenia patients , as wellOur study indicates that adjunct theta-tACS might contribute to the improvement of negative symptoms by modulating theta-band functional connectivity between spatially separated brain structures within the DMN in patients with schizophrenia. Furthermore, the change in right hemispheric PC-PHG functional connectivity in response to theta-tACS may serve as a biomarker to track the therapeutic effect of this novel non-invasive brain stimulation. Our findings may be a new starting point for the development of individualized and effective brain stimulation therapies in treating negative symptoms of schizophrenia.


In this article, we describe the potential efficacy of GLP-1RAs for the induction of axonal regeneration and remyelination following nerve lesions and the prevention and alleviation of demyelinating disorders, particularly multiple sclerosis.Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were developed as insulinotropic and anti-hyperglycemic agents for the treatment of type 2 diabetes, but their neurotrophic and neuroprotective activities have been receiving increasing attention. Myelin plays a key role in the functional maintenance of the central and peripheral nervous systems, and recent  Endogenous GLP-1 is quickly metabolized into the inactive peptide by dipeptidyl peptidase (DPP)-4, whereas GLP-1R agonists (GLP-1RAs) have a substantially longer plasma half-life than GLP-1 because of their resistance to DPP-4. Numerous GLP-1RAs have been developed and utilized in the treatment of type 2 diabetes as injections ), lixisenatide, semaglutide, glutide) . GLP-1Rsglutide) . Recent glutide) . In partglutide) . The neuglutide) . Recent glutide) . Togethein vivo and in vitro studies suggest that Ex-4 accelerates the process of axonal regeneration and remyelination (etc.) are intractable and life-threatening, as well as the neurodegenerative disorders described above. Recent studies have shed light on the therapeutic potential of liraglutide and Ex-4 for demyelinating disorders, mainly MS  is an autosomal recessive neurodegenerative disorder characterized by childhood-onset diabetes mellitus and various neurological manifestations, including progressive optic nerve atrophy, sensorineural hearing loss and cognitive impairment . Seppa eThere is enough evidence that the main pathology of diabetic neuropathy is axonal degeneration, which precedes demyelination observed in patients with the disease at advanced stages . HoweverCo-culture systems of neurons and Schwann cells have enabled us to generate myelin structures nearly equivalent to those in living bodies, thereby being recognized as useful tools to investigate neuron-Schwann cell interactions . Immortain vitro, growing evidence with Schwann cells may be applicable to CNS myelination in the future.Although there have been no reports regarding the efficacy of GLP-1RA for oligodendrocyte function OECs are the glial cells of the primary olfactory system, and its transplantation is a promising strategy for functional repair following spinal cord and peripheral nerve injuries . Tseng eThere are more than 2 million patients with MS worldwide. Like AD and PD, MS can be categorized into neurodegenerative disorders in the CNS; however, it has distinct features of progressive immune-mediated neuro-inflammatory evens resulting in multiple demyelinating lesions . Althoug01, in EAE mice has been documented , and cuprizone-induced demyelination models are widely used . The potcumented , althougcumented . These fcumented , intrapecumented  and the cumented , it seemetc.). However, accumulating evidence regarding their utility toward MS might be diverted to those diseases. The dual effects of GLP-1RAs, such as modulatory actions to immune cells  and trophic and protective activities to oligodendrocytes and Schwann cells, would be variable for the strategies of myelin protection and repair in the CNS and PNS. Immune checkpoint inhibitors (ICIs), a novel class of antineoplastic remedies, have shown clinical efficacy toward a variety of intractable tumors. However, ICIs can evoke demyelinating disorders in the CNS (etc)  .We briefly summarized the recent progress regarding the beneficial effects GLP-1RAs on myelin formation and maintenance and their potential efficacy toward MS and other demyelinating disorders. The underlying action mechanisms remain largely obscure, and no clinical trials of GLP-1RAs toward axonal injury or MS have been conducted; however, the broad distribution of GLP-1R in the nervous tissue and diverse biological activities of GLP-1RAs  would en


The development of bio-based polymers from vegetable oils start emerging with different properties to generate a value-added system. This review will give an impression to readers about how coatings generated from vegetable oils can find a way towards better protective properties against corrosion either by using fillers or by using molecular structure modifications in the system, thus covering a range of vegetable oil-based self-healing polymers and their application in anti-corrosion coatings.Sustainable development is a critical concern in this fast-paced technological world. Therefore, it is essential to employ renewable resources to move towards sustainable development goals (SDGs). The polyols attained from renewable resources, including lignin, chitosan, vegetable oils, cellulose,  The article covers coating materials using bio-chemical derived molecules (vegetable oils) and their properties including mechanical, self-healing and anti-corrosion properties. To convert vegetable oils into polyols, chemical conversion of oils via epoxidation, hydroformylation, ozonolysis, transesterification,19 amidation and thiol–ene reaction is performed.20–22 Among different vegetable oil-based polymers, polyurethanes are widely used due to their excellent physio-chemical properties.23 These properties vary with sources of polyols, preparation methods and functional groups present in resultant polymers.24,25Since mid of the 1900s, petroleum-based polymers have been widely used in the coating industry; however, from the environmental point of view, it is high time we shift towards renewable resources.25–27 Self-healing can be generally classified into two main groups: intrinsic and extrinsic self-healing materials. These materials primarily differ in their mechanisms as well as their chemistries. While intrinsic self-healing materials are based on supramolecular hydrogen bonding interactions and reversible reactions.28–32 Extrinsic self-healing materials require the embedding of microcapsules filled with healing agents in a matrix system or vascular networks.33–36 The capsule-based self-healing system , and microvascular networks are the two pathways frequently used in the preparation of extrinsic self-healing materials.22,37–45 For the addition of self-healing properties, the presence of phenolic groups is advantageous in order to support the cross-linking, which results in a fast self-damage curation9 therefore, some phenolic biomolecules known for their affinity towards the modification of vegetable oil-based polymers for coating applications. The –OH (hydroxyl group) containing molecules like flavones, tannin, and flavonoids also act as a suitable corrosion inhibitors. Taking Tannin biomolecules for this purpose provides adequate corrosion protection and self-healing abilities. Tannins are one of the components found in natural extracts and organic products.46,47 However, polymeric coatings derived from vegetable oils perform poor chemical and thermal resistance as compared to petroleum-based polymeric coating.48 To enhance the thermal and mechanical properties including preventing the moisture/water penetration, a wide range of nanofillers have been incorporated into the coating matrix.5,13,49–51 Carbonized materials such as carbon nanotubes (CNTs), graphene, and mesoporous carbon structures have been attracted to researchers due to their chemical, thermal, electrical, and mechanical properties, thus, leading towards the enhancement of mechanical, anti-corrosion, antimicrobial properties.10,46,52–56 Carbonaceous hybrid nanostructure materials implanted with different functionalities enhance the self-healing properties. Hydrogen bond donor-acceptor moieties bonded to filler walls show repetitive dynamic repair on damages due to hydrogen bond exchange in the polymeric network via click chemistry30,35,57,58 vegetable oils derived metals containing polymeric coatings are considered to enhance anti-corrosion and anti-fungal properties, whereas aliphatic tri-ester moiety of oils provides hydrophobic nature and inherent flexibility to the coating.59–61 This review will give an impression to readers about how coatings generated from vegetable oils can find a way towards better protective properties against corrosion.To enhance the durability of polymeric materials, the addition of a self-healing function is highly advantageous.1.1.62,63 Therefore, an intelligent coating able to repair itself and protect the assets from corrosion and improve durability is highly desirable. The whole idea of self-healing coating was inspired by nature, given how natural healing of wounds and cuts occur in living species. The era of self-healing materials is gradually settling in where the macro/micro-cracks in structural materials can close on their own without any external influence, and the scratches on the designed materials can seal up with a complete restoration. In particular, self-healing coatings are helpful to reduce costs and labor associated with coating maintenance for offshore application, where inspection and maintenance are complex due to the location of the asset. However, due to geopolitical challenges, coating industry need to shift its focus from conventional petroleum-based polymers to bio-chemicals derived polymers. Lined up from the biomaterial to smart protective coatings, vegetable oil is worth to utilize for the synthesis of high-performance material, given that oils provide a wide range of fatty acids like oleic acid, linoleic acid, palmitic acid and stearic acid. Leaving an impression of interest, sustainable polymeric protective coatings have been in prime focus for corrosion inhibition of metallic surfaces and thus explored in this report.6,42 Along with the inherent properties of vegetable oils, external materials/groups can be easily coupled due to the presence of different functional moieties in oil, as required for different coating applications.64–66Although so many polymeric protective coatings are present in the market, approx. 3.6% of total GDP  is being spent on the maintenance of structural substrates and instruments caused by distruction due to corrosion.2.2.1.via solvent extraction or mechanical pressing. In the case of solvent extraction, the main constituent obtained is ricinoleic acid, which is present at around 90% of the whole oil and comes under the euphorbiaceous group. Other components, including linoleic acid, oleic acid, stearic acid, palmitic acid, etc., are present in trace amounts.9,67 The presence of –COOH groups in castor oil facilitates the esterification and amidation, whereas double bonds proceed to hydrogenation and epoxidation. In addition, –OH groups promote acetylation and alkoxylation or dehydration, leading to the formation of a different range of polymers, including polyether, polyurethanes, polyesters, polyamides, etc. which is being discussed in detail in Castor oil, a readily available organic chemical can be extracted 68 Deewan and coworkers studied the effects of incorporating boron-based nanofillers in polyester and polyurethane matrix during synthesis.60 The reaction involves esterification of hydroxyl group of castor oil (BCPE) followed by polyaddition between BCPE and Toluene,2,4-diisocyanate (TDI). The coating results in highly effective anti-corrosion properties with no weight loss in the basic medium for 50 hours, whereas a loss in weight was observed in the acidic medium. Good thermal stability (∼220 °C) and physio-chemical properties were observed for boron-polyurethane-based coatings. To understand the significance of castor oil-based shape memory PUs, Karak and coworkers discussed the advantages of using sulfur containing reduced graphene oxide based coatings (SRGO).69 The presence of functional groups on the graphene surface gives better dispersion properties in polymeric matrix than to pristine graphene nanosheet. In addition, poly(ε-caprolactone)-diol (PCL) and SRGO were mixed to get the final hyperbranched PU/SRGO (HPU/SRGO) hybrid. Due to the strong interaction between pre-polymer and functionalised GO, improvement in thermal stability and mechanical properties was observed. The presence of PCL helped to achieve excellent shape recovery and shape-healing properties  under sunlight and microwave. In addition, authors have studied microwave radiation-promoted SH composites.70 The microwave radiation oscillates dipoles, thus helpful in transferring the energy into the polymer matrix. This absorbed energy is beneficial to raise the matrix temperature above Tg and consequently facilitates the repairing of reported coatings. The synthesis mechanism and exclaimed properties of nanocomposite are substantiated in schematic diagram in [To enhance coating properties, filler incorporation is highly advantageous.agram in .Hyperbranched polyurethane iron oxide reduced graphene oxide (HPU-IO-RUO) nano-composites were prepared using different compositions of nanohybrids . The heavia reacting isocyanates and alcohols catalysed by tertiary amines (with low steric hindrance to facilitate the reaction), or Pb, Sn based catalysts, e.g. N,N-dimethyl cyclohexylamine or stannous octoate.71 Reacting pre-urethanes along with another polymeric matrix results in the formation of interpenetrating polymer networks (IPN) possessing impressive thermal stability. By controlling the composition of isocyanates and polyols, the matrix demonstrated adhesive properties and is beneficial for vast applications including coatings. Shahidul and coworkers have reported the TiO2 dispersed hyperbranched poly-(ester amide)(HBPEA) nanocomposites derived from castor oil using A2 + B3 approach.72 In this process, firstly, N,N-bis(2-hydroxy ethyl) castor amide (HECA) was synthesized by reacting diethanol amine and sodium methoxide at 110 °C and the addition of castor oil was performed dropwise, which was further used for the synthesis of hyperbranched poly (ester-amide). The reported composite was found to have hydrophobic properties (due to the hydrophobic surface of TiO2 increasing cross-linking density) with contact angle in the range of 89° to 107°, and thermal stability of 452 °C.Urethane linkages can be obtained 10 These carbonised nanoparticles were obtained by burning the leaves in atmospheric oxygen and treating them with piranha solution, which leads to delignified carbon nanoparticles. Further, biobased hybrid polyurethane was synthesized by reacting polymeric 4,4′-methylene diphenyl diisocyanate, carbonized nano particles (CNM-COOH) and 4-methyle pentene-2-one along with castor oil. The study found that with increasing the percentage of CNM doping, cross-linking power of urethane and thermal stability (399 °C) was enhanced. The corrosion resistance of the composite coating was improved with Ecorr = 12.4 mV, Icorr = 4.4 × 10−4 A cm−2, Rp = 7.02 × 104 K ohm cm2 and Rcorr = 5.1 × 10−6 ohm on mild steel.Moving further, eucalyptus leaves were used to synthesize the carbonized nanoparticles as bio-resourced nano-fillers.73 The reported polymer matrix possesses high hardness due to TDI (because of aromatic moiety), impact resistance 200 lb per inch, and corrosion inhibition efficiency of 94% & 90% in acidic and alkaline environments, respectively. In another study, it was observed that castor oil-derived alkyd resin has a good affinity towards corrosion inhibition.74Kashif and coworkers investigated corrosion inhibition behaviour of castor oil-derived polyurethane, synthesised by reaction of the castor oil with diethanol-amine and sodium methoxide followed by the addition of toluene2,4-diisocyanate(TDI).75 Hyperbranched polyol was synthesised by a transesterification reaction between CO, 2,2-bis (hydroxymethyl)propionic acid (DMPA) and p-toluene-sulfonic acid (P-TSA) under nitrogen environment [In order to strengthen the anti-corrosion and hydrophobic properties; lotus leaves inspired self-cleaning coatings is highly advantageous. Wei and coworkers has developed anti-smudge bio-based polymeric coatings ncorporated with poly(dimethyl-siloxane) (PDMS)).ironment . PDMS-OHironment . A studyironment . Mechani76 Castor oil was treated with Iso-phorone diisocyanate (IPDI) to synthesize the water-borne polyurethane network. Afterwards, titanium carbide was grafter on the polymer moiety in different proportions along with 2-aminophenyl disulfide (AD). The film prepared was mechanically robust due to presence of H-bonding. Though ADWPU polymeric film synthesised is very effective against electromagnetic waves, after adding Ti3AlC2 about 99.9% of waves were found to be blocked either by reflecting, scattering or absorbing the radiations.Recently, there has been a high demand for electromagnetic interference (EMI) shielding materials. Jingu Lu and coworkers worked on castor oil-based polyurethanes coating films with properties like self-healing and EMI shielding.2.2.Tg and strength-based challenges epoxidized soybean oil has remain magnificent starting point for the formation of polymers with diverse properties.47 The properties exhibited and possible applications for a different set of polymers derived from soybean oil has been listed in 7 In the wake of exploring soybean oil for synthesising self-healing coating materials, Altuna and coworkers tailored the epoxy resin with gold nanoparticles.24 In this study, citric acid was used to synthesise epoxy to synthesise an epoxy-based polymer network followed by the incorporation of gold nanoparticles, where gold NPs were prepared in situ through the Turkevich poly(vinyl-pyrrolidone) (PVP) medium. The prepared network is a non-toxic and biologically compatible polymer. The presence of PVP facilitates the linear alignment of the NPs in the polymeric matrix, which promote stress relaxation and self-healing properties of the nanocomposite. The tensile strength of the coating was quite good, and stress relaxation at 60 °C and self-healing properties were well facilitated through localized healing with green laser radiation to ease the reach of thermal effect for the crack healing process. Thiol–ene click reactions are currently in vogue in the self-healing coating industry as it is very economical to carry out at very high-speed kinetics. Prakash and coworkers83 used a photo-induced thio-ene click reaction approach to synthesize the castor oil polyol(MCO) and soybean oil(MSO) polyol in the presence of DMPA and ME followed by the formation of thermoplastic PU from MCO and MSO using chain extender 1,4-butanediol (BD) and dibutyltin dilaurate (DBTDL).24 The prepared thermoplastic PU was found to have excellent transparency, elasticity and high mechanical strength. Altogether, Kocaman suggested the use of coconut-based bio-fillers to enhance the coating properties.82 Acrylated and epoxidized soybean oil (AESO) based epoxy resins can be fused with bio-fillers generated from grinded coconut waste (CW) particles. Coconut waste particles were functionalized with poly(hexafluoro butyl acrylate) (PHFBA) which is hydrophobic in nature. This modification in polymeric matrix benefits the material with several properties like water repellence, high thermal stability, flammability, good acid and alkali resistance which exhibit anti-corrosion properties. The results show that with high cellulosic content, the flammability of the material increases as lignin content is high. Prakash and coworkers suggested that soybean polyols can be prepared through a thio-ene reaction between soybean oil and 2-mercaptoethanol (ME) in the presence of DMPA and THF.83 The soybean-based polyol was further used for the formation of polyurethane coating by reacting it with toluene 2,4-diisocyanate (TDI) and DBTDL at room temperature. The resultant coating was found to have good anti-corrosion properties on mild steel panels (tests conducted in 3.5% NaCl and 0.5N HCl aqueous solution). The coating provides excellent tensile strength and barrier properties against corrosion, due to notable high H-bonding in methane linkage between PU coating where no damage or fracture was observed on the coating surface. According to thermal studies, first degradation was observed at 250 °C and second degradation observed at 390 °C due to breakage of ester linkage.Soybean oil has majorly been used in the polymeric coating industry for last decade. In spite of high Tg, however, a further increase in TVP concentration Tg increase from 40 °C to 75 °C.84Generally, imine-based polymers show good mechanical properties and irretrievability, where due to lower in bond energies and easy dissociation, H- bonds provide efficient self-healing properties. Initially, epoxidized soybean oil was treated with trivanillinyl-phosphate (TVP), which was further used to prepare the multilayer-CNT (MWCNT) composites. With the increase in TVP concentration H-bonding abundancy increases while stable imine bonds go down, which results an increase in cross-linking, thus enhances the rigidity of polymer. With the elevation in temperature multi-exchange of network come in existence to achieve self-healing and re-processibility. With a low TVP concentration polymer show rubbery character above 85 Kamal and coworkers produce three different types of novel polyester resins by reacting mono-glyceride (from soybean oil) with phthalic and maleic anhydride. The monoglyceride was obtained by glycerolysis of oil via reversible ester interchange reaction.86 Yuan and coworkers have reported the synthesis of lignin and soybean oil-based azide-functionalized sustainable elastomers via controlled thermal azide−alkyne cycloaddition (TAAC) [Tg less than 5 °C [50. Alongside this, a catalyst-free bio-based vitrimer from soybean oil was done by Guillermina and coworkers. The thermal and mechanical behaviour of the material was found to be controlled by the content of the precursor used.87Vitrimeric polymers can be synthesised from the epoxidized oil in the absence of the catalyst. Liu and coworkers developed catalyst-free epoxy based vitrimeric network using soybean oil and 4,4'dithiodiphenylamine(APD) as curing agents . The poln (TAAC)  along wihan 5 °C 50. Along88Despite limited application due to water resistance, methacrylate gelatine can be used in bio-coating to improve moisture resistance. Being able to perform photo-crosslinking reactions and be prepared from renewable resources, methacrylate gelatine is found to enhance hydrophobicity and mechanical properties. Single layer application is reported to be very useful and spontaneously stratifying into layers, whereas multilayer application is quite complex, expensive and energy consuming. Self-stratification is blending incompatible polymers to form a collective multilayer structure. Sahar and coworkers reported that to enhance the mechanical properties and breathability, this self-stratifying light curable AESO-based coating material could be formulated.2.3.79 Drying oil Linseed oil-derived polymers are known for their self-healing abilities, and the recent advance in properties and applications for the same has been discussed in 95 The reported coating prepared was cured at the ambient environment, which possess appreciable anti-corrosion and physio-mechanical properties. Initially, linseed oil was used to form N, N-bis 2-hydroxy ethyl linseed oil fatty amide diol (HELA), followed by the formation of hydroxyl-terminated polyester-amide (Ed-PEA) by treating with ethylenediaminetetraacetic acid (EDTA). The resultant material was cured while reacting with poly  (SMA) at ambient temperature. Polyester-amide coating was thermally stable upto 150 °C and possesses significant corrosion inhibiting properties. Subsequently, polyester amines have also been known for their uses in anti-bacterial and anti-corrosion coatings. To improve the anti-bacterial properties, durability and anti-corrosion properties, H. Abd El-Wahab and coworkers modified polyester amine with N-phthaloyl-glutamic acid.96 In this study, linseed oil and diethanolamine (DEA) reacted to get N,N-bis-(2-hydroxyethyl)linseed oil fatty acid amide (HELA) which was made to treat with phthalic anhydride (PA) and N-phthaloyl-glutamic acid (NPGA) (synthesised in situ) to obtain modified resin for coating. The reported coating exhibits notable chemical resistance and anti-corrosion properties along with excellent mechanical properties. The coating was tested to have less permeability for water, oxygen, and other ions to pass, owing to enriching the adhesion of the hydroxyl group connected to metal surfaces. Although bio oil-based nanocomposites are potential alternatives for replacing petroleum coatings, advancing the properties of composite polymers can do wonders to address the issues like corrosion, optical transparency, and flexibility. Shabnam Pathan and team attempted to address these noted issues by tailoring the linseed oil-based water-borne alkyd resin with 3-iso-cynato-propyl-tri-ethoxy silane (IPTES) and di-methyl-tin-di-neo-decanoate.97 In nanohybrid composite, flexibility is due to the synergistic reinforcing effect and merging of organic and inorganic phases of the system. Shabnam Pathan and coworkers used water-borne linseed oil-based alkyd composites to improve the mechanical properties,98 where silane-based coupling agents have been used to address the limitations and escalate the interaction between two phases. Cross-linked polymer coatings derived from linseed oil using melamine formaldehyde (MF) and 3 iso-cynato-propyl tri-ethoxy silane (IPTES) exhibits great mechanical and anticorrosive performance [Due to its rich inherent properties, linseed oil is one of the highly utilised vegetable oils in the coating industry. Linseed oil has been widely used among researchers because it is eco-friendly, economical, available, and suitable to form the polymeric network.formance . It was formance .2O nano-cube based filler into alkyd resin to achieve high thermal stability (∼324 °C) along with better mechanical and corrosion inhibition properties.79 The hyper-branched poly-alkyd resin was synthesized by adopting A2 + B3 approach, where glycerol and adipic acid were reacted in the presence of dibutyltin oxide . The prepared materials were and further treated with linseed oil fatty acid and P-TSA as catalyst under poly-condensation reaction. The resultant resin incorporated with Cu2O nanoparticles was used for coatings, where coating possess excellent corrosion inhibition abilities, significant mechanical features as well as stability against chemicals. For further advancement of the study in vegetable oil-based alkyd resin Deepak M. Patil and coworkers synthesised epoxidized alkyd resin from linseed oil using itaconic acid for the application as anti-corrosion coating.99 It was a two-step process, where linseed oil was converted into mono-glyceride via an esterification process. Furthermore, the unsaturated binds present in the alkyd moity were converted into oxirane and later to epoxidized alkyd resin. The resultant polymer was modified by using 3-amino propyl-trimethoxy-silane (APTMS) to obtain a coating with good mechanical and adhesive properties. It is due to its ability to form H-bonding with the metal surface. The coating was able to create a good barrier against acid alkaline medium and corrosion and showed increased thermal stability up to 247 °C and high cross-linking density.In another approach, Mohamed and coworkers introduced Cu100 To address these issues, Mirabedini and coworkers have modified the microcapsules with 3-aminopropyltrimethoxy silane coupling agent to improve the surface interaction.101 Microcapsules generated from polyurea-formaldehyde filled with linseed oil were found to exhibit self-healing properties. The reported polymeric matrix shows improved tensile strength and anti-corrosion properties. To create a coating with enhanced anti-corrosion and self-healing properties, Sehrish and coworkers made an attempt to incorporate of talc nanoparticles (TNP) and urea-formaldehyde micro (UFM) capsules[102 Talc falls into the category of mineral clay having corrosion inhibitor properties, composed of magnesium silicate [3, this film inhibits corrosion from spreading on the substrate surface with a corrosion inhibition efficiency 99%. Likewise, to extend the lifetime of the oil-based polymeric coatings. David and coworkers used acrylated epoxidized linseed oil as the base matrix.103 Linseed oil was converted into acrylated epoxidized linseed oil and copolymerised with dihemiacetal ester ) and 3,4-dihydroxyphenetyl acrylamide(DHPA) for adding desired cross-linking property to the polymeric matrix. The corrosion protection by the coating on the surface was found to be appreciable, as DBES addition to the matrix results in an increase in hydrophobic property and high thermal stability, however, it does not lead the matrix towards barrier properties. Though interesting barrier properties were observed in absence of DB.Regarding microcapsule-based matrix, incompatibility of microcapsules with polymeric metric results in poor mechanical properties of the coating. capsules.102 Talcsilicate . The autsilicate . Linseed2.4.105 Neem oil underwent amidation reaction with a diethanolamine and PbO as catalyst to result into Azadirachta indica juss Fatty-amide (AIJFA), which was used to synthesis polyester amide. Microcapsules were prepared using poly-amido-amine (PAMAM) and linseed oil as core material in it and further used for the development of polyurethane coatings. The prepared coating shows thermal stability up to 221 °C, resistance against water and chemical interaction including good adhesive and anti-corrosion properties on the metal substrate.Due to the difference in their functionality and degree of unsaturation present in their molecular structures, vegetable oils exhibit their unique features and qualities to deliver specific properties, as discussed in 106 Corn fatty amide reacted with isosorbide in the presence of sulfuric acid as catalyst to get poly(isosorbide-ether-amide) (PIEtA), which was further converted into PUIEtA/fused silica nanocomposite. Prepared silica based nanocomposite manifests excellent anticorrosion properties and barrier against chemicals with the notable thermal stability of 275 °C and increased adhesion up to 98%, impact resistance with corrosion inhibition efficiency 99%. In addition, authors have investigated corn oil-based poly network to improve the properties of the matrix by incorporating multi-walled carbon nanotubes (MWCNTs) as filler.107N,N-bis(2-hydroxyethyl) corn oil fatty amide (HECA) was reacted with malonic acid in toluene to obtain malonic polyester-amide(MPEA) followed by the preparation of poly using iso-phorone diisocyanate (IPDI) which finally get incorporated with MWCNTs. The integration of CNTs in polymeric network increases contact angle (110°) and provides hydrophobic nature to it, making it suitable for anti-corrosion coatings with excellent thermal stability and mechanical performance. Aung and coworkers suggested that ZnO can be used as a nano-filler for corrosion inhibition in polymeric coating.108 To synthesize the epoxy acrylate of jatropha oil (AEJO), epoxidized jatropha oil was made to react with triethylamine, 4-methoxyphenol and acrylic acid, which is further processed to prepare the composite by reacting AEJO with reactive diluent tetra-methyl-ol-propane tri-acrylate (TMPTA) and photo-initiator 2-hydroxy-2-methylpropiphenone, followed by the addition of ZnO as nano-filler in different compositions. These nano-hybrid resins possess properties to protect the metal surface from corrosion owing to the hydrophobic nature of ZnO. Incorporating a 5% weight% ZnO loading showed significant enhancement in corrosion resistance and coating performance. Tung oil is being used in polymeric coating industries for its positive impact as filler inside microcapsules. A study by Gonçalves and co-researchers reported that composites prepared from poly positively impact corrosion inhibition and self-healing properties.109 Zinc phosphate is being used as a corrosion inhibitor as the hydroxyl group in the base network reacts with zinc phosphate and results in an even more stable zin oxide film, helping to protect the substrate from corrosion.To add on to green composite materials with improved properties, Manawwer and coworkers studied corn oil-based organic coating using isosorbide.110 Tung oil-based microcapsules were prepared in situ using formaldehyde for the formation of shell and urea, resorcinol and ammonium chloride [Along with all the properties of the coating, the thickness of the coating is also essential to study in polymeric coatings. Usually, in self-healing polymeric coatings, large microcapsules facilitate the release of a good amount of healing agents, which results in a thick coating. In comparison, a thin application of the coating is enough to protect the metal surface. Aiming toward the characteristic of diameter, Li and coworkers studied the tung oil microcapsules subsumed in epoxy matrix.110 Tungchloride . Self-hechloride .3.2-emissions, the perspective of using biobased materials in the coating applications is attractive. The use of bio-chemical derived molecules mainly aims to reduce the number of synthetic molecules, however, achieving material performance similar to the commercial coating product represents a significant challenge. Certainly, in spite of great economic and ecological values, vegetable oil based polymeric coatings are facing numerous challenges in making place in industrial market,114e.g. polymeric network often possess low crosslinking density which lead towards lower in mechanical properties and solvent resistivity, due to the triglyceride long chain structure of vegetable oil based polymeric moiety, though it also offers flexibility to the network compared to the petroleum based polymeric networks.5,20 These drawbacks can be overcome through the addition of suitable crosslinker as well as by addition of fillers. In addition, to avoid the environmental oxidation and physical stability, vegetable oil based self-healing materials can be used in encapsulated form for developing self-healable polymeric coatings. But with encapsulated networks there are limitation in terms of reusability, re-processibility and low mechanical properties.115,116In view of the governing procedures and pressing need to reduce CO117,118 On the other hand, vegetable oil based self-healing networks require particular conditions to reprocess and to reflect the characteristic behavior (like high temperature and high pressure), which is not feasible to provide at industrial level.100,119 To address such issues various techniques can be applied in case of advanced materials (e.g. vitrimers), where instead of conventional thermal heating electromagnetic radiation or induced heating can be used to attain the energy, required for the dynamic bond exchange reaction in order to facilitate the self-healing property at different working environment.100,118 To acquire the radiation heating of the system, the chemistry can be obtained with the presence of carbonaceous materials or the molecules with dielectric constant. In consideration of bio-integrated electronic devices, longer healing time of the cracks could result into failure of the device, apparently rapid healing of the network at ambient temperature would be required to avoid the damage.120 Overall, bio-molecules derived coatings can be advantageous when factors like the availability of the biobased additives and their true sustainability are considered. In addition, sometimes designing desirable molecules from petrochemicals is difficult, thus, availability of new bio-molecules/monomers opens the door for researchers to construct novel molecules difficult to be obtained from petrol-chemicals. Along with this, a bio-material design is made from scratch, allowing them to plan material properties in line with their future life cycle from the very beginning, thus, these functional materials could find versatile application by collaboration of chemist and industrial researchers.As the low thermal stability of the VO based coating network ultimately lead towards the lower shelf life and hence the early degradation of the network, which can be answered by using the various fillers in the form of graphene based nanosheets, metal nanoparticles or metal-legend composites.There are no conflicts to declare.


Little is known about the relationships between symptomatic early-time SARS-CoV-2 viral load and upper airway mucosal gene expression and immune response. To examine the association of symptomatic SARS-CoV-2 early viral load with upper airway mucosal gene expression, we profiled the host mucosal transcriptome from nasopharyngeal swab samples from 68 adults with symptomatic, mild-to-moderate COVID-19. We measured SARS-CoV-2 viral load using qRT-PCR. We then examined the association of SARS-CoV-2 viral load with upper airway mucosal immune response. We detected SARS-CoV-2 in all samples and recovered >80% of the genome from 85% of the samples from symptomatic COVID-19 adults. The respiratory virome was dominated by SARS-CoV-2, with limited co-detection of common respiratory viruses i.e., only the human Rhinovirus (HRV) being identified in 6% of the samples. We observed a significant positive correlation between SARS-CoV-2 viral load and interferon signaling , chemokine signaling (CXCL10 and CXCL11), and adaptive immune system  genes in symptomatic, mild-to-moderate COVID-19 adults, when adjusted for age, sex and race. Interestingly, the expression levels of most of these genes plateaued at a CT value of ~25. Overall, our data shows that early nasal mucosal immune response to SARS-CoV-2 infection is viral load dependent, which potentially could modify COVID-19 outcomes. Several prior studies have shown that SARS-CoV-2 viral load can predict the likelihood of disease spread and severity. A higher detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity. However, the relationship between SARS-CoV-2 viral load and airway mucosal gene expression and immune response remains elusive. We profiled the nasal mucosal transcriptome from nasal samples collected from adults infected with SARS-CoV-2 during Spring 2020 with mild-to-moderate symptoms using a comprehensive metatranscriptomics method. We observed a positive correlation between SARS-CoV-2 viral load with interferon signaling, chemokine signaling, and adaptive immune system in adults with COVID-19. Our data suggest that early nasal mucosal immune response to SARS-CoV-2 infection was viral load-dependent and may modify COVID-19 outcomes. After qWith a stringent cut-off of >80% genome coverage, we identified SARS-CoV-2 in 58 (85.29%) out of 68 samples. All SARS-CoV-2 genomes were identified were placed to the B.1 lineage in the Nextclade tree . In addiDifferential expression analysis between high and low viral load groups revealed 48 genes were significantly upregulated and 4 genes were significantly downregulated (based on a threshold of log2 fold change > |1| and adjusted p < 0.05) in the high viral load subjects –b and imr 0.28, q-value: 0.02) with SARS-CoV-2 viral load  chemokines that were both upregulated in our analysis, and their gene expression was corelated with viral load. Both chemokines are highly produced in bronchial and alveolar epithelial cells and have been implicated as predictors of COVID-19 severity cal data , 39. Addcal data , 40–42 acal data . Recent et cells  and Siglet cells  and enhaet cells .Our study has many strengths, such as the inclusion of an overall young population with no underlining comorbidities , no receWe should also acknowledge several limitations. First, our study was cross-sectional; thus, there is a possibility of reverse causation. Second, there is a possibility of residual confounding, as we lacked data on the participants’ atopic status or other unknown morbidities that could modify immune response. Third, though all samples were collected within 24 hours after the first diagnosis of COVID-19, it is still impossible to ascertain the days since infection as the pre-symptomatic period can vary considerably (3–15 days) between patients. Nasal viral titers drop dramatically after 10–15 days of infection ; thus, pIn summary, we determined early SARS-CoV-2 viral load was associated with URT gene expression during COVID-19 and potentially modifies both the innate and adaptive immune response to SARS-CoV-2 infection. Future studies with larger sample sizes, serial sample collection, and with patients who develop severe disease outcomes will be needed to examine how SARS-CoV-2 interacts with the mucosal gene expression and how these viral-host interactions can impact the clinical progression, severity, and recovery of COVID-19. Exclusion criteria for these patients included current use of nasal saline irrigations or other intranasal medications, inability to perform nasal irrigations or to collect URT samples in a separate house bathroom or away from household contacts, or need for hospitalization related to SARS-CoV-2 infection. Thus, only patients with mild or moderate COVID-19  infection  at Vanderbilt University Medical Center or one of its affiliated centers in Nashville, Tennessee. These patients were enrolled as part of a clinical trial examining the effect of several types of nasal irrigations on upper respiratory tract (URT) symptoms and viral load during coronavirus disease 2019 (COVID-19). The detailed methods for this clinical trial have been previously reported.anization) were in® screw-cap tubes (NextAdvance) pre-filled with RNase-free zirconium oxide beads and QIAzol Lysis Reagent (Qiagen) was added. Samples were then homogenized in a Bullet Blender 24 Gold (NextAdvance) for 3 minutes at maximum speed. Following homogenization, genomic DNA was eliminated with gDNA Eliminator columns (Qiagen) and RNA purified using the RNeasy Mini Plus Kit (Qiagen) following the manufacturer’s protocol. The RNA quality was measured using an Agilent 2100 Bioanalyzer (Agilent Technologies). The United States Centers for Disease Control and Prevention primers and probes designed for the detection of SARS-CoV-2 (2019-nCoV) were purchased from Integrated DNA Technologies (IDT)[To measure viral load in SARS-CoV-2-infected patients, we performed quantitative reverse transcription PCR (RT-qPCR) in the mid-turbinate swabs. Total RNA was extracted from the swabs using a phenol-chloroform-based method. The swabs were placed in Red 1.5 mL RINOies (IDT). Both thThe nasal swab samples in the self-collection kit  were vortexed for 2 minutes, then an aliquot of 250μL nasal swap sample was used for RNA extraction. The total RNA from these samples were extracted as describe previously . In briebbduk from bbtools [sourceforge.net/projects/bbmap/).Adapter removal and quality-based trimming of the raw reads were performed using Trimmomatic v0.39  using de bbtools  with entbbmap from bbtools, the mapped reads were discarded. The remaining reads were binned into human genome, bacterial rRNA, and a bin that contains all microbiome reads, using seal, from bbtools, with default parameters. The human genome (GRCh38) and SILVA bacterial rRNA database were used as references. Binning resulted in an average of 98,120,791  reads mapping to the human genome and an average of 2,263,290  microbiome reads. The microbiome reads bin contains viral, bacterial, fungal, and unclassified reads.Reads were mapped to human rRNA and the human mitochondrial genome using Reads from the microbiome bin were subjected to taxonomic classification using KrakenUniq  with defde novo transcriptome assemblies, followed by putative virome identification using BLAST searches, and finally high confidence virome profiling based on read mapping to reference virus genomes. This workflow was implemented in a bash script. First, reads that were classified as viral by KrakenUniq were extracted using the script krakenuniq-extract-reads, with taxonID 10239 . If more than 100,000 reads were extracted, they were first normalized to a target depth of 100 using bbnorm from bbtools. Reads were assembled using the metaSPAdes assembler. Resulting contigs were filtered for length, using reformat from bbtools, and only contigs that were at least 300bp were retained. Nucleotide BLAST (blastn) searches were performed on the resulting contigs, against the NCBI nt database with -max_target_seqs and -max_hsps set to 1. From the blast results, a list of subjects was compiled and their genome sequences (fasta) were extracted from the nt blast database using the blastdbcmd from BLAST. Each of those genome sequences were used as a reference and all the virome reads were mapped using bowtie2. Genome coverage and average read depth statistics were extracted from this mapping using samtools [To produce a high confidence virome profile, we developed a method that first produces samtools . The highttps://pangolin.cog-uk.io/). Consensus genome sequences were submitted to GISAID.Full sets of reads  were utilized to produce the SARS-CoV-2 genome sequences. They were mapped to the SARS-CoV-2 reference genome NC_045512 using bowtie2 with default parameters. Consensus sequence was called using samtools, and lineages were determined using the Pangolin web application (The reads identified as originating from human transcripts were mapped to the human genome (hg19) using HISAT2 . The reaSpearman’s rank correlation coefficient was calculated for gene expression counts and CT value  using the cor.test function in R. The Benjamini-Hochberg method was used for multiple comparisons and p-value adjustments.


Vegetarians diets are characterized by the absence of some animal foods (e.g. red and processed meats), and a high consumption of plant-based foods. However, plant-based foods can include foods with varying nutritional value and health effects. We examined the association of three different pro-vegetarian (PVG) food patterns defined as general (gPVG), healthful (hPVG) and unhealthful (uPVG), with the risk of all-cause and cardiovascular disease (CVD) mortality in Italians.Longitudinal analysis on 22,912 men and women (mean age 55±12 y) from the Moli-sani Study (2005-2010) followed up for 11.2 y (median). Food intake was assessed by a 188-item FFQ. A provegetarian food pattern (FP) was constructed by assigning positive scores to plant foods and reverse scores to animal foods. A healthful and an unhealthful pro-vegetarian FP, which distinguished between healthy  and less-healthy plant foods , were also built up.In multivariable-adjusted analyses controlled for known risk factors, higher adherence to a gPVG was associated with lower all-cause  but not CVD mortality . Increasing adherence to a hPVG was associated with reduced all-cause mortality risk  as well as lower risk of CVD mortality . Finally, the uPVG was directly associated with both all-cause  and CVD mortality risks .A general pro-vegetarian food pattern was associated with longer survival in Italians. Preferring healthful vegetarian foods provided protection against CVD mortality too. Consistently, a large dietary share of unhealthful vegetarian foods, mostly highly processed, was associated with increased risk mortality. Thus the quality of the plant food consumed is paramount to achieve diet-related benefits on mortality.• A pro-vegetarian food pattern was associated with longer survival but preferring healthful vegetarian foods provided protection against CVD mortality too.• The quality of the plant food consumed is paramount to achieve diet-related benefits on mortality.


The role of tRNAs is best known as adapter components of translational machinery. According to the central dogma of molecular biology, DNA is transcribed to RNA and in turn is translated into proteins, in which tRNA outstands by its role of the cellular courier. Recent studies have led to the revision of the canonical function of transfer RNAs (tRNAs), which indicates that tRNAs also serve as a source for short non-coding RNAs called tRNA-derived small RNAs (tsRNAs). tsRNAs play key roles in cellular processes by modulating complicated regulatory networks beyond translation and are widely involved in multiple diseases. Herein, the biogenesis and classification of tsRNAs were firstly clarified. tsRNAs are generated from pre-tRNAs or mature tRNAs and are classified into tRNA-derived fragments (tRFs) and tRNA halves (tiRNA). The tRFs include five types according to the incision loci: tRF-1, tRF-2, tRF-3, tRF-5 and i-tRF which contain 3′ tiRNA and 5′ tiRNA. The functions of tsRNAs and their regulation mechanisms involved in disease processes are systematically summarized as well. The mechanisms can elaborate on the specific regulation of tsRNAs. In conclusion, the current research suggests that tsRNAs are promising targets for modulating pathological processes, such as breast cancer, ischemic stroke, respiratory syncytial virus, osteoporosis and so on, and maintain vital clinical implications in diagnosis and therapeutics of various diseases. Transfer RNAs (tRNAs) are an essential type of RNA involved in protein biosynthesis . tRNAs cWith the development of high-throughput sequencing technology, tRNA was found to be the source of a class of small noncoding RNAs (ncRNAs) with important functions . These nRecent studies identified that novel tsRNAs play important roles both in transcriptional and posttranscriptional gene regulation . tsRNAs 2O2 treatment, though it has little relation with biogenesis of tsRNAs  were reported to be generated by ANG at the anticodon loop of mature tRNA under stress induction , namely 5′ tiRNA  and 3′ tiRNA  . tiRNA gnscripts .Sanadgolnscripts . FurtherThe development and application of deep-sequencing and microarray facilitate the research on tsRNAs . MicroarE. coli AlkB before RT in library preparation  which is a vital step in most RNA-seq protocols . AQRNA-sparation . RNAs caparation .E. coli AlkB enzyme to pinpoint RT signatures caused by methylation, thus more accurate tRNA sequencing data and the influence of methylations to tRNA fragmentation can be investigated , a web server applied for identifying tRFs from small RNA sequencing datasets from various cancer types, is created (http://bioinformatics.zju.edu.cn/OncotRF) provides an integrated view of dysregulated tRFs among cancers (http://rna.sysu.edu.cn/tsRFun/(http://www.tsrbase.org) was newly developed to integrate over 14,000 public small RNA-seq data across 20 organisms and to identify protein-binding tsRNAs and their targets for the first time. Such databases serve as a starting point for users to study gene regulation and functional roles of tsRNAs in cancers, thus facilitating the future investigations of the novel class of tsRNAs. Due to complicated origin of tsRNAs, the naming of them is incomplete in current tsRNA databases. Thus, unifying naming standard and integrating annotation information will be helpful for further exploration.The development of techniques for identifying tsRNAs has boosted the establishment of several tsRNA-related databases . Initialdu/trfdb/. Later, MINTbase/. Then th created . Moreove cancers . TsRFun,n/tsRFun/  globally, which has surpassed lung cancer as the most common cancer . It has As reported, the expressions of some tsRNAs are elevated in the subtypes of BC, for example, tRNA-Val-CAC, tRNA-Val-ACC, tRNA-Gly-GCC, tRNA-Gly-CCC, tRNA-Glu-CUC, tRNA-Lys-CUU, and tRNA-His-GUG were highly expressed in 26 triple-negative breast cancer (TNBC) cells . Also, oSome tsRNAs can play anti-tumor role which are usually downregulated in BC patients. For example, tRF3E is a tRF-3 derived from tRNA-Glu-TTC, known as a tumor suppressor . The serContrarily, certain tsRNAs that are upregulated in BC patients may promote tumor progression. tDR-0009 (tRF-5 derived from tRNA-Gly-GCC-1-1) and tDR-7336 (tRF-5 derived from tRNA-Gly-GCC-1-2) were significantly raised under hypoxia conditions and were reported to enhance the chemoresistance in TNBC which was resulted from the activation of STAT3 phosphorylation . Such inSex hormones and their receptors are critical in the development and progression of the breast and prostate cancers . BC progSome tsRNAs were recognized as microRNAs (miRNAs) at first . Such miOvarian cancer is another sex hormone-associated cancer and one of the gynecologic malignancies with the highest mortality rate . Ovarianvia downregulating its target gene Homeobox-containing protein 1 (HMBOX1) which was a transcription factor belonging to the hepatocyte nuclear factor family (It was reported that tRF-03357 promoted SK-OV-3 cell (an ovarian cancer derived cell line) proliferation, migration and invasion r family . HMBOX1 r family . Its expr family . The anar family . Particur family . Thus, tSome tsRNAs inhibit ovarian cancer progression. For example, 5′ tRF-Glu bound to the 3′ UTR of breast cancer anti-estrogen resistance 3 (BCAR3) mRNA and decreased the expression level of BCAR3 which can suppress proliferation in ovarian cancer development . FurtherProstate cancer (PCa) is the main leading cause of disease-related death among men globally . In the tRF-315, from tRNA-Lys-CTT, was highly expressed in PCa patients and the knockdown by siRNA targeting tRF-Lys-CTT could inhibit the proliferation of LNCaP cells (a PCa cell line) . Yang etMoreover, tRF-544 from tRNA-Phe-GAA was downregulated in PCa tissues compared to healthy counterparts . Therefo+/CD5+ B cells and is the most common human adult leukemia (Chronic lymphocytic leukemia (CLL) is a heterogeneous disease featured by the expansion of CD19leukemia . CLL infleukemia .Ts-101, leukemia . FurtherLung cancer is one of the most common cancers worldwide nowadays . At presColorectal cancer (CRC) ranks third of the most common malignance and is one main cause of cancer-related death in the world . AlthougIt was reported that tRF-20-M0NK5Y93 was downregulated in CRC cells under hypoxic conditions . The invStructural and functional disorders of nervous system induce neurological diseases . The expIschemic stroke is a kind of clinical disorder and leads to vascular and neuronal damage . Li et atrans-silencing function  is a leading cause of lower respiratory tract infection, especially in infants, the elderly, and immune compromised patients . Currentfunction . Precisefunction . A mechafunction . What’s function . To contfunction .via functioning as a primer for HTLV-1 reverse transcriptase  infected T cells compared with healthy ones . Among scriptase . Such inOsteoporosis is a common orthopedic disease characterized by low bone mineral density . Little Osteoarthritis (OA) is a musculoskeletal disorder which has affected millions of people worldwide . It can The knee is the largest synovial joint in humans, composed by osseous structures , cartilage , ligaments and a synovial membrane . The kneThe knowledge of tsRNAs in OA is so far sparse. It is surprising that in diverse tissues and organisms, tsRNAs are the most abundant group of small RNA next to miRNAs . TherefoBesides the tsRNAs mentioned above, some other kinds are also been suggested to have correlation with diseases. For example, tRNA-Ala-TGC-5-1 can be an indicator because it has more than 85% sensitivity and specificity in differentiating melanoma patients . The lowThere are fewer studies on diseases regulated by tiRNAs compared to tRFs. Some studies have demonstrated that tiRNAs can be potential therapeutic targets for cancers. As Pekarsky et al. investigated, ts-3676 from tRNA-Thr and ts-4521 from tRNA-Ser were mutated and these two tiRNAs were significantly downregulated in CLL . In addiAmong examples illustrated above, tsRNAs are abundant and display the potential to be biomarkers and therapeutic targets of diseases. The underlying mechanisms of tsRNAs are demonstrated below.miRNAs regulate gene expression by binding to complementary sequences at the 3′UTR end of the target mRNAs . AccordiIn addition, tRF/miR-1280 could suppress CRC cell proliferation by inhibiting the Notch signaling pathway through directly interacting with the 3′ UTR of JAG2 mRNA . JAG2, aAnother tRNA-derived fragment called CU1276, a 22-nt small RNA, is derived from tRF-Gly-GCC, and expressed in human mature B cells which was misunderstood as miRNA before because it functioned as a miRNA and repressed mRNA targets in an Argonaute (AGO)-dependent miRNA-like fashion . CU1276 tsRNAs are capable of regulating gene expression by binding to proteins . Kumar eIt is demonstrated that tsRNAs are capable of regulating translation in different manners such as affecting the biogenesis of protein through modulating the initiation of translation .Promoting ribosome biogenesis can activate translation . RibosomtiRNAs can directly inhibit protein synthesis resulting in the repression of translation . The mecContinuous stress responses leading to inflammation and disease pathogenesis . When fa1A in tRNAs and contain a tRNA-binding motif (AlkB homolog 1 (ALKBH1), as a tRNA demethylase catalyzes demethylation of mng motif . ALKBH1-ng motif . For exang motif .Demethylase α-KG-dependent alkB homolog3 (ALKBH3) could catalyze the demethylation which made tRNA more sensitive to the cleavage of ANG and generate 5′-tRF-Gly-GCC with ease . Such tstsRNAs have been found to regulate kinase activity. As Studies on tsRNAs have opened a new era of their potential uses: in the diagnosis and prognosis of multiple diseases. We summarized the functions of diverse tsRNAs in different diseases and the underlying mechanisms. This review can provide valuable cues for further research of tsRNAs. Besides the functional tsRNAs in the above-mentioned diseases, there are also other types of disease related tsRNAs, but the amount and depth of these investigation are still in their infancy, in the meantime, the future study is urgently needed.β-thalassaemia (Meanwhile, in the pursuit of tRNA-based therapeutics, besides tsRNAs, many researchers focus on designing tRNAs to bypass premature stop signals and incorporate desired amino acids instead . Approxiassaemia .When compared with other gene therapeutic agents, tRNA therapy is of obvious advantages because tRNA is universal in treating multiple diseases. tRNA therapy has raised much attention and many breakthroughs have been made in recent years. In the future, we will continuously focus on the functions and mechanisms of tsRNAs and other tRNA-based therapeutics.