Cerebral diffuse gliomas present peculiar molecular features tightly linked to phenotypic characteristics that are not readily appreciated by means of standard neuroimaging. In the present Part B of our two-review series, the potential of exploiting glioma vascular and hemodynamic alterations for a better characterization of tumor subtype, differentiation of tumor recurrence from treatment effects, and prognosis prediction is critically discussed together with the advancements related to radiomics and machine learning for innovative imaging biomarkers development.Gliomas, and glioblastoma in particular, exhibit an extensive intra- and inter-tumoral molecular heterogeneity which represents complex biological features correlating to the efficacy of treatment response and survival. From a neuroimaging point of view, these specific molecular and histopathological features may be used to yield imaging biomarkers as surrogates for distinct tumor genotypes and phenotypes. The development of comprehensive glioma imaging markers has potential for improved glioma characterization that would assist in the clinical work-up of preoperative treatment planning and treatment effect monitoring. In particular, the differentiation of tumor recurrence or true progression from pseudoprogression, pseudoresponse, and radiation-induced necrosis can still not reliably be made through standard neuroimaging only. Given the abundant vascular and hemodynamic alterations present in diffuse glioma, advanced hemodynamic imaging approaches constitute an attractive area of clinical imaging development. In this context, the inclusion of objective measurable glioma imaging features may have the potential to enhance the individualized care of diffuse glioma patients, better informing of standard-of-care treatment efficacy and of novel therapies, such as the immunotherapies that are currently increasingly investigated. In Part B of this two-review series, we assess the available evidence pertaining to hemodynamic imaging for molecular feature prediction, in particular focusing on isocitrate dehydrogenase (IDH) mutation status, MGMT promoter methylation, 1p19q codeletion, and EGFR alterations. The results for the differentiation of tumor progression/recurrence from treatment effects have also been the focus of active research and are presented together with the prognostic correlations identified by advanced hemodynamic imaging studies. Finally, the state-of-the-art concepts and advancements of hemodynamic imaging modalities are reviewed together with the advantages derived from the implementation of radiomics and machine learning analyses pipelines. In recent decades, the traditional histopathological grading of diffuse gliomas has been complemented by a more refined molecular analysis of tumor markers. Gliomas, and glioblastomas in particular, exhibit an extensive intra- and inter-tumoral molecular heterogeneity which represent complex biological features, correlating to the efficacy of treatment response and survival . This brHemodynamic imaging of brain tumors adopts several techniques, including perfusion MRI sequences, such as dynamic susceptibility contrast (DSC)-MRI, dynamic contrast-enhanced (DCE)-MRI, arterial spin labelling (ASL)-MRI and perfusion computed tomography (PCT) together with a number of other advanced hemodynamic imaging approaches that are increasingly investigated. A description of hemodynamic imaging modalities and relative assessed parameters is presented in Part A of the present review (see Tables 1 and 2 of Part A) .In this context, the inclusion of objective measurable glioma imaging features may have the potential to enhance the individualized care of diffuse glioma patients, which can better inform standard-of-care treatment efficacy and novel therapies, such as immunotherapies that are currently being increasingly investigated . In Parthttps://www.cancerimagingarchive.net/ Last accessed on 21 December 2021). More importantly, this hypothesis has been also extensively explored in hemodynamic imaging [6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation, and epidermal growth factor receptor (EGFR) alterations.With the increasingly understood role of biology in correlating tumor aggressiveness and prognosis, the old histological entities are now outdated and tumor classification depends on underlying molecular features . This in imaging ,33,34,35IDH mutations are the most important prognostic factors according to the present molecular classification of gliomas whereby the absence of mutation (mut), i.e., IDH wildtype (wt) tumors, is characterized by a worse prognosis. IDH1/2 mutations occurring in the catalytic pocket generate a neomorphic enzyme that converts α-ketoglutarate and NADPH to (R)-2hydroxyglutarate (2-HG). The IDHmut and the accumulation of the “oncometabolite” 2-HG are associated with the hypermethylation phenotype, called glioma CpG island methylator, ultimately altering metabolism to promote malignant growth ,37. As tOligodendroglioma is genetically defined as a tumor harboring a IDH1/IDH2 mutation involving the co-deletion of chromosome arms 1p and 19q. Diagnosis can be obtained only using pathological tissue after a biopsy or resection ,47 but hMGMT promoter methylation has drawn considerable attention as its presence contributes to the response to temozolomide. A selected population of MGMT unmethylated glioblastoma patients may reach a comparable outcome when chemotherapy is withhold . Due to Following the detection of epidermal growth factor receptor (EGFR) gene alterations  in a high percentage of glioblastomas, the attempt to develop treatment strategies targeting EGFR has been pursued . Given tGiven the relationship of aberrant glioblastoma vasculature with hypoxia playing a role in its development and invasion, a number of studies have investigated the potential for correlating the perfusion measures to hypoxic and angiogenic markers ,28,69,70An additional clinically relevant limitation of the current standard imaging is a suboptimal differentiation between tumor progression/recurrence and radionecrosis, pseudoprogression, or pseudoresponse . PseudopDCE was more scarcely assessed but provided analogous results ,88,95,96In the treatment of diffuse cerebral glioma, a precise stratification of outcome can support the multidisciplinary team caring for the patient, strengthening the evidence-based therapeutic decisions. Currently, a prognostic evaluation is based on clinical factors, standard imaging, and histopathological-immunochemical tissue analysis . UltimatThe perfusion parameters and permeability parameters allow for the description of the pathophysiological characteristics of abnormal vasculature in the tumor, yet the lesional histopathological heterogeneity suggests that a more refined hemodynamic and metabolic assessment of the glioma features could better describe tumor type, aggressiveness, and prognosis through an enhanced characterization of the microvascular hemodynamic habitat .https://www.oncohabitats.upv.es/ Last accessed on 21 December 2021), i.e., of the microvascular habitat, as part of the identification of diffuse glioma regarding both the enhanced tumor and edema [A few exemplary studies supporting this concept are now presented. Stadlbauer et al. applied a multiparametric MRI approach focusing on microvascular architecture including parameters such as microvascular density, vessel size index , neovascular activity , and oxygen metabolism i.e., oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2), and oxygen partial pressure (PO2) (by means of quantitative blood-oxygen level dependent (BOLD) MRI). In their series of publications, they show that this approach is able to predict glioblastoma recurrence through the identification of early pathophysiological alterations . The samnd edema  with impnd edema ,163 to ind edema ,164 and nd edema . ExternaIntraoperative CE ultrasound (CEUS) has been also gaining attention for the intra-operative assessment of tumor vasculature . This teBased on a model proposed by Le Bihan et al. in the late 80s ,176, IVIThe basic model underlying cerebrovascular reactivity has been addressed in Part A of the present review. As mentioned, in recent years, BOLD-cerebrovascular reactivity (CVR) has also been developed and intensively investigated in diffuse gliomas. Preliminary studies under breath-holding stimuli have revealed that the physiological cerebrovascular response is impaired in diffuse cerebral glioma patients possibly due to the altered vascular response in tumor tissue resulting in flow redistribution and the steal phenomenon ,192. CVRThe new development of radiomics allows for the extraction of a high number of quantitative features to identify relations in the data that are not appreciable through traditional analytical methods ,208. RadAdvanced hemodynamic imaging research has provided yet another promising imaging development to complement traditional tumor grading by correlating the specific hemodynamic patterns posed by diffuse glioma to molecular and pathophysiological alterations. Despite promising associations being found, the evidence remains overall scarce and often conflicting with traditional histopathological and immunohistochemical analysis remaining the gold standard for diffuse cerebral glioma diagnosis. The monitoring of treatment effects and the differentiation of tumor progression/recurrence from treatment-induced changes can benefit significantly from hemodynamic imaging. The present literature points out the encouraging results for this purpose with the caveat that the lack of acquisition and processing standardization still limits its reliability for diffuse clinical integration. The identification of hemodynamic biomarkers correlated to prognosis can assist clinical management decisions and provide the basis for trial stratification to reveal missed patterns in connection to the treatment effects. As methodological optimization continues to be pursued, innovative hemodynamic imaging approaches are emerging with the potential to further advance the characterization of diffuse cerebral gliomas pre-operatively and during the follow-up by overcoming known technical limitations. The integration of radiomics and machine learning in the analysis pipeline can further extend the diagnostic and prognostic potential of hemodynamic imaging in cerebral diffuse glioma.


Spontaneous fetal loss is one of the most important challenges that commercial pig industry is still facing in North America. Research over the decade provided significant insights into some of the associated mechanisms including uterine capacity, placental efficiency, deficits in vasculature, and immune-inflammatory alterations at the maternal-fetal interface. Pigs have unique epitheliochorial placentation where maternal and fetal layers lay in opposition without any invasion. This has provided researchers opportunities to accurately tease out some of the mechanisms associated with maternal-fetal interface adaptations to the constantly evolving needs of a developing conceptus. Another unique feature of porcine pregnancy is the conceptus derived recruitment of immune cells during the window of conceptus attachment. These immune cells in turn participate in pregnancy associated vascular changes and contribute toward tolerance to the semi-allogeneic fetus. However, the precise mechanism of how maternal-fetal cells communicate during the critical times in gestation is not fully understood. Recently, it has been established that bi-directional communication between fetal trophoblasts and maternal cells/tissues is mediated by extracellular vesicles (EVs) including exosomes. These EVs are detected in a variety of tissues and body fluids and their role has been described in modulating several physiological and pathological processes including vascularization, immune-modulation, and homeostasis. Recent literature also suggests that these EVs (exosomes) carry cargo  as unique signatures associated with some of the pregnancy associated pathologies. In this review, we provide overview of important mechanisms in porcine pregnancy success and failure and summarize current knowledge about the unique cargo containing biomolecules in EVs. We also discuss how EVs (including exosomes) transfer their contents into other cells and regulate important biological pathways critical for pregnancy success. The pig industry around the world produces more than 100 million of pork annually and the value of U.S. and Canadian pork and pork products exports to the world reached a record $11 billion , 3. An aSuccessful porcine pregnancy is dependent on conceptus attachment and placental development, which requires a bidirectional communication between conceptus and endometrium. Previous studies have suggested many important factors that play a crucial role in pregnancy success. These factors include but not limited to conceptus-derived estrogen and growth factors , progestPleiotropic glycoprotein molecules such as cytokines are secreted by a variety of immune and non-immune cells in the uterine microdomain. Cytokines regulate several pregnancy related mechanisms including inflammation , 43, angImmune cell recruitment to the maternal-fetal interface in porcine pregnancy is largely driven by conceptus derived signals and set of specific chemokines and growth factors –54. SecrCXCR3 and CCR5 mRNA, and there was greater expression of CXCL10, CCL5, CCR5, and CXCR3 mRNA in the endometrium around peri-attachment period (gd20). Recently, Han and colleagues examined the expression of CXCL12 and CXCR4 at the maternal-conceptus interface during pregnancy in pigs. This study reported the highest expression of CXCL12 on day 15of pregnancy. Furthermore, CXCL12 protein expression was localized in endometrial epithelial cells, however, CXCR4 protein was detected in vascular endothelial cells, subepithelial stromal cells, and endometrial immune cells. CXCL12 increased the migration of cultured porcine trophectoderm cells and peripheral blood mononuclear cells as well as along with CXCR4 induced the migration of trophectoderm cells and T cells at the implantation in pigs. These experiments highlight role of CXCL12 in regulating trophoblast migration and T cell recruitment into the endometrium during implantation period in pigs  and their receptors  in luminal epithelial cells. This study suggests that CCL8 actively participates in embryo implantation and CXCL12 participates in endometrial receptivity and promotion of embryo attachment  and chemocentryx decoy receptors (CCX-CKR). The mRNAs for decoy receptors (DARC and CCX-CKR) were dysregulated in the endometrium and chorioallantoic membrane; however, there was no difference in their expression at the protein level. A post-transcriptional and/or epigenetic modification of chemokines and their specific receptors, as well as action by proteolytic enzymes could explain these differences in expression during pregnancy . In anot in pigs . Recentltachment . Similartachment . These stachment .Previous studies in our laboratory and others have identified deficits in angiogenic stimuli that likely results in impaired vascular development at the maternal-fetal interface , 49, 59.It is important to note that the conceptus attachment to the endometrium is critical for the recruitment of uterine natural killer (uNK) cells in pigs as the decidualization is not induced in these species. However, in case of humans, mice and rats, where decidualization occurs, presence of conceptus is not critical for uNK cell recruitment , 64. T cThe regulation of gene expression at the porcine maternal-fetal interface is controlled by several biomolecules at the genomic level. One of the most important implicated biomolecules are microRNAs (miRNAs), a class of small non-coding RNAs (~18–22 nucleotide in length) that play a major role in RNA silencing and post-transcriptional gene regulation . MiRNAs Because of their unique expression pattern in both physiological and pathological processes, miRNAs are projected as biomarkers of both healthy pregnancy and associated disorders. In one study, a set of 17 miRNAs were identified in the porcine placenta samples obtained from pigs at gd 30 and 90. Differentially expressed 8 miRNAs between the two time points, such as let-7i, miR-106a, miR-17, miR-24, miR-92b, miR-125b, miR-20, and miR-27a were validated by stem-loop RT-PCR. Further bioinformatic analysis of mRNA targets and potential biological pathways indicated that these miRNAs are involved in regulation of cell growth, trophoblast differentiation, maintenance of adherence junctions and angiogenesis . miRNAs LAMC1 (encodes laminin subunit gamma 1), COL1A2 , and COL3A1 . Further, miR-200 family and miR-205 shown to control the trophoblast epithelial cell adherens junctions by interacting with ZEB2 and CDH1. Similarly, miR-17-92 regulate trophoblast proliferation by interacting with HBP1 and ULK1 miRNAs  as well as miRNAs such as miR-140 were investigated in pregnant and cyclic endometria obtained on gd 12, 16, and 20 in pigs. The expression of DROSHA, XPO5, DICER1, TARBP, and AGO1 was altered by the reproductive status of animals. Overall, these studies suggest that the interaction between miRNAs and genes involved in miRNA synthesis and transport likely involved in the regulation of estrous cycle and initial stages of embryo attachment  is a general term used to describe membrane bound vesicles secreted by several cells for differing functions. Although previously thought to be exclusively intended for the secretion and elimination of waste, EVs contain coding and non-coding nucleic acids, lipids, and proteins, which are highly relevant for intercellular communication, homeostatic processes and also contribute to pathologies including those at the maternal fetal interface , 86, 87.via budding of the plasma membrane and are thought to be released faster, as the cargoes targeted by these are situated at the plasma membrane. Whereas, exosomes are first formed as intralumenal vesicles (ILVs) within multivesicular endosomes (MVEs) of the cell and secretion requires sorting of cargoes through endosomal-sorting-complex-required-for-transport (ESCRT) dependent or independent pathways. Recent studies in the field have explored the possibility of sorting machineries, especially ESCRT complexes to be involved in decision making to target MVEs for either degradation or secretory pathway  , taxin 5) , 101. Hovia genetic material and activated receptor transfer to the target cell. Transmembrane proteins  and extracellular matrices are primarily involved in binding exosomes to the target cells. Adhesion proteins such as intracellular adhesion molecules (ICAM) have been identified to interact during uptake with the integrins present on exosomes , and 110 novel piRNAs were identified. Subsequent bioinformatics analysis revealed that the miRNA enriched in the EVs involved in important pregnancy associated pathways such as immunomodulation, endometrial receptivity, implantation and embryo development. These studies add to the miRNA repository as well as serve as a resource to further investigate crosstalk at the maternal-fetal interface . As intePlacental angiogenesis is an important pregnancy related processes crucial for conceptus development and remodeling of endometrium especially in early pregnancy to provide nutrients to the fetus. The placentation in pig typically initiates gd 15–20, which involves an abrupt change in endometrial microenvironment and associated biological processes including angiogenesis , 142. Stin vivo evidence is needed to exploit the idea that miRNA loaded EVs can be used to potentially reduce spontaneous fetal loss in pigs in future.The development of immunological tolerance against semi-allogeneic fetus is a crucial event in the pregnancy success. Since fetal allografts carry paternal antigens, the maternal immune system should reprogram itself to not to recognize fetal antigens and elicit an immune response. EVs have been reported to modulate maternal immune response toward the newly attaching conceptus . DependiExtracellular vesicles in porcine pregnancy: Early pregnancy diagnosis or detecting early embryonic mortality could substantially improve reproductive efficiency in pigs and overall improve the economy of swine industry. Failure to conceive after insemination or undetected pregnancy at an early stage in pigs could result in severe economic loss. While there are many well-established techniques currently available, miRNAs and miRNAs packaged within the exosomes could be another important tool to be used as the earliest possible (before 25 days after fertilization) biomarkers of pregnancy . Zhou anInterestingly, in one of our previous studies miR-17-5p was one of highly enriched miRNA present in the porcine trophectoderm cells, derived from day 12 of pregnancy, and porcine endothelial cells as well as exosomes released by these two cell types . miR-17-via exosomes while evading the host immune response (Role of extracellular vesicles in porcine reproductive and respiratory syndrome pathogenesis: EVs have been shown to play a role in diseases affecting reproductive organs in pigs. Porcine reproductive and respiratory syndrome (PRRS) is one of the important diseases affecting reproductive organs in pigs and causes a heavy economic loss to pork industry. It is characterized by reproductive failures in sows and respiratory syndrome in pigs of all ages . An emerresponse .via receptor-mediated endocytosis. They generated two recombinant adenoviruses expressing the effective artificial miRNAs. It was observed that sequence-specific artificial miRNAs were expressed adequately and released from recombinant adenovirus transduced pig cells via exosomes. Overall, PRRSV infection of pulmonary alveolar macrophages was inhibited by transduction of two artificial miRNA expressing recombinant adenoviruses and or treatment with two artificial miRNAs packaged within the exosomes. This study suggest that exosomes can be utilized to effectively treat infectious diseases such as PRRS  and CD163 for PRRS virus infection of porcine alveolar macrophages. They designed artificial miRNAs that can directly target Sn and CD163 as PRRS virus enters the target cells  as PRRS . Another strains . Montane strains . Further strains .Co-ordinated interactions between maternal endometrium and fetal trophoblasts at the highly dynamic interface is critical to ensure pregnancy success. In epitheliochorial placentation seen in pigs, the fetal trophoblasts lie in simple opposition with luminal epithelial cells of the endometrium but there is no invasion. The significant alterations in the uterine stroma as seen in other species such as human and mice is also lacking in pigs except localized branching of new blood vessels to support the needs of a growing conceptus. We and others have shown that the conceptus mediates the recruitment of immune cells that adopt a specialized phenotype and these immune cells contribute to and regulate angiogenesis at the porcine maternal-fetal interface. It is important to recognize that because of the non-invasive placentation in pigs, trophoblasts do not physically interact with maternal-immune cells. In fact, trophoblasts in contact with luminal epithelium lacks SLA class I and II molecules and therefore avoid recognition by the maternal-immune cells. Maternal-immune cells predominantly NK cells and T cells are recruited around gd-12-15 at the maternal-fetal interface by conceptus mediated signals as well as specific sets of chemokines. The pro-inflammatory microenvironment and chemokine gradient is regulated by chemokine decoy receptors such as D6 and DARC. Recent evidence indicate that immune cell differentiation and function is also regulated by specific sets of miRNAs. Indeed, miRNAs are involved in modulating several physiological, homeostatic, and pathological processes including vascularization and inflammation. Several reports also indicate suitability of unique miRNA signatures in body fluids as predictors of health and disease.The paradox of bi-directional communication between maternal and fetal compartments can be better explained by extracellular vesicle mediated inter-cellular cross talk, especially in species with epitheliochorial placentation where physical interactions between trophoblast and maternal immune cells is limited. The EV cargo containing genomic DNA fragments, RNAs, mRNAs, miRNAs, proteins, and lipids are specifically packaged and can be traced back to the cell of origin. The EV cargo contents are also influenced by the localized microenvironment cues and are involved in embryo implantation, placentation, pregnancy maintenance, and pregnancy associated disorders. With the advent of newer sequencing technologies and bioinformatics machine learning tools, the contents of EVs and their utility in understanding physiological changes in pregnancy and spontaneous fetal loss will be of immense value in future.MB, MK, and CT conceived ideas and associated themes. HL and JM contributed sections of the manuscript. MB, HL, JM, MK, and CT wrote and edited manuscript. CT provided research funding and oversight. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Isoprene-emitting plants are better protected against thermal and oxidative stresses but only about 20% of the terrestrial plants are able to synthesize isoprene. Many studies have been performed to understand the still elusive isoprene protective mechanism. Isoprene reacts with, and quenches, many harmful reactive oxygen species (ROS) like singlet oxygen (1O2). A role for isoprene as antioxidant, made possible by its reduced state and conjugated double bonds, has been often suggested, and sometimes demonstrated. However, as isoprene is present at very low concentrations compared to other molecules, its antioxidant role is still controversial. Here we review updated evidences on the function(s) of isoprene, and outline contrasting indications on whether isoprene is an antioxidant directly scavenging ROS, or a membrane strengthener, or a modulator of genomic, proteomic and metabolomic profiles  eventually leading to priming of antioxidant plant defenses, or a signal of stress for neighbor plants alike other VOCs, or a hormone-like molecule, controlling the metabolic flux of other hormones made by the MEP pathway, or acting itself as a growth and development hormone. Isoprene (C NPQ may remain stable because thylakoids are less challenged by ROS that are scavenged by isoprene before they reach the membranes under stress conditions . HoweverIn recent studies, it has been shown that cells of isoprene-emitting leaves maintain the same elasticity and fluidity at rising temperature at which cells of non-emitting leaves become stiff and loose fluidity ,47,48. IAvailability of transgenic plants with induced or repressed isoprene synthesis has allowed to study in depth isoprene-induced changes on the biology of plants from genes to phenotypes. These studies have generally shown that isoprene-emitting plants display different genes expression, and proteomic and metabolomic profiles when compared to non-emitting plants grown under the same conditions. An overview of the results of these studies is reported in Populus spp.) with repressed levels of the gene encoding for isoprene synthase (IspS) showed a reduced expression of genes involved in phenylpropanoids regulatory and biosynthetic pathways, as well as a down regulation of condensed tannins and anthocyanins biosynthetic genes in high light and heat stress conditions [Arabidopsis and tobacco expressing IspS and thus emitting isoprene, as well as non-emitting Arabidopsis fumigated with isoprene in unstressed conditions, showed that isoprene alters the expression of genes involved in abiotic and biotic stress defense, growth regulator signaling pathways, photosynthesis, seed germination, and seedling and plant growth. Most of these genes belong to jasmonic acid (JA) mediated defense signaling, phenylpropanoid biosynthesis and regulation, and cytokinin (CK)-mediated wound repair. Similar results were found by Harvey and Sharkey [Arabidopsis plants for 24 h with isoprene under non-stressful conditions. This study revealed an induction of chloroplast, phenylpropanoid biosynthetic and translation machinery genes, as well as of transcription factor-enriched gene networks. Another study showed that Arabidopsis plants that can emit isoprene because of IspS insertion were more sensitive to exogenous ABA supplement, which leads to an upregulation of RD29B, a gene involved in abscisic acid-activated signaling pathway [Arabidopsis [At the gene transcription level, poplars  have higher contents of chlorophylls and carotenoids than non-emitting wild types. In poplars that naturally emit isoprene, the contents of carotenes, xanthophylls and chlorophylls are higher than in non-emitting transgenic lines, both in light and dark conditions [Finally, consequences of isoprene emission on the plant metabolome have been often investigated.  showed tnditions . Behnke nditions ,58 showenditions , implyinnditions . The lipnditions .In summary, in isoprene-emitting plants the potentially higher antioxidant activity at cellular level may not be only due to the presence of isoprene itself, but also to a concurrently enhanced synthesis of other antioxidants .10), for instance, have been recently demonstrated to contribute to systemic acquired resistance (SAR) to pathogens and participate to plant-to-plant defense-signal propagation [5), the building block of isoprenoids, has been overlooked for many years, whereas recently it has become a realistic mode of action of its effects on plants. This line of research gained credit following the observation that Arabidopsis plants, which naturally do not emit isoprene, reprogram their transcriptome when exposed to isoprene fumigation [Several plant signaling molecules and phytohormones have isoprenoid origin . Monoterpagation ,64. Curimigation   is not sufficient by itself to prove the establishment of a primed state . Early uase gene . In partreatment . In summreatment . This paductance . ABA is ductance .Arabidopsis plants exposed for 3 days to the isoprene presence in the surrounding gas phase became more resistant to the infection with the bacterium Pseudomonas syringae pv. tomato (Pst) when subsequently infected [NPR1 and ALD1 genes, demonstrating that isoprene can induce resistance by activating or by priming SA-dependent defenses [Pst infection in Arabidopsis, highlighting the potential biological relevance of these new findings and countering the idea that isoprene is not active in plant-plant communication because of its high dilution in the air [Another very recent study has also highlighted the ability of isoprene to induce resistance against microbial pathogens . Arabidoinfected . Resistadefenses . Interesdefenses . In addi the air .Arabidopsis lines overexpressing an isoprene synthase gene [In the light of these recent reports it appears now crucial to specifically address the capacity of isoprene to prime tolerance or resistance mechanisms against abiotic or biotic stressors, both in the producing plant as suggested by transgenic ase gene  and in pase gene .We have reviewed literature that attributed to isoprene emitted by plants different functions. Isoprene emission seems to be beneficial for plants, but studies originally indicating a mere antioxidant action, are now revealing an increasingly complex network of processes and mechanisms that are influenced by isoprene. This simple volatile compound which can easily diffuse in plants and out of them, in the surrounding atmosphere, is emerging as a multitasking and helpful molecule that, besides acting as an antioxidant, also primes defensive pathways, acts as an infochemical and cooperates with hormones . The abu


Surgery remains the most effective cancer treatment, but residual disease in the form of scattered micro-metastases and tumor cells is usually unavoidable. Whether minimal residual disease results in clinical metastases is a function of host defense and tumor survival and growth. The much interesting intersection of anesthesiology and immunology has drawn increasing clinical interest, particularly, the existing concern of the possibility that the perioperative and intraoperative anesthetic care of the surgical oncology patient could meaningfully influence tumor recurrence. This paper examines current data, including recent large clinical trials to determine whether the current level of evidence warrants a change in practice. Available pieces of evidence from clinical studies are particularly limited, largely retrospective, smaller sample size, and often contradictory, causing several questions and providing few answers. Recent randomized controlled clinical trials, including the largest study (NCT00418457), report no difference in cancer recurrence between regional and general anesthesia after potentially curative surgery. Until further evidence strongly implicates anesthesia in future clinical trials, clinicians may continue to choose the optimum anesthetic-analgesic agents and techniques in consultation with their cancer patients, based on their expertise and current best practice. Cancer constitutes an enormous burden on society in both poor and rich global economies alike. Factors contributing to the increasing occurrence of cancer include the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, physical inactivity, overweight, and changing reproductive patterns associated with urbanization and economic development . Some ofMetastatic disease is the most important cause of cancer‐related death in patients after malignant tumor surgery . The hypThe perioperative use of anesthesia forms a crucial part of daily clinical practice in patients undergoing surgery. In cancer surgery, the perioperative period constitutes an important stage for the further course of the disease, as circulating tumor cells shed from the primary tumor into the patient’s bloodstream might form new micro-metastases independent of complete tumor removal . VariousLocal anesthesia is employed to numb a small part of the body when surgery is minor and does not require general or regional anesthesia. Local anesthetics are common medication and a mainstay of anesthesia since the introduction of cocaine in 1884 and are administered systemically or used as part of regional anesthesia techniques for a variety of reasons. They are effective in pain relief due to their ability to block the voltage-gated sodium channel, thus inhibiting nerve cell depolarization , 8, and in vitro, and efficient to target residual disease or cells that form micro-metastasis. Lidocaine, one of the most applied local anesthetics in clinical settings, has been shown to exhibit multi-activities, including the potential in cancer therapy. Growing evidence shows that lidocaine might not only work as a chemosensitizer that induces other conventional chemotherapies to eliminate certain resistant cancer cells but could also suppress cancer cell growth by single-use at different doses or concentrations  modulation, or activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, and possibly contribute to long-term tumor recurrence after surgical intervention  anesthetics or a combination of both. Opioids and benzodiazepines are often employed as adjuvants during general anesthesia , 21. Thervention –24.Concerning cancer patients, the immunosuppression associated with general anesthesia, including the dysfunction of natural killer (NK) cells and lymphocytes, could promote the immune evasion, growth, and metastasis of residual cancer cells, hence worsening patients’ prognoses , 26. Forin vitro studies suggest that these agents are associated with elevated expression of tumorigenic markers, and increased migration and proliferation of cancer cells  and insulin-like growth factors –69. RepoThe local anesthetics, lidocaine, and ropivacaine decrease the viability and proliferation of cancer cells and increase their apoptosis. Mechanistically, lidocaine upregulates the mRNA level of adenomatous polyposis coli, which serves as an inhibitor of the Wnt/β-catenin pathway, while ropivacaine reduces the mRNA level of important cell cycle modulators such as cyclin A2, cyclin B1, cyclin B2, cyclin-dependent kinase 1, and the nuclear marker of cell proliferation MKI67 . LidocaiMetastatic colon and breast cancer cells express adult and neonatal splice variants of NaV1.5 voltage-activated Na(+) channels. Blockade of these channels inhibits cell invasion. Local anesthetics employed during surgical tumor excision inhibit NaV1.5 voltage-activated Na(+) channels activity on nociceptive neurons, providing regional anesthesia , 79. RopSeveral human studies, mainly retrospective, have shown different effects of anesthetics on cancer cell growth and recurrence after surgical removal. These studies mainly compare the different patient outcomes between anesthesia techniques or anesthetic agents. A systematic review of the overall mortality and post-surgery complications after tumor surgery with intravenous and inhalational anesthesia techniques reported that four propensity-adjusted retrospective studies show intravenous anesthesia to be the preferred technique in tumor surgery . The resVolatile anesthetic agents have been implicated in metastasis-enhancing effects on cancer cells. Notwithstanding, Xenon, but not sevoflurane, inhibits the migration of both estrogen receptor-negative and positive breast adenocarcinoma cells, and reduces the release of the pro-angiogenic factor RANTES  . In a reHowever, several others studies have reported no significant difference between the type or method of anesthesia used during tumor surgery. For example, in non-randomized retrospective analysis, neither propofol nor desflurane anesthesia for breast cancer surgery exhibited any significant effect on patient prognosis and survival . Again, The largest available randomized controlled trial at 13 hospitals in Austria, Argentina, China, Ireland, Germany, New Zealand, USA, and Singapore was carried out from 2007 to 2018 and involved 2132 women with breast cancer. Participants were assigned to undergo regional anesthesia-analgesia (1043 patients) using paravertebral blocks and the anesthetic propofol and general anesthesia (1065 patients) using the volatile anesthetic sevoflurane and opioid analgesia. Results showed that 102 (10%) of patients who underwent regional anesthesia-analgesia had breast cancer recurrences compared to 111 (10%) of those allocated to general anesthesia. Moreover, incisional pain was reported by 442 (52%) of 856 patients and 239 (28%) of 854 patients in the regional anesthesia-analgesia group at 6 and 12 months respectively, compared to 456 (52%) of 872 patients and 232 (27%) of 852 patients in the general anesthesia group. Neuropathic breast pain did not also differ by the anesthetic technique used . Based oAnother clinical trial that assessed postoperative circulating tumor cell count in breast cancer patients to determine how anesthesia might indirectly affect prognosis has been documented. In that randomized controlled trial, 210 participants were assigned to either sevoflurane (107 patients) or propofol (103 patients) anesthesia. Results showed that anesthesia type did not affect circulating tumor cell counts over time or positivity. However, in one secondary analysis, the administration of sevoflurane was associated with a significant increase in maximal tumor cell counts postoperatively. There was no link between NK cell activity and circulating tumor cell counts . CD 39 aSeveral small-sized clinical trials have also been documented. These include the report that propofol/remifentanil-based total intravenous anesthesia effectively prevents the expression of VEGF-C induced by breast surgery compared to sevoflurane-based inhalational anesthesia, but appears to be non-beneficial in the short-term recurrence rate of breast cancer . The cliSurgery remains a central component of treatment for patients with many types of cancer. However, it is well documented that surgery, regardless of how extensive it is applied, cannot eliminate all cancer cells from the patient. Certain anesthesia, surgical stress, and pain medications commonly given during anesthesia for cancer surgery are known to suppress body defenses. In addition to any pre-existing micro-metastases, surgical removal of tumors results in spillage of tumor cells locally and into the bloodstream and lymphatics system. Multiple peri-operative factors, inflammatory and neurohumoral factors, patient’s physiologic response to surgery, and care of the patient after the procedure, can encourage the invasiveness and proliferation of residual tumor cells while enhancing neo-angiogenesis to support the growth. Parallel to these effects on the tumor cells, the factors could also inhibit cell-mediated immunity, the body’s capability to eliminate these tumor cells, within this same vulnerable period. Therefore, surgery and anesthesia might contribute to long‐term cancer recurrence. Current laboratory experimental data show that perioperative interventions influence cancer recurrence or metastasis by affecting cancer cell signaling, immune response, and regulating the neuroendocrine stress response.In effect, both anesthesia and surgery depress cell-mediated immunity and upregulate angiogenesis and could therefore enhance the proliferation and metastasis of tumor cells during the perioperative period. Declined levels of circulating anti-inflammatory cytokines and alterations in the function of NK cells are among the mechanisms by which anesthetic agents and techniques can influence immune function. Other studies have asserted that the use of regional analgesia, including epidural and paravertebral block, is effective in reducing inflammation and preventing immunosuppression in patients undergoing cancer surgery. However, there are reports of no significant difference between the types or methods of anesthesia used and cancer recurrence or patients’ outcomes. Unfortunately, current evidence from clinical studies is particularly limited, largely retrospective, smaller sample size, and often contradictory, causing several questions and providing few answers. Moreover, these pieces of evidence suffer moderate to serious risk of bias and of low quality, hence randomized clinical trials are needed for concrete confirmation of these findings. In the phase of the limited data in clinical trials upon which to make concrete recommendations, clinicians and anesthesiologists may seek optimal anesthesia and analgesia for their cancer patients based on the best available evidence on outcomes and individual risk-benefit analysis.Available evidence from experimental cell culture and animal model studies, as well as clinical retrospective studies, indicate that current data are sufficient only to generate a hypothesis that anesthetic or analgesic agents contribute to cancer recurrence and metastasis. Moreover, recent randomized controlled clinical trials, including the largest study (NCT00418457), report no difference in cancer recurrence between regional and general anesthesia after potentially curative surgery. Again, the severity and frequency of persistent incisional pain are unaffected by the anesthetic technique. Until further evidence strongly implicates anesthesia in clinical trials, clinicians may continue to choose the optimum anesthetic-analgesic agents and techniques in consultation with their cancer patients, based on their expertise and current best practice.XL designed the study and participated in manuscript writing. QW constructed the tables and figures and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Sleep is increasingly recognized as an important lifestyle contributor to health; however, its relationship with Motoric cognitive risk syndrome (MCR) is still unclear. The present study aimed to examine the associations between sleep duration, sleep quality, and MCR among community-dwelling Chinese older adults.Methods: We recruited 5,387 participants aged ≥60 years from the China Health and Retirement Longitudinal Study (CHARLS). Sleep-related variables including night sleep duration and sleep quality were assessed via self-reported questionnaires. MCR syndrome was defined as cognitive complaints and slow gait speed without dementia or impaired mobility. Multivariate logistic regression analysis was performed to explore the associations between sleep-related variables and MCR after controlling for all potential confounders including demographic characteristics, lifestyle factors, and comorbidities.Results: We found that sleep duration was significantly associated with MCR, and the multivariate-adjusted odds ratios (OR) were highest for those with the shortest  and longest  sleep durations. Moreover, an increasing frequency of self-perceived poor sleep quality was significantly associated with MCR in the adjusted model .Conclusions: Our study indicated an inverted U-shaped association between night sleep duration and MCR. Poor sleep quality was also associated with higher odds of MCR in community-dwelling Chinese elders. Longitudinal studies with a larger population size are needed to establish causality in the future and further explore potential action mechanisms. In recent decades, the proportion of people aged 60 years or older has increased rapidly and is projected to be greater than one-fifth of the global population in 2050 , a nationally representative longitudinal study, to examine the inverted U-shaped association between sleep duration and probability of MCR, and to investigate the associations between sleep quality and MCR among community-based Chinese older adults.We used the national baseline data from the CHARLS to investigate the association between sleep duration, sleep quality, and MCR among Chinese middle-aged and older adults adjusting for socio-demographical factors, lifestyle factors, and comorbidities. The CHARLS baseline data collection took place from June 2011 to March 2012 and included 17,708 respondents from 10,257 households. The target population was middle-aged and older adults and their spouses aged 45 years and above and currently residing in a household in China  and sex-  appropriate mean values of gait speed in our cohort ?” and respondents were categorized into five groups according to their answers based on previous research ,” “2 Some or a little of the time (1–2 days),” “3 Occasionally or a moderate amount of the time (3–4 days), ” and “4 Most or all of the time (5–7 days).”2), smoking history, and alcohol consumption. Health comorbidities included a self-reported history of hypertension, diabetes, chronic lung disease, kidney disease, and cardiac disease.Demographic characteristics, lifestyle factors, and self-reported comorbidities were controlled as covariates in this study. Demographic characteristics included age, gender, marital status, and educational level. Lifestyle factors included body mass index .All reported p values were two-tailed with a significance level of 0.05. All analyses were performed using STATA software .In the nationally representative cohort of community-dwelling Chinese older adults, we found that, compared to median night sleep duration, shorter and longer night sleep durations were significantly associated with increased odds of MCR diagnosis, indicating an inverted U-shaped association between nighttime sleep duration and cognitive performance. Moreover, an increasing frequency in self-reported poor sleep quality was also significantly associated with higher odds of MCR after adjusting for potential confounders, including demographic characteristics, lifestyle factors, and self-reported comorbidities.Several epidemiological studies on Asian populations have also reported a U-shaped association between sleep duration and cognitive function, which is in concordance with our results. Ohara et al.  investigPrevious studies have also investigated the relationship between changes in sleep duration and cognitive decline, but the results were contradictory.Hahn et al.  used datAlthough several studies have examined the relationship between sleep duration and cognitive function, few have investigated the relationship between sleep duration and odds of MCR. Only one cross-sectional study among 940 Chinese older adults aged ≥65 years in the Ningbo Community Study on Aging (NCSA) reported that longer night sleep duration (>8.5 h) was associated with higher odds of MCR compared to a shorter night sleep duration (<8 h). The relatively few participants with extremely short sleep durations prevented this study from exploring a possible U-shaped association (Zeng et al., Besides sleep duration, we also found that subjective poor sleep quality was significantly associated with higher odds of MCR after adjusting for confounders. Few previous studies have assessed whether subjective sleep disturbance predicts cognitive decline or cognitive impairment among older adults, and the results were inconsistent. Tworoger et al.  found thThe mechanisms underlying the association between sleep disturbance and odds of MCR remain unclear, although several potential biological pathways between sleep disturbance and cognitive function have been identified. Firstly, reduced or prolonged sleep duration has been found to be related to changes in the brain’s ventricular volume (Lo et al., Our study has several strengths. First, it is the first study to use a nationally representative cohort of community-dwelling Chinese adults to evaluate the association between sleep disturbance and MCR, which adds generalizability to our findings. Moreover, our results revealed that self-reported sleep duration and subjective poor sleep quality may be useful clinical tools to help predict persons at risk of progressing to dementia. Second, respondents were asked about sleep duration without being given example durations, and the classification of different nighttime sleep periods was set based on previous literature, both of which contributed to the identification of a reliable U-shaped association between sleep duration and odds of MCR. Third, a wide range of potential confounding parameters including demographic background, lifestyle factors, and history of comorbidities was adjusted for within the multivariable analyses, thus providing robust statistical power. However, several limitations should also be acknowledged. Firstly, the assessments of nighttime sleep duration were collected based on self-reporting in this study, which may have been influenced by recall bias. Although self-reported sleep has been shown to reflect objective assessments of sleep accurately (Biddle et al., In summary, this study demonstrated that shorter or longer sleep durations than average and subjective poor sleep quality were associated with increased odds of MCR. These findings have substantial public health implications and emphasize the need to improve the quality and quantity of sleep to prevent the prevalence of pre-dementia symptoms in developing countries where the number of older adults with dementia is expected to increase. In the future, longitudinal studies with comprehensive assessments of sleep disturbance among a larger population are required to establish causality and further explore potential mechanisms between sleep-related factors and MCR.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Peking University’s Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.WX wrote and participated in all aspects of this research, including the field investigation. AB and XH analyzed the data and interpreted the results. YG and LL designed this research. All authors reviewed the manuscript and agree to be accountable for the content of the work. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Stem cell therapy has been used to treat several types of diseases, and it is expected that its therapeutic uses shall increase as novel lines of evidence begin to appear. Furthermore, stem cells have the potential to make new tissues and organs. Thus, some scientists propose that organ transplantation will significantly rely on stem cell technology and organogenesis in the future. Stem cells and its robust potential to differentiate into specific types of cells and regenerate tissues and body organs, have been investigated by numerous clinician scientists and researchers for their therapeutic effects. Degenerative diseases in different organs have been the main target of stem cell therapy. Neurodegenerative diseases such as Alzheimer’s, musculoskeletal diseases such as osteoarthritis, congenital cardiovascular diseases, and blood cell diseases such as leukemia are among the health conditions that have benefited from stem cell therapy advancements. One of the most challenging parts of the process of incorporating stem cells into clinical practice is controlling their division and differentiation potentials. Sometimes, their potential for uncontrolled growth will make these cells tumorigenic. Another caveat in this process is the ability to control the differentiation process. While stem cells can easily differentiate into a wide variety of cells, a paracrine effect controlled activity, being in an appropriate medium will cause abnormal differentiation leading to treatment failure. In this review, we aim to provide an overview of the therapeutic effects of stem cells in diseases of various organ systems. In order to advance this new treatment to its full potential, researchers should focus on establishing methods to control the differentiation process, while policymakers should take an active role in providing adequate facilities and equipment for these projects. Large population clinical trials are a necessary tool that will help build trust in this method. Moreover, improving social awareness about the advantages and adverse effects of stem cell therapy is required to develop a rational demand in the society, and consequently, healthcare systems should consider established stem cell-based therapeutic methods in their treatment algorithms. Stem cells are primal cells that are mutual to all multicellular organisms and can renew themselves through cell divisions, and differentiate into a wide range of specialized cell types .One of tIn the present study, we have reviewed the literature reporting the stem cell-based treatments for a range of prevalent diseases in the society. We aim to provide a concise overview of the application of stem cell therapy on diseases of different body systems, including, cardiovascular, neurological, respiratory, gastrointestinal, and genitourinary systems.The mammalian stem cells can be categorized into five broad categories .th to 5th day of fertilization in humans. The blastocyst consists of 50-150 cells embryonic stem cells (ESCs) which are pluripotent and can transform to all derivatives of the three primary germ layers, including ectoderm, endoderm, and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body, when given the sufficient and necessary stimulation for a specific cell type [in vitro after the administration of proper stimulant agents for differentiation, in which each daughter cell will also remain pluripotent. The pluripotency of ESC -in vitro and in vivo- has been repeatedly demonstrated in previous research [Embryonic cell lines are derived from the epiblast tissue of the blastocyst structure, which is aligned in the inner wall of the blastocyst -6. The bell type , 7-11. Eresearch . Becauseresearch -8, 13.Fetal stem cells (FSCs) are cell lines that are derived from fetal tissues, which have the ability to divide, proliferate, and differentiate into specialized cells. Fetal stem cells can be isolated from fetal hematopoietic stem cells, fetal mesenchymal stem cells, and neural crest stem cells . StudiesInfant  stem cells can be derived from perinatal tissues, including, placenta membranes, amniotic fluid, and umbilical cords . These tASCs or somatic stem cells are undifferentiated cells that can be found in post-natal adult tissues, which could be unipotent or multipotent , 17. HowInduced pluripotent stem cells (iPSCs) are generated from somatic stem cells that have been reprogrammed into ESC-like state. iPSCs have the properties of ESCs, and can differentiate to the three primary germ layers. These cells have several advantages as they are derived from the patients’ own somatic cells leading to lower risks of rejection .Stem cells have the potential of self-renewal and differentiation as described below .Stem cells can undergo multiple cycles of cell division while preserving the undifferentiated state , 20.Stem cells also have the capability to differentiate into any mature cell type. This makes stem cells either totipotent, pluripotent, or multipotent .Totipotent stem cells (TSCs) are the outcome of the fusion of a sperm cell and an oocyte. The fertilized egg initiates a few divisions and forms cells that have totipotent properties. TSCs have the ability to differentiate into embryonic and extraembryonic types of cells , 22.Pluripotent stem cells (PSCs) are the descendants of totipotent cells and can differentiate into cells that construct the three germ layers of ectoderm, mesoderm, and endoderm which subsequently give rise to various system organs -23.Multipotent stem cells (MPSCs) are among the major groups of stem cells which hold similar basic properties of all stem cells . These cStem-cells have two types of cell division in order to remain self-renewed and potent. Firstly, a symmetric division resulting in two identical daughter cells both having the stem-cell potentials. The second type is called asymmetric division whose outcome is one stem-cell with the aforementioned properties and a progenitor cell with less self-renewal potential , 28, 29.Stem cell therapy has been applied in various disorders in which here we review some of the diseases in this regard (Congestive Heart Failure (CHF) and Ischemic Heart Disease (IHD)Cardiovascular diseases (CVD) account for about 20% of the burden of noncommunicable diseases (NCD) . These dRising evidence demonstrated stem-cell therapy could improve heart failure by inducing neovascularization, decreasing cardiomyocyte apoptosis, and forming resident stem-cells -35. AnimThe first U.S. randomized controlled clinical trial, using a three dimensional guided catheter system to provide the heart with muscular stem-cells, was done in 2009; and after 1 year of follow-up, the results showed significant improvements in New York Heart Association (NYHA) and Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores, besides the increase of ventricular viability . EndomyoParkinson’s diseaseParkinson’s disease (PD) is a neurodegenerative disease that is common worldwide and clinically demonstrates itself by symptoms of resting tremor, bradykinesia, rigidity, and postural instability , 45. ThePromising evidence has been found regarding neuroprotective and neuroregenerative benefits of stem-cell therapy –while applying with neurotrophic agents. Transplantation of embryonic mesencephalic into the brain of animal models showed improvement of dopamine transmission -50.The proof-of-principle has been achieved by several studies in which evidence was in favor of the hypothesis that the dead dopaminergic neurons can be replenished by stem-cell transplantation in patients with PD , 51-53. Due to the aforementioned issues, the current researches emphasize the adjustment of hFSCs, and also producing well-characterized dopaminergic neurons by using brain-derived NSCs. Stem cell tissues –to be grafted in the striatum- must be analogous to substantia nigra neurons, regenerate the dopamine network in the brain, produce long-term and high symptomatic relief, and have no adverse effects . It is sHuntington’s diseaseHuntington’s disease (HD) is an uncommon neurodegenerative disease characterized by undesirable motor and cognitive functions, besides psychiatric syndromes. The disease is considered a genetic disorder that is inherited in an AD  fashion and results in cell loss in the striatum and cerebral cortex . CurrentSeveral studies on animal models have suggested that stem-cell therapy could be used in the case of HD . BehavioThis accumulating evidence indicates that cell transplantation therapy could be well justified as a treatment of HD. Several studies experimented with the feasibility of cell therapy in this regard and showed promising results. Positron emission tomography (PET) scanning of 3 out of 5 patients who underwent hFSCs transplantation into the striatum demonstrated increased metabolic activity in the region; besides the patients showed improved cognitive and motor functions, through six years of follow-up , 64. TheAlzheimer’s diseaseAlzheimer’s disease (AD) is the most common neurodegenerative disease which results in irreversible loss of neurons in the brain, mainly in the hippocampus and cortex . The disMultiple theoretical approaches have been proposed in order to design stem-cell therapy for AD such as the upregulation of the local NSCs, and stem-cell transplantation . The uprInvestigations on animal models of AD showed ESCs have the potential to restore cognitive function; however, no tangible clinical evidence has been succeeded yet . A recenRecently, a phase 1 clinical trial showed that human umbilical cord blood-derived mesenchymal stem-cells (hUCB-MSCs) which injected by stereotactic technique into the brain of AD patients could have neuroprotective effects, as patients didn’t show a decline in their cognitive functions; besides, no adverse effects were observed during 24-months follow-up .Given that the rate of neuroregeneration in the adult brain is minimal and that the pathology of AD consists of Ab formation from amyloid precursor protein (APP), Alzhimer’s patients have markedly reduced brain functions. Stem-cell transplantation therapy for AD may not be effective in that environment, where APP metabolism is altered, and it may, conversely, lead to excessive gliogenesis and tumorigenesis. Studies must consider the regulation of APP processing to develop effective stem-cell transplantation protocols for AD patients -95.Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder that involves degenerations of motor neurons at all stages including the cerebral cortex, brainstem, and spinal cord . The symPreclinical studies and treatment of animal models of ALS with human umbilical cord blood cells demonstrated the increase of lifespan in a dose-dependent way , 100. MoMultiple sclerosisMultiple sclerosis (MS) is an autoimmune, inflammatory, and chronic neurological condition that involves myelinated axons of the central nervous system (CNS) . The defPrevious studies have found that NSCs and MSCs administration may have a protective role against the progression of MS in both rodents and primates . SeveralStrokeStroke disorders are the major cause of morbidity in many areas of the world that could lead to irrecoverable brain tissue damages and functional disabilities. Current therapeutic approaches are mostly focused in order to modify risk factors for stroke such as hypertension, heart diseases, diabetes mellitus, heavy cigarette and alcohol consumption, and hypercholesterolemia . SurgicaA variety of precursor cell types such as human bone marrow cells, neuroepithelial stem cell line, NTera-2 cell line have been investigated to renovate brain function after stroke in animal models of stroke which showed improvement of sensorimotor function, spatial memory, neurological severity score, and asymmetrical motor behavior -128. AltThe curative effects of stem-cell therapy on animal models of stroke made the basis for the treatment to be addressed for use in human subjects. Initial clinical trials showed that stem-cell therapy could be safe, feasible, and therapeutic in patients with stroke; however, more comprehensive is needed to approve the aforementioned issue.Spinal cord injurySpinal cord injury (SCI) is a destructive condition that involves both upper and lower motor neurons and could result in paraplegia and quadriplegia. The incidence of traumatic SCI, primarily caused by motor vehicle accidents, is estimated to be between 28 and 55 per million people each year, in the US . The manThe emerging perspective of stem cell therapy as a viable therapeutic tool for the treatment of SCI is based on the preclinical studies which have been performed on animal models and have shown that transplanted progenitor cells can migrate into the injured tissues to improve axonal regeneration and motor function. ESCs have been used for the treatment of paralyzed rats, the paralyzed rodents showed partial recovery from the condition as the transplanted ESC–derived axons restored SCI . MoreoveNSC transplantation is under investigation at phase I/II clinical trial and is proved to be safe and feasible for perilesional intramedullary injections , 149. ThBriefly, animal models of SCI who received stem-cell therapy have demonstrated several promising results, and preclinical investigations have validated scientific principles and approaches. Additionally, multiple signs of progress have been made by a number of studies with practical concerns in this regard.AutismAutism and autism spectrum disorders are referred to as neurodevelopmental disorders that are caused by both genetic and environmental factors and are characterized by disruption of social interactions and stereotypic behaviors -153. CurRecently, researchers have conducted several investigations regarding the use of stem cell therapy for autism. Intracerebroventricular transplantation of MSC for animal models of the disease showed promising results, as a reduction in stereotypical behaviors and an improvement of social behaviors were observed during the investigation in animal models who received the transplantation .Consistently with prior results, a phase I/II clinical trial showed that the patients who received the transplantation of human cord blood mononuclear cells and umbilical cord-derived MSCs had improvements in visual, emotional, and intellectual reactions, along with body use, adaptation responses, and non-verbal communications . AutologCerebral palsyCerebral palsy (CP) is a group of chronic neurological diseases that result in cognitive and motor impairments in children. This may be caused by perinatal infection, asphyxia, and preterm birth, or even postnatal brain injuries . The oveSeveral lines of stem cells such as MSCs, NSCs, and ESCs have been administered to CP patients in previous investigations -164. SteAlcohol-use disordersAlcohol-use disorders have been reported to be responsible for 1 out of 10 deaths among working-age adults in the US and are also among the leading causes of morbidity and premature mortality worldwide . Also, cChronic obstructive pulmonary disease (COPD)COPD has been reported to be the third-leading cause of mortality in the US , 173. ReMeta-analytic studies on animal models of COPD have shown that intra-tracheal instillation or intravenous injection of MSC have satisfactory results, through the significant improvement of lung function and stimulation of lung repair. Furthermore, a considerable reduction of airway infiltration by macrophages, neutrophils, and products of pro-inflammatory cytokines such as IL-6 and IL-1b, but accompanied with substantial stimulated anti-inflammatory cytokine IL-10 and growth factors such as EGF, HGF, TGF-b, and VEGF was detected through MSC administration, suggesting this method as an effective approach in the treatment of animal models of COPD/emphysema, and therefore hold the foundation of further research and application of administering MSC in COPD patients .AsthmaAsthma, affecting around 300 million individuals worldwide, is known to be primarily a chronic inflammatory disease presenting with lifelong conditions with different levels of severity , 176. WhIdiopathic pulmonary fibrosisIdiopathic pulmonary fibrosis (IPF) with a prevalence from 4.6 to 16.3/100,000 cases worldwide is characterized by chronic, progressive fibrosing interstitial pneumonia without a known etiology , 183. DeThere is evidence that MSCs can prevent the progression of animal model IPF and decrease inflammation, if administered early during the disease, however such evidence during the latent and established fibrosis period of the disease is limited and requires further studies in order to apply in clinical studies , 185.Pulmonary arterial hypertensionPulmonary arterial hypertension (PAH) is considered a rare and progressive disease which is characterized by the elevation of blood pressure of the lung arteries. While manageable, no effective therapeutic option has yet been approved in order to reduce mortality .Animal studies have demonstrated that administration of MSCs, either intravenous or intratracheal, can decrease factors associated with PAH, including lung inflammation, endothelial dysfunction, and ventricular remodeling -191. TheSilicosisSilicosis is among the known occupational diseases which cause extensive lung fibrosis and subsequently respiratory failure . CurrentLiver diseasein vitro, in vivo, and even in clinical studies for the treatment of liver diseases [Liver injury can be subsequent to causes such as ischemia, cytotoxic, toxic–metabolic, or other insults causing tissue inflammation and therefore result in innate and adaptive immune responses which in turn can also directly cause additional injury . The curdiseases , 206. Nediseases -209.Inflammatory bowel diseaseInflammatory bowel disease (IBD), which consists of Crohn’s disease (CD) and ulcerative colitis (UC) is assumed to be due to inappropriate response of the host’s immune system to intestinal microbes . StandarAcute kidney injuryAcute kidney injury (AKI) is characterized by stimulation of the immune system and elevated oxidative stress which can be caused by ischemia-reperfusion injury (IRI) -217. SteChronic kidney disease and end stage renal diseaseIn renal injury, the progression to end-stage renal disease (ESRD) is presently only partially understood due to its complexity . There aMale InfertilityInfertility is the inability to achieve pregnancy despite one-year attempts, in which the rate of related factors for male infertility alone has been reported from 6.4% to 42.4% in studies , 236. VaFemale infertilityThe incidence of female infertility ranges from 33 to 41% worldwide . The US Among the many causes of female infertility, reproductive system-related diseases are considered the main causes. The efficacy of bone marrow stromal cells has been demonstrated in several animal model studies regarding the treatment of chemotherapy-induced ovarian failure, indicating structure and functional restoration , 245. StStress urinary incontinenceStress urinary incontinence (SUI) is a common urinary system disease affecting more than 200 million people worldwide and notably females, resulting in a serious decrease in QoL with no ideal therapeutic option until now -253. SteDiabetesDiabetes is a group of metabolic disorders that are characterized by hyperglycemia which is developed for a defect in insulin production, insulin function, or both. Diabetes mellitus (DM) is considered as one of the most common non-communicable diseases worldwide, with a global growing prevalence . PersistIn vitro studies have also revealed the possibility of therapeutic administration of bone marrow-derived cells for DM patients, as these cells have generated insulin-producing cells (IPCs) under appropriate circumstances [in vivo and in vitro studies have been conducted to produce IPCs and functional pancreatic islet cells from human ESCs and ASCs [Several investigations have been done regarding the therapeutic use of both ESCs and ASCs in DM and its complications. ESC-derived insulin-producing tissue alleviated diabetes in mice , 263. HSmstances , 271. Simstances -285. Mormstances -292. Sevand ASCs -297. TheIn humans, pancreatic islet transplantation was suggested as a therapeutic approach through DM over two decades ago . After tLysosomal storage diseasesLysosomal storage diseases (LSDs) is an inherited defect in normal lysosomal functions which are identified by several different pathophysiologies . LSD mayStudies on animal models of LSDs have shown the possible protective effects of bone marrow transplantation (BMT) against the progression of the disease -308. MorAllogeneic BMT was firstly done over 3 decades ago for patients who suffer from LSDs which showed promising results regarding the amelioration of the patients’ symptoms . Later, Acute lymphocytic leukemiaAcute lymphocytic leukemia (ALL) is an aggressive malignancy that the lymphoid line of blood cells tend to be immaturely produced in large numbers. The main therapeutic approaches through this condition are chemotherapy and HSC transplantation that could help the patients to recover and maintain remission . CurrentAcute myeloid leukemiaThe main characteristics of acute myeloid leukemia (AML) are a rise in the number of immature myeloid cells which could result in several hematopoietic insufficiencies and leukocytosis. Stem cell transplantation has been administered for this condition since over 3 decades ago, however, there is still uncertainty regarding the optimal treatment of AML .Chronic myeloid leukemiaChronic myeloid leukemia (CML) is another malignancy of bone marrow cell which is characterized by an increased count of white blood cells in peripheral blood. It has been noticed in previous studies that CML is the most common indication of allogeneic HSC transplantation globally .Myelodysplastic syndromeMyelodysplastic syndromes are a group of bone marrow disorders that the blood cells are not properly matured. The main treatment of this condition is chemotherapy and HSC transplantation , 327.LymphomaAnother group of blood cancer is lymphoma which originated from the lymphatic system and could affect the whole body. The treatment of lymphoma is commonly chosen according to the type and severity of the disease. Radiation therapy, chemotherapy, immunotherapy, and HSC transplantation are considered as the main therapeutic options in this regard , 329.Severe aplastic anemiaSevere aplastic anemia (SAA) is a condition characterized by the failure of bone marrow to make enough mature blood cells. Stem cell transplantation is a promising therapeutic approach through SAA; as previous investigations mentioned that unrelated cord blood transplantation and allogeneic bone marrow transplantation can be a salvage procedure for SAA patients -332.B-thalassemia majorB-thalassemia is an early-onset and inherited blood disease which is characterized by severe anemia requiring regular blood transfusion. The main treatments of this condition consist of transfusion therapy, chelation therapy, surgical interventions such as splenectomy and cholecystectomy, and stem cell transplantation . Bone maFanconi’s anemiaFanconi’s anemia (FA) is a rare genetic blood disorder that is caused by bone marrow failure to produce blood cells. HSC transplantation has been suggested as an effective and exclusive therapeutic intervention for these patients -337. HowMuscular dystrophyMuscular dystrophy (MD) is among the muscle wasting diseases, and is a condition affecting a million individuals worldwide which are the result of mutations in structural proteins and are presented with loss of functional muscle subsequent to muscle fiber injury, deposition of fibrotic tissue, and inflammation . PresentThe use of stem cell therapy has demonstrated evidence of replacing injured tissue through the fusion of healthy cells with damaged fibers along with replacing the ASC pool for long-term muscle maintenance . Based oOsteoarthritisOsteoarthritis (OA) is the most prevalent joint disease globally, and it has been estimated that about 10% of men and 18% of women with the age of 60 or older suffer from the condition . The patA 2-year follow-up, proof-of-concept trial showed that intra-articular injection of MSCs into OA knees improved the joint function and pain without any adverse events by regeneration of hyaline-like articular cartilage , 353. MoCurrently, there are over 500 clinical trials registered on ClinicalTrials.gov, exploring the safety and efficacy of stem cells in order to find a comprehensive protocol to cure OA. Long-term follow-up is needed to evaluate the exact effects of stem-cells therapy in the condition.OsteoporosisOsteoporosis is considered the most common skeletal disease which is characterized by decreased bone mineral density and bone structural deformations, which is probably caused by an acceleration in bone resorption by osteoclasts . CurrentThe application of MSCs has increased bone regeneration and angiogenesis in osteoporotic mice . OsteopoStroke-induced retinal ischemiaAmong the complications of cerebral ischemia one can name its effect on the retinal, causing cell loss and optic nerve damage -369. AvaThere is rising evidence that MSCs can significantly affect the pathogenesis of the disease , 374. BoAutoimmune UveitisAutoimmune uveitis (AU) is among the leading reasons for visual disability. Current treatment options consist of long-term use of corticosteroids and immunosuppressive medicines, which in turn leads to serious side effects and possible progress of cataract and glaucoma; therefore, new and alternative therapeutic options are urgently needed , 378. ReHearing lossHearing loss by affecting more than 360 million people worldwide is among the diseases with a significant impact on the individuals’ physical and mental health -386. TheWoundThe cutaneous wound is still considered as a global health care concern and its treatments include topical antibiotics, debridement, and application of grafts. There is growing evidence regarding the promising effect of stem cell therapy in wound healing. Both ESCs and MSCs were found to have wound healing properties. As human ESC-derived endothelial precursor cells improved excisional wounds in rats, and adipose-derived MSCs enhanced wound healing rate in animal models of DM , 392. FuBurnsBurns are considered to be one of the most prevalent public health problems, causing high rates of morbidity and mortality particularly in low- and middle-income countries . Finding. Having said that, several studies suggested that the administration of MSCs could be applied as an alternative treatment for chronic non-healing wounds [. Moreover, prior clinical trials noticed that stem cell therapy could significantly decrease the scar formation and skin contracture [Stem cell therapy could be a promising intervention regarding burn injuries as previous investigations have shown the beneficial effects of EDSCs, MSCs, and ADSCs in wound healing . Criticag wounds , 400. Thg wounds . Moreovetracture . OverallVitiligoVitiligo is a depigmenting condition of the skin caused by the loss of melanocytes that globally affects about 2% of the general population . Severalin vitro [The skin is composed of several populations of stem-cells such as EDSCs, HFSCs, and dermal mesenchymal stem cells , 405. Moin vitro . So thatin vitro , 406. Inin vitro . ADSC wein vitro .AlopeciaAlopecia is one of the most common concerns of many individuals who come for medical consultations, and is caused by reduced hair follicle regenerative functions. The prevalence of the condition is estimated to be high in many regions of the world; for example, it has been calculated that 2% of individuals might suffer from alopecia areata (AA) and androgenetic alopecia (AGA) could be diagnosed in 31% (40-55 years old) to 53% (65-69 years old) men , 410. CoIt has been found that stem cells could mitigate hair loss by reversing the underlying mechanisms involved in hair loss, regenerating hair follicles, and neogenesis of follicles using stem cell technologies. Having said that, the injection of cultured dermal papilla cells (DPC) in combination with cultured epithelial cells (EC) to animal models resulted in induction of hair growth . SimilarCurrently, the gold standard treatment for the disease is autologous hair transplant, however, this approach also has inadequate usability because of limited material and low viability of cells achieved by the method, that should be improved . In ordeCoronavirus disease 19The novel coronavirus disease of 2019  resulting in acquired immune deficiency syndrome (AIDS) affects around 2 million people worldwide and 40,000 Americans, which leads to lifelong infection, accompanied by several co-infecting diseases in addition to high mortality rates with no effective treatment up to now , 431. StThere are several dilemmas and controversies surrounding stem-cell therapy and research in this regard. For example, ESC investigations are ethically and politically controversial, as it causes the destruction of human embryos. Some individuals believe that an embryo is a person with the identical rights and moral status as adults; they insist on that “human life begins at conception” because of their religious or moral beliefs . From thOther ethical issues regarding the field of stem cell therapy are the importance of reducing adverse effects, the matter of overpromising by physicians, adjustment of patient optimism and expectations levels. Moreover, one must be wary of profit making entities trying to pass these novel methods too quickly into the clinic, at the price of not understanding the basic mechanisms.Policymakers have been discussing several issues around stem-cell therapy such as whether moral and/or religious sights should have a part in strategies, the basis, and level of the association between science and politics, and public engagement and their suitable role in the field; along with the evasion of experts to less restrictive instructions, and probability of falling behind other countries in scientific skills because of restrictive rules . ReligioWide-ranging demands have been made globally in order to make an international regulation that has a consensus and jurisdictional consistency, regarding stem-cell therapy; hence, an international description of bioethics is needed.Decades of exploration showed that stem cell therapy can be a potential cure for diseases that were once thought to be untreatable. Today, patients are routinely undergoing stem cell transplants for conditions such as leukemia, lymphoma, congenital immune deficiencies, neurodegenerative, and congenital metabolic diseases. While there are numerous publications on the therapeutic uses of stem cells, both in vitro and in vivo, experimental and clinical, finding solid methods to take control of the division and differentiation processes of these cells, as well as methods of administration in different diseases has remained to be a challenge. On the other hand, in many healthcare systems, stem cell therapies are still considered as a research field rather than a therapeutic choice showing that these systems have not still put trust in this method. Hence, future efforts should be focused on removing these challenges both in the clinics and in the administration. A big step towards these goals would be large population clinical trials. If a stem cell-based treatment method can pass a clinical trial, trust will be built in it, and barriers will fall. Another suggestion is to educate society about the benefits and disadvantages of stem cell therapy. Knowledge will bring about demand and demand will motivate the healthcare system to take this therapeutic method into account.