Evaluating nephrotoxicity reduction in a novel polymyxin B formulation: insights from a 3D kidney-on-a-chip model.

This study aimed to assess the nephrotoxicity associated with VRP-034 (novel formulation of polymyxin B [PMB]) compared to marketed PMB in a three-dimensional (3D) kidney-on-a-chip model. To model the human kidney proximal tubule for analysis, tubular structures were established using 23 triple-channel chips seeded with RPTEC/hTERT1 cells. These cells were exposed to VRP-034 or PMB at seven concentrations (1-200 µM) over 12, 24, and 48 h. A suite of novel kidney injury biomarkers, cell health, and inflammatory markers were quantitatively assessed in the effluent. Additionally, caspase and cytochrome C levels were measured, and cell viability was evaluated using calcein AM and ethidium homodimer-1 (EthD-1). Exposure to marketed PMB resulted in significantly elevated levels (P < 0.05) of four key biomarkers (KIM-1, cystatin C, clusterin, and OPN) compared to VRP-034, particularly at clinically relevant concentrations of ≥10 µM. At 25 µM, all biomarkers demonstrated a significant increase (P < 0.05) with marketed PMB exposure compared to VRP-034. Inflammatory markers (interleukin-6 and interleukin-8) increased significantly (P < 0.05) with marketed PMB at concentrations of ≥5 µM, relative to VRP-034. VRP-034 displayed superior cell health outcomes, exhibiting lower lactate dehydrogenase release, while ATP levels remained comparable. Morphological analysis revealed that marketed PMB induced more severe damage, disrupting tubular integrity. Both treatments activated cytochrome C, caspase-3, caspase-8, caspase-9, and caspase-12 in a concentration-dependent manner; however, caspase activation was significantly reduced (P < 0.05) with VRP-034. This study demonstrates that VRP-034 significantly reduces nephrotoxicity compared to marketed PMB within a 3D microphysiological system, suggesting its potential to enable the use of full therapeutic doses of PMB with an improved safety profile, addressing the need for less nephrotoxic polymyxin antibiotics.

Structure-Guided Identification of Novel Aromatase Inhibitors Targeting Breast Carcinoma.

Aromatase inhibitors play a critical therapeutic role in treating ER+ breast cancer, especially in postmenopausal women. However, their efficacy is often limited by resistance and severe side effects. Identifying new compounds that can disrupt aromatase enzyme function is essential. In this study, structural anomalies in the aromatase enzyme were corrected through energy minimization, and the structure was validated via Ramachandran plot. We screened 170,269 natural compounds from the ASINEX Biodesign library using high-throughput screening algorithms to target the aromatase enzyme. Molecular docking identified three compounds: BDD30170158, BDE33872639, and BDE30177677, all showing stable binding interactions with the aromatase enzyme. Molecular dynamics simulations over 100 ns confirmed the conformational stability of these compounds. Although all three compounds exhibited the desired pharmacokinetic and drug metabolism properties, only one compound (BDE33872639) was identified as a non-blocker, demonstrating a reduced risk of adverse cardiac effects. This compound exhibits significant potential as a novel aromatase inhibitor, warranting further experimental research to develop it as a therapeutic option for ER+ breast cancer.

A Drug Repurposing Approach to Identify Therapeutics by Screening Pathogen Box Exploiting SARS-CoV-2 Main Protease.

Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) and is responsible for a higher degree of morbidity and mortality worldwide. There is a smaller number of approved therapeutics available to target the SARS-CoV-2 virus, and the virus is evolving at a fast pace. So, there is a continuous need for new therapeutics to combat COVID-19. The main protease (Mpro ) enzyme of SARS-CoV-2 is essential for replication and transcription of the viral genome, thus could be a potent target for the treatment of COVID-19. In the present study, we performed an in-silico screening analysis of 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties against Mpro drug target. Ten compounds showed a higher binding affinity for Mpro than the reference compound (N3), with desired physicochemical properties. Furthermore, in-depth docking and superimposition revealed that three compounds (MMV1782211, MMV1782220, and MMV1578574) are actively interacting with the catalytic domain of Mpro . In addition, the molecular dynamics simulation study showed a solid and stable interaction of MMV178221-Mpro complex compared to the other two molecules (MMV1782220, and MMV1578574). In line with this observation, MM/PBSA free energy calculation also demonstrated the highest binding free energy of -115.8 kJ/mol for MMV178221-Mpro compound. In conclusion, the present in silico analysis revealed MMV1782211 as a possible and potent molecule to target the Mpro and must be explored in vitro and in vivo to combat the COVID-19.

Delineation of molecular interactions of plant growth promoting bacteria induced ß-1,3-glucanases and guanosine triphosphate ligand for antifungal response in rice: a molecular dynamics approach.

BACKGROUND: The plant growth is influenced by multiple interactions with biotic (microbial) and abiotic components in their surroundings. These microbial interactions have both positive and negative effects on plant. Plant growth promoting bacterial (PGPR) interaction could result in positive growth under normal as well as in stress conditions. METHODS: Here, we have screened two PGPR's and determined their potential in induction of specific gene in host plant to overcome the adverse effect of biotic stress caused by Magnaporthe grisea, a fungal pathogen that cause blast in rice. We demonstrated the glucanase protein mode of action by performing comparative modeling and molecular docking of guanosine triphosphate (GTP) ligand with the protein. Besides, molecular dynamic simulations have been performed to understand the behavior of the glucanase-GTP complex. RESULTS: The results clearly showed that selected PGPR was better able to induce modification in host plant at morphological, biochemical, physiological and molecular level by activating the expression of ß-1,3-glucanases gene in infected host plant. The docking results indicated that Tyr75, Arg256, Gly258, and Ser223 of glucanase formed four crucial hydrogen bonds with the GTP, while, only Val220 found to form hydrophobic contact with ligand. CONCLUSIONS: The PGPR able to induce ß-1,3-glucanases gene in host plant upon pathogenic interaction and ß-1,3-glucanases form complex with GTP by hydrophilic interaction for induction of defense cascade for acquiring resistance against Magnaporthe grisea.

Probiotics, prebiotics and synbiotics: Safe options for next-generation therapeutics.

Probiotics have been considered as an economical and safe alternative for the treatment of a large number of chronic diseases and improvement of human health. They are known to modulate the host immunity and protect from several infectious and non-infectious diseases. The colonization, killing of pathogens and induction of host cells are few of the important probiotic attributes which affect several functions of the host. In addition, prebiotics and non-digestible food substances selectively promote the growth of probiotics and human health through nutrient enrichment, and modulation of gut microbiota and immune system. This review highlights the role of probiotics and prebiotics alone and in combination (synbiotics) in the modulation of immune system, treatment of infections, management of inflammatory bowel disease and cancer therapy. KEY POINTS: • Probiotics and their derivatives against several human diseases. • Prebiotics feed probiotics and induce several functions in the host. • Discovery of novel and biosafe products needs attention for human health.

Transcriptome analysis reveals immune pathways underlying resistance in the common carp Cyprinus carpio against the oomycete Aphanomyces invadans.

Infection with Aphanomyces invadans is a serious fish disease with major global impacts. Despite affecting over 160 fish species, some of the species like the common carp Cyprinus carpio are resistant to A. invadans infection. In the present study, we investigated the transcriptomes of head kidney of common carp experimentally infected with A. invadans. In time course analysis, 5288 genes were found to be differentially expressed (DEGs), of which 731 were involved in 21 immune pathways. The analysis of immune-related DEGs suggested that efficient processing and presentation of A. invadans antigens, enhanced phagocytosis, recognition of pathogen-associated molecular patterns, and increased recruitment of leukocytes to the sites of infection contribute to resistance of common carp against A. invadans. Herein, we provide a systematic understanding of the disease resistance mechanisms in common carp at molecular level as a valuable resource for developing disease management strategies for this devastating fish-pathogenic oomycete.

Photoreceptor Cells Constitutively Express IL-35 and Promote Ocular Immune Privilege.

Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, the intrinsic roles of IL-35 in CNS tissues are unknown. Thus, we generated IL-35/YFP-knock-in reporter mice (p35-KI) and demonstrated that photoreceptor neurons constitutively secrete IL-35, which might protect the retina from persistent low-grade inflammation that can impair photoreceptor functions. Furthermore, the p35-KI mouse, which is hemizygous at the il12a locus, develops more severe uveitis because of reduced IL-35 expression. Interestingly, onset and exacerbation of uveitis in p35-KI mice caused by extravasation of proinflammatory Th1/Th17 lymphocytes into the retina were preceded by a dramatic decrease of IL-35, attributable to massive death of photoreceptor cells. Thus, while inflammation-induced death of photoreceptors and loss of protective effects of IL-35 exacerbated uveitis, our data also suggest that constitutive production of IL-35 in the retina might have housekeeping functions that promote sterilization immunity in the neuroretina and maintain ocular immune privilege.

Transcription Factor MAFB as a Prognostic Biomarker for the Lung Adenocarcinoma.

MAFB is a basic leucine zipper (bZIP) transcription factor specifically expressed in macrophages. We have previously identified MAFB as a candidate marker for tumor-associated macrophages (TAMs) in human and mouse models. Here, we analyzed single-cell sequencing data of patients with lung adenocarcinoma obtained from the GEO database (GSE131907). Analyzed data showed that general macrophage marker CD68 and macrophage scavenger receptor 1 (CD204) were expressed in TAM and lung tissue macrophage clusters, while transcription factor MAFB was expressed specifically in TAM clusters. Clinical records of 120 patients with lung adenocarcinoma stage I (n = 57), II (n = 21), and III (n = 42) were retrieved from Tsukuba Human Tissue Biobank Center (THB) in the University of Tsukuba Hospital, Japan. Tumor tissues from these patients were extracted and stained with anti-human MAFB antibody, and then MAFB-positive cells relative to the tissue area (MAFB+ cells/tissue area) were morphometrically quantified. Our results indicated that higher numbers of MAFB+ cells significantly correlated to increased local lymph node metastasis (nodal involvement), high recurrence rate, poor pathological stage, increased lymphatic permeation, higher vascular invasion, and pleural infiltration. Moreover, increased amounts of MAFB+ cells were related to poor overall survival and disease-free survival, especially in smokers. These data indicate that MAFB may be a suitable prognostic biomarker for smoker lung cancer patients.

Modeling defluoridation of real-life groundwater by a green adsorbent aluminum/olivine composite: Isotherm, kinetics, thermodynamics and novel framework based on artificial neural network and support vector machine.

The kinetic, isotherm, and thermodynamics of adsorptive removal of fluoride from the real-life groundwater was evaluated to assess the applicability of a green adsorbent, aluminum/olivine composite (AOC). The isotherm and kinetics were demonstrated by the Freundlich and Elovich model indicating significant surface heterogeneity of AOC in favouring the fluoride sorption. The fluoride removal efficiency of AOC was achieved as 87.5% after 240 min of contact time. The diffusion kinetic model exhibited that both the intra-particle and film diffusion together control the rate-limiting step of fluoride adsorption. A negative value of ΔG0 (-19.919 kJ/mol) at 303 K confirmed the spontaneous adsorption reaction of fluoride, and its endothermic nature was supported by the negative value of ΔH0 (39.504 kJ/mol). A novel framework for a predictive model by artificial neural network (ANN), and support vector machine (SVM) considering the real and synthetic fluoride-containing water was developed to assess the efficiency of adsorbent under different scenarios. ANN model was observed to be statistically significant (RMSE: 1.0955 and R2: 0.9982) and the proposed method may be instrumental in a similar area for benchmarking the synthetic and real-life samples. The low desorption potential of the spent adsorbent exhibited safe disposal of sludge and the secondary-pollutant-free treated water by the efficient and green adsorbent AOC enhanced the field-scale applicability of the green technology.

Biocomputational Assessment of Natural Compounds as a Potent Inhibitor to Quorum Sensors in Ralstonia solanacearum.

Ralstonia solanacearum is among the most damaging bacterial phytopathogens with a wide number of hosts and a broad geographic distribution worldwide. The pathway of phenotype conversion (Phc) is operated by quorum-sensing signals and modulated through the (R)-methyl 3-hydroxypalmitate (3-OH PAME) in R. solanacearum. However, the molecular structures of the Phc pathway components are not yet established, and the structural consequences of 3-OH PAME on quorum sensing are not well studied. In this study, 3D structures of quorum-sensing proteins of the Phc pathway (PhcA and PhcR) were computationally modeled, followed by the virtual screening of the natural compounds library against the predicted active site residues of PhcA and PhcR proteins that could be employed in limiting signaling through 3-OH PAME. Two of the best scoring common ligands ZINC000014762512 and ZINC000011865192 for PhcA and PhcR were further analyzed utilizing orbital energies such as HOMO and LUMO, followed by molecular dynamics simulations of the complexes for 100 ns to determine the ligands binding stability. The findings indicate that ZINC000014762512 and ZINC000011865192 may be capable of inhibiting both PhcA and PhcR. We believe that, after further validation, these compounds may have the potential to disrupt bacterial quorum sensing and thus control this devastating phytopathogenic bacterial pathogen.

Low-dose naltrexone rescues inflammation and insulin resistance associated with hyperinsulinemia.

The incidence of diabetes, obesity, and metabolic diseases has reached an epidemic status worldwide. Insulin resistance is a common link in the development of these conditions, and hyperinsulinemia is a central hallmark of peripheral insulin resistance. However, how hyperinsulinemia leads to systemic insulin resistance is less clear. We now provide evidence that hyperinsulinemia promotes the release of soluble pro-inflammatory mediators from macrophages that lead to systemic insulin resistance. Our observations suggest that hyperinsulinemia induces sirtuin1 (SIRT1) repression and stimulates NF-κB p65 nuclear translocation and transactivation of NF-κB to promote the extracellular release of pro-inflammatory mediators. We further showed that low-dose naltrexone (LDN) abrogates hyperinsulinemia-mediated SIRT1 repression and prevents NF-κB p65 nuclear translocation. This, in turn, attenuates the hyperinsulinemia-induced release of pro-inflammatory cytokines and reinstates insulin sensitivity both in in vitro and in vivo diet-induced hyperinsulinemic mouse model. Notably, our data indicate that Sirt1 knockdown or inhibition blunts the anti-inflammatory properties of LDN in vitro Using numerous complementary in silico and in vitro experimental approaches, we demonstrated that LDN can bind to SIRT1 and increase its deacetylase activity. Together, these data support a critical role of SIRT1 in inflammation and insulin resistance in hyperinsulinemia. LDN improves hyperinsulinemia-induced insulin resistance by reorienting macrophages toward anti-inflammation. Thus, LDN treatment may provide a novel therapeutic approach against hyperinsulinemia-associated insulin resistance.

Discovery of novel inhibitors targeting Plasmodium knowlesi dihydrofolate reductase using molecular docking and molecular dynamics simulation.

Plasmodium knowlesi, recognized as the fifth Plasmodium parasite, is the least studied malaria parasite. It is a significant cause of morbidity and mortality in the South-East Asia region. Enzymes of folate synthesis, especially dihydrofolate reductase (DHFR), is a well-approved drug target in other Plasmodium species, but its role in Plasmodium knowlesi is poorly studied. This work characterizes PkDHFR as a drug target and identifies inhibitors that can withstand the upcoming problem of resistance. The 3D structure of the PkDHFR target is modelled using comparative modelling, and further, it is refined and validated using energy minimization and torsional angle analysis methods. We extracted 13 compounds from DrugBank and ZINC databases using the "target similarity search" criteria. These compounds were categorized based on their binding affinity (-4.49 to -10.08 kcal/mol) and pose prediction against the active site of PkDHFR. Later on, the top 5 PkDHFR-compound complexes with high or equivalent binding affinity to its natural ligand (dihydrofolate) have undergone for dynamics. The simulation experiments reveal the higher stability of DB00563-PkDHFR complex and less conformational fluctuations and share a similar degree of compactness throughout the simulation trajectory. The MM/GBSA calculation of free energy of DB00563 is also the least (-72.84 kcal/mol) compared to others. Furthermore, the flexible side chain of DB00563 can bind and block the active site of PkDHFR more efficiently. Thus, the identified drug may be considered as a potential candidate for treating P. knowlesi malaria.

Polydiacetylene vesicles acting as colorimetric sensor for the detection of plantaricin LD1.

The interaction of antimicrobial peptides with membrane lipids plays a major role in numerous physiological processes. In this study, polydiacetylene (PDA) vesicles were synthesized using 10, 12-tricosadiynoic acid (TRCDA) and 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). These vesicles were applied as artificial membrane biosensor for the detection of plantaricin LD1 purified from Lactobacillus plantarum LD1. Plantaricin LD1 (200 µg/mL) was able to interact with PDA vesicles by changing the color from blue to red with colorimetric response 30.26 ± 0.59. Nisin (200 µg/mL), used as control, also changed the color of the vesicles with CR% 50.56 ± 0.98 validating the assay. The vesicles treated with nisin and plantaricin LD1 showed increased infrared absorbance at 1411.46 and 1000-1150 cm-1 indicated the interaction of bacteriocins with phospholipids and fatty acids, respectively suggesting membrane-acting nature of these bacteriocins. Further, microscopic observation of bacteriocin-treated vesicles showed several damages indicating the interaction of bacteriocins. These findings suggest that the PDA vesicles may be used as bio-mimetic sensor for the detection of bacteriocins produced by several probiotics in food and therapeutic applications.

Transcriptome analysis of liver elucidates key immune-related pathways in Nile tilapia Oreochromis niloticus following infection with tilapia lake virus.

Nile tilapia (Oreochromis niloticus) is one of the most important aquaculture species farmed worldwide. However, the recent emergence of tilapia lake virus (TiLV) disease, also known as syncytial hepatitis of tilapia, has threatened the global tilapia industry. To gain more insight regarding the host response against the disease, the transcriptional profiles of liver in experimentally-infected and control tilapia were compared. Analysis of RNA-Seq data identified 4640 differentially expressed genes (DEGs), which were involved among others in antigen processing and presentation, MAPK, apoptosis, necroptosis, chemokine signaling, interferon, NF-kB, acute phase response and JAK-STAT pathways. Enhanced expression of most of the DEGs in the above pathways suggests an attempt by tilapia to resist TiLV infection. However, upregulation of some of the key genes such as BCL2L1 in apoptosis pathway; NFKBIA in NF-kB pathway; TRFC in acute phase response; and SOCS, EPOR, PI3K and AKT in JAK-STAT pathway and downregulation of the genes, namely MAP3K7 in MAPK pathway; IFIT1 in interferon; and TRIM25 in NF-kB pathway suggested that TiLV was able to subvert the host immune response to successfully establish the infection. The study offers novel insights into the cellular functions that are affected following TiLV infection and will serve as a valuable genomic resource towards our understanding of susceptibility of tilapia to TiLV infection.

Endoscopic Third Ventriculostomy in Infants Less than One Year of Age: A Short Series of 14 Cases.

BACKGROUND: Endoscopic third ventriculostomy (ETV) is currently considered as an alternative to cerebrospinal fluid (CSF) shunt systems in the treatment of obstructive hydrocephalus. This procedure allows the CSF to drain in the basal cisterns and reabsorbed by arachnoid granulations, and avoiding implantation of exogenous material. AIMS AND OBJECTIVES: The purpose of this study was to assess the success rate of ETV in infants less than 1 year of age with congenital noncommunicating hydrocephalus. MATERIAL AND METHODS: This study was a 2-year prospective study from August 2017 to July 2019. ETVs were performed in 14 patients younger than 1 year with diagnosis of noncommunicating hydrocephalous. A failure was defined as the need for shunt implantation after ETV. Phase-contrast MRI of the brain was done after 6 months to see patency of ETV fenestration and CSF flow through ventriculostomy. RESULTS: ETV was tried in 18 patients and successfully performed in 14 patients. Out of the 14 patients, shunt implantation after ETV was performed in 3 patients (failed ETV). In the successful cases, etiology was idiopathic aqueductal stenosis in 8, shunt complications in 2, and 1 case was a follow-up case of occipital encephalocele; the mean age was 7.7 months (range 3-12). In the 3 failed cases, etiology was aqueductal stenosis, mean age was 7.6 months (range 3-11). In all ETVs, failed patients MPVP shunting was done. Follow-up of nonshunted patients was done from 6 to 24 months (mean 15 months). There was no mortality or permanent morbidity noted following ETV. CONCLUSION: ETV is a good surgical procedure for less than 1-year-old children.

Effect of coexisting ions on adsorptive removal of arsenate by Mg-Fe-(CO3) LDH: multi-component adsorption and ANN-based multivariate modeling.

The adsorptive removal of a pollutant from water is significantly affected by the presence of coexisting ions with various concentrations. Here, we have studied adsorption of arsenate [As(V)] by calcined Mg-Fe-(CO3)-LDH in the presence of different cations (Mg2+, Na+, K+, Ca2+, and Fe3+) and anions (CO32‒, Cl‒, PO43‒, SO42‒, and NO3‒) with their different concentrations to simulate the field condition. The experimental results indicated that Ca2+, Mg2+, and Fe3+ have a synergistic effect on removal efficiency of As(V), whereas PO43‒ and CO32‒ ions have a significant antagonistic impact. Overall, the order of inhibiting effect of coexisting anions on adsorption of As(V) was arrived as NO3-˂Cl-

Transcription factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome. Spontaneous remission of FSGS is rare and steroid-resistant FSGS frequently progresses to renal failure. Many inheritable forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. Here, we show that a basic leucine zipper transcription factor, MafB, protects against FSGS. MAFB expression was found to be decreased in the podocytes of patients with FSGS. Moreover, conditional podocyte-specific MafB-knockout mice developed FSGS with massive proteinuria accompanied by depletion of the slit diaphragm-related proteins (Nphs1 and Magi2), and the podocyte-specific transcription factor Tcf21. These findings indicate that MafB plays a crucial role in the pathogenesis of FSGS. Consistent with this, adriamycin-induced FSGS and attendant proteinuria were ameliorated by MafB overexpression in the podocytes of MafB podocyte-specific transgenic mice. Thus, MafB could be a new therapeutic target for FSGS.

Phenotypic analysis of mice carrying human-type MAFB p.Leu239Pro mutation.

The transcription factor, MafB, plays important role in the differentiation and functional maintenance of various cells and tissues, such as the inner ear, kidney podocyte, parathyroid gland, pancreatic islet, and macrophages. The rare heterozygous substitution (p.Leu239Pro) of the DNA binding domain in MAFB is the cause of Focal Segmental Glomerulosclerosis associated with Duane Retraction Syndrome, which is characterized by impaired horizontal eye movement due to cranial nerve maldevelopment in humans. In this research, we generated mice carrying MafB p.Leu239Pro (Mafbmt/mt) and retrieved their tissues for analysis. As a result, we found that the phenotype of Mafbmt/mt mouse was similar to that of the conventional Mafb deficient mouse. This finding suggests that the Leucine residue at 239 in the DNA binding domain plays a key role in MafB function and could contribute to the diagnosis or development of treatment for patients carrying the MafB p.Leu239Pro missense variant.

Transcription factor MafB is a marker of tumor-associated macrophages in both mouse and humans.

The transcription factor MafB is specifically expressed in macrophages. We have recently demonstrated that MafB is expressed in anti-inflammatory alternatively activated M2 macrophages in vitro. Tumor-associated macrophages (TAMs) are a subset of M2 type macrophages that can promote immunosuppressive activity, induce angiogenesis, and promote tumor cell proliferation. To examine whether MafB express in TAMs, we analyzed green fluorescent protein (GFP) expression in Lewis lung carcinoma tumors of MafB-GFP knock-in heterozygous mice. FACS analysis demonstrated GFP fluorescence in cells positive for macrophage-markers (F4/80, CD11b, CD68, and CD204). Moreover, quantitative RT-PCR analysis with F4/80+GFP+ and F4/80+GFP- sorted cells showed that the GFP-positive macrophages express IL-10, Arg-1, and TNF-α, which were known to be expressed in TAMs. These results indicate that MafB is expressed in TAMs. Furthermore, immunostaining analysis using an anti-MAFB antibody revealed that MAFB is expressed in CD204-and CD68-positive macrophages in human lung cancer samples. In conclusion, MafB can be a suitable marker of TAMs in both mouse and human tumor tissues.

Understanding the Plant-microbe Interactions in CRISPR/CAS9 Era: Indeed a Sprinting Start in Marathon.

Plant-microbe interactions can be either beneficial or harmful depending on the nature of the interaction. Multifaceted benefits of plant-associated microbes in crops are well documented. Specifically, the management of plant diseases using beneficial microbes is considered to be eco-friendly and the best alternative for sustainable agriculture. Diseases caused by various phytopathogens are responsible for a significant reduction in crop yield and cause substantial economic losses globally. In an ecosystem, there is always an equally daunting challenge for the establishment of disease and development of resistance by pathogens and plants, respectively. In particular, comprehending the complete view of the complex biological systems of plant-pathogen interactions, co-evolution and plant growth promotions (PGP) at both genetic and molecular levels requires novel approaches to decipher the function of genes involved in their interaction. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 (CRISPR-associated protein 9) is a fast, emerging, precise, eco-friendly and efficient tool to address the challenges in agriculture and decipher plant-microbe interaction in crops. Nowadays, the CRISPR/CAS9 approach is receiving major attention in the field of functional genomics and crop improvement. Consequently, the present review updates the prevailing knowledge in the deployment of CRISPR/CAS9 techniques to understand plant-microbe interactions, genes edited for the development of fungal, bacterial and viral disease resistance, to elucidate the nodulation processes, plant growth promotion, and future implications in agriculture. Further, CRISPR/CAS9 would be a new tool for the management of plant diseases and increasing productivity for climate resilience farming.