Natural colonizers effectively restore heavy metal polluted wasteland.

In India, ∼30% of total land is degraded due to pollution, salinization, and nutrient loss. Change in soil-quality at urban waste-dumping site prior and after cow-dung amendment was compared with control agriculture soil. The soil at waste-dumping site had elevated pH, EC, temperature and lowered OC and NPK concentrations when compared to control. Polymetallic pollution of Cr, Cd, Pb, and Ni beyond permissible limits was obtained. Cow-dung amendment restored soil physicochemical properties at the waste-dumping site, with increasing soil moisture, CEC and OC; however, a slight change in soil bulk-density and heavy-metal concentration post-amendment was noted. The seven natural colonizers present at the waste-dumping site accumulated more metals in roots than shoots. Datura innoxia had maximum bioaccumulation of Cr, Calotropis procera of Cd and Ni and Parthenium hysterophorus of Pb in roots. All these plants had Bioacccumulation factor (BAfroot )>1 and translocation factor (Tf) <1 for Cd and serve as its phytostabilizer except Calotropis procera which had BAfroot >1 and Tf >1 and is identified as a phytoextractor for Cd. Cow-dung amendment alone appeared to be insufficient and additionally the revegetation of natural colonizers is recommended for effective reduction in heavy metal load and improving overall soil health at wasteland. Such eco-restoration may also minimize risks to biodiversity in India.

The novelty of the work lies in revegetation of natural colonizers at polluted wasteland to reduce heavy metal load and improve overall soil health. Calotropis procera, Datura innoxia, Parthenium hysterophorus, and S. nigrum showed maximum bioaccumulation of Cr, Cd, Pb, and Ni. The work confirms C. procera as non-edible, fast growing natural colonizer as potential phytoextractor for Cd and taken into consideration to effectively restore heavy metals polluted wasteland.

1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.

BACKGROUND: Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells. METHOD: We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo. RESULT: PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model. CONCLUSION: Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.

CDK5: an oncogene or an anti-oncogene: location location location.

Recent studies have uncovered various physiological functions of CDK5 in many nonneuronal tissues. Upregulation of CDK5 and/or its activator p35 in neurons promotes healthy neuronal functions, but their overexpression in nonneuronal tissues is causally linked to cancer of many origins. This review focuses on the molecular mechanisms by which CDK5 recruits diverse tissue-specific substrates to elicit distinct phenotypes in sixteen different human cancers. The emerging theme suggests that CDK5's role as an oncogene or anti-oncogene depends upon its subcellular localization. CDK5 mostly acts as an oncogene, but in gastric cancer, it is a tumor suppressor due to its unique nuclear localization. This indicates that CDK5's access to certain nuclear substrates converts it into an anti-oncogenic kinase. While acting as a bonafide oncogene, CDK5 also activates a few cancer-suppressive pathways in some cancers, presumably due to the mislocalization of nuclear substrates in the cytoplasm. Therefore, directing CDK5 to the nucleus or exporting tumor-suppressive nuclear substrates to the cytoplasm may be promising approaches to combat CDK5-induced oncogenicity, analogous to neurotoxicity triggered by nuclear CDK5. Furthermore, while p35 overexpression is oncogenic, hyperactivation of CDK5 by inducing p25 formation results in apoptosis, which could be exploited to selectively kill cancer cells by dialing up CDK5 activity, instead of inhibiting it. CDK5 thus acts as a molecular rheostat, with different activity levels eliciting distinct functional outcomes. Finally, as CDK5's role is defined by its substrates, targeting them individually or in conjunction with CDK5 should create potentially valuable new clinical opportunities.

Determinants and Stratification of Microvascular Complications of Type 2 Diabetes Mellitus.

Background Diabetes mellitus (DM) is a prevalent metabolic disorder characterized by high blood sugar levels. It is classified into type 1 (T1DM) and type 2 (T2DM), which have different mechanisms and complications. The global prevalence of diabetes, particularly T2DM, has increased significantly in recent decades, leading to a need for standardized data collection of macrovascular and microvascular complications to track disease progression and guide treatment options. This study aims to assess and correlate the prevalence and severity of microvascular complications in patients with T2DM. Methodology This observational, cross-sectional study was conducted at Poonam Multispeciality Hospital in Ahmedabad, India. A total of 4,123 diabetic patients admitted to the hospital were included. Information on sociodemographics and medical history was collected using standardized forms. Fundus photography and fluorescein angiography were performed to assess diabetic retinopathy, and estimated glomerular filtration rate and albumin-to-creatinine ratio were measured to evaluate renal function. Neurological examinations were conducted to score diabetic neuropathy. Chi-square tests were used to determine associations between medical history with diabetic retinopathy and nephropathy, and t-tests were used to compare diabetic neuropathy scores. Kendall's Tau correlation was used to determine correlations between diabetic retinopathy and nephropathy. P-values <0.05 were considered statistically significant. Results The overall prevalence of diabetic retinopathy, nephropathy, and neuropathy was 37.5%. Of the patients included, 47.9% had diabetic nephropathy and 28.9% had diabetic neuropathy. A significant association was observed between the severity of diabetic retinopathy and age, body mass index, duration of diabetes, and hemoglobin A1c (HbA1C) levels. Similarly, significant associations were found between these factors and the severity of diabetic nephropathy. Unpaired t-tests revealed significant differences in diabetic neuropathy examination scores based on the duration of diabetes and Hba1C levels. Moreover, correlation analysis indicated a low, positive correlation between diabetic retinopathy and diabetic nephropathy. Conclusions This study provides insights into the prevalence, severity, and associations of microvascular complications in patients with T2DM, contributing to the understanding and management of these conditions. Additionally, the research revealed a direct association between diabetic retinopathy and different stages of chronic kidney disease determined by the Kidney Disease Improving Global Outcome guidelines.

A Rare Case of Visual Hallucinations Associated With Hyponatremia.

Visual hallucinations are rare occurrences in patients presenting with hyponatremia. When they occur, the patient experiences these hallucinations with their eyes closed (vs. opened) and is insightful about the false perception. We present the case of a 64-year-old male diagnosed with hyponatremia caused by a gastrointestinal illness, which led to visual hallucinations. The patient was treated with electrolyte infusion, and the hallucinations were resolved. Detailed history-taking is significant when dealing with such cases as hallucinations to differentiate it from other causes. Hallucination caused by hyponatremia can resolve with prompt correction of sodium, and the patients can be reassured.

Design, synthesis and anticancer activity of N-aryl indolylsulfoximines: Identification of potent and selective anticancer agents.

A facile and efficient approach utilizing copper-mediated cross-coupling reaction of N-boc-3-indolylsulfoximines with aryl iodides was developed to synthesize a diverse range of N-arylated indolylsulfoximines 11a-m in excellent yields (up to 91%). The key precursors, free NH sulfoximines 9 were readily prepared by the treatment of N-boc-3-methylthioindoles 8 with a combination of IBD and ammonium carbamate. Under similar conditions NH-free indolylsulfoximine 9a was successfully prepared in gram-scale quantities. The reaction is highly chemoselective and tolerant of a wide range of functional groups. The process is environmentally friendly and is amenable to scale-up. Among the prepared N-arylated indolylsulfoximines 11a-m, compounds 11i-j (2.68-2.76 µM), 11f-g (1.9-3.7 µM) and 11k (1.28 µM) showed potent and selective cytotoxicity against 22Rv1, C4-2 and MCF7 cells, respectively. Indolylsulfoximine derivative 11l displayed a broad spectrum of activity (1.7-8.2 µM) against the tested cancer cell lines. These compounds were found to be non-cytotoxic to normal HEK293 cells, indicating their potential selectivity for cancer cells. We analysed the impact of 11l on various cellular assays to uncover its mechanism of action. Cellular assay shows that 11l increases the endogenous level of ROS, leading to the increased level of p-53 and c-jun inducing apoptosis. 11l also induced mitochondrial dysfunction, further promoting apoptotic pathways. Besides, 11l also restricts cell invasiveness, indicating that it could serve as an effective anti-metastatic agent. As oxidative stress severe F actin causing tubulin depolymerization, we examined the impact of 11l on tubulin dynamics. Accordingly, 11l treatment decreased the levels of polymerized tubulin in 22Rv1 and C4-2 cells. Although future studies are needed to determine their exact molecular target(s), our data shows that N-aryl indolylsulfoximines could serve as effective anti-cancer agents.

Comparison of the Efficacy of Light's Criteria With Serum-Effusion Albumin Gradient and Pleural Effusion Glucose.

Introduction While Light's criteria exhibit high sensitivity (98%) in detecting exudative pleural effusions, the capacity to rule out transudates is relatively limited. A previous study showed that approximately one-fifth of patients with congestive cardiac failure on diuretics also met the criteria for exudate. This study compares the diagnostic value of Light's criteria, the serum-effusion albumin gradient (SEAG) method, and pleural effusion glucose levels for accurately categorizing pleural effusion as transudate or exudate. Methodology We conducted this cross-sectional observational study in a tertiary care hospital in Ahmedabad, India. Two hundred patients with pleural effusion undergoing thoracentesis were included. Laboratory parameters measured in pleural fluid analysis included pleural fluid protein, pleural fluid lactate dehydrogenase (LDH), pleural fluid albumin, and pleural fluid glucose. Serum protein, serum LDH, and serum albumin were also collected. Mean values and standard deviations (SDs) were calculated for analysis. Results A significant difference was observed in the mean value of exudative and transudative effusions for each parameter (pleural fluid protein/serum fluid protein ratio, pleural fluid LDH/serum fluid LDH ratio, pleural fluid LDH, SEAG, and pleural fluid glucose) (P < 0.001). Light's criteria demonstrated the highest efficacy in diagnosing exudates (accuracy = 97.50%), while SEAG demonstrated the highest efficacy in diagnosing transudates (accuracy = 97.50%). Conclusion SEAG is an effective alternative diagnostic tool for identifying transudates misclassified by Light's criteria. Its use can contribute to prompt diagnosis and timely treatment of patients with pleural effusion, improving patient outcomes.

LIMK2: A Multifaceted kinase with pleiotropic roles in human physiology and pathologies.

LIMK2, a serine-specific kinase, was discovered as an actin dynamics regulating kinase. Emerging studies have shown its pivotal role in numerous human malignancies and neurodevelopmental disorder. Inducible knockdown of LIMK2 fully reverses tumorigenesis, underscoring its potential as a clinical target. However, the molecular mechanisms leading to its upregulation and its deregulated activity in various diseases largely remain unknown. Similarly, LIMK2's peptide substrate specificity has not been analyzed. This is particularly important for LIMK2, a kinase almost three decades old, as only a handful of its substrates are known to date. As a result, most of LIMK2's physiological and pathological roles have been assigned to its regulation of actin dynamics via cofilin. This review focuses on LIMK2's unique catalytic mechanism, substrate specificity and its upstream regulators at transcriptional, post-transcriptional and post-translational stages. Moreover, emerging studies have unveiled a few tumor suppressors and oncogenes as LIMK2's direct substrates, which in turn have uncovered novel molecular mechanisms by which it plays pleiotropic roles in human physiology and pathologies independent of actin dynamics.

Mesenteric inflammatory myofibroblastic tumor mimicking acute appendicitis: A case report.

Introduction: An Inflammatory myofibroblastic tumor, a neoplasm of intermediate biological potential, of the small bowel mesentery, is a rare tumor, most commonly reported in but not confined to the pediatric age group. Case presentation: This case report underlines a case of a (small bowel) mesentery IMT in an adult female presenting with recurrent symptoms similar to acute appendicitis. Discussion: It can present with symptoms similar to acute appendicitis necessitating a high index of suspicion for its prompt diagnosis. Treatment primarily includes surgical resection with recent advances in targeted therapy with tyrosine kinase inhibitors showing promising results. Conclusion: IMTs can present as clinical as well as histopathological mimickers of a variety of diseases especially in the abdomen. Prompt diagnosis requires both imaging and histopathological examination.

Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis.

Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.

Evaluation of binding of potential ADMET/tox screened saquinavir analogues for inhibition of HIV-protease via molecular dynamics and binding free energy calculations.

Developing novel drug molecules against HIV is a scientific quest necessitated by development of drug resistance against used drugs. We report comparative results of molecular dynamics simulation studies on 11 structural analogues of Saquinavir (SQV) - against HIV-protease that were earlier examined for pharmacodynamic and pharmacokinetic properties. We reported analogues S1, S5 and S8 to qualify the ADMET criterion and may be considered as potential lead molecules. In this study the designed molecules were successively docked with native HIV-protease at AutoDock. Docking scores established relative goodness of the 11 analogues against the benchmark for Saquinavir. The docked complexes were subjected to molecular dynamics simulation studies using GROMACS 4.6.2. Four parameters viz. H-bonding, RMSD, Binding energy and Protein-Ligand Distance were used for comparative analyses of the analogues relative to Saquinavir. The comparison and analysis of the results are indicative that analogues S8, S9 and S1 are promising candidates among all the analogues studied. From our earlier work and present study it is evident that among the three S8 and S1 qualify the ADMET criterion and between S1 and S8, the analogue S8 shows more target efficacy and specificity over S1 and have better molecular dynamics simulation results. Thus, of the 11 de novo Saquinavir analogues, the S8 appears to be the most promising candidate as lead molecule for HIV-protease inhibitor and is best suited for testing under biological system. Further validation of the proposed lead molecules through wet lab studies involving antiviral assays however is required.Communicated by Ramaswamy H. Sarma.

Reciprocal deregulation of NKX3.1 and AURKA axis in castration-resistant prostate cancer and NEPC models.

BACKGROUND: NKX3.1, a prostate-specific tumor suppressor, is either genomically lost or its protein levels are severely downregulated, which are invariably associated with poor prognosis in prostate cancer (PCa). Nevertheless, a clear disconnect exists between its mRNA and protein levels, indicating that its post-translational regulation may be critical in maintaining its protein levels. Similarly, AURKA is vastly overexpressed in all stages of prostate cancer (PCa), including castration-resistant PCa (CRPC) and neuroendocrine PCa (NEPC), although its transcripts are only increased in ~ 15% of cases, hinting at additional mechanisms of deregulation. Thus, identifying the upstream regulators that control AURKA and NKX3.1's levels and/or their downstream effectors offer an alternative route to inhibit AURKA and upregulate NKX3.1 in highly fatal CRPC and NEPC. AURKA and NKX3.1 have not linked to each other in any study to date. METHODS: A chemical genetic screen revealed NKX3.1 as a direct target of AURKA. AURKA-NKX3.1 cross-talk was analyzed using several biochemical techniques in CRPC and NEPC cells. RESULTS: We uncovered a reciprocal loop between AURKA and NKX3.1 in CRPC and NEPC cells. We observed that AURKA-mediated NKX3.1 downregulation is a major mechanism that drives CRPC pathogenesis and NEPC differentiation. AURKA phosphorylates NKX3.1 at three sites, which degrades it, but AURKA does not regulate NKX3.1 mRNA levels. NKX3.1 degradation drives highly aggressive oncogenic phenotypes in cells. NKX3.1 also degrades AURKA in a feedback loop. NKX3.1-AURKA loop thus upregulates AKT, ARv7 and Androgen Receptor (AR)-signaling in tandem promoting highly malignant phenotypes. Just as importantly, we observed that NKX3.1 overexpression fully abolished synaptophysin and enolase expression in NEPC cells, uncovering a strong negative relationship between NKX3.1 and neuroendocrine phenotypes, which was further confirmed be measuring neurite outgrowth. While WT-NKX3.1 inhibited neuronal differentiation, 3A-NKX3.1 expression obliterated it. CONCLUSIONS: NKX3.1 loss could be a major mechanism causing AURKA upregulation in CRPC and NEPC and vice versa. NKX3.1 genomic loss requires gene therapy, nonetheless, targeting AURKA provides a powerful tool to maintain NKX3.1 levels. Conversely, when NKX3.1 upregulation strategy using small molecules comes to fruition, AURKA inhibition should work synergistically due to the reciprocal loop in these highly aggressive incurable diseases.

LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer.

NKX3.1's downregulation is strongly associated with prostate cancer (PCa) initiation, progression, and CRPC development. Nevertheless, a clear disagreement exists between NKX3.1 protein and mRNA levels in PCa tissues, indicating that its regulation at a post-translational level plays a vital role. This study identified a strong negative relationship between NKX3.1 and LIMK2, which is critical in CRPC pathogenesis. We identified that NKX3.1 degradation by direct phosphorylation by LIMK2 is crucial for promoting oncogenicity in CRPC cells and in vivo. LIMK2 also downregulates NKX3.1 mRNA levels. In return, NKX3.1 promotes LIMK2's ubiquitylation. Thus, the negative crosstalk between LIMK2-NKX3.1 regulates AR, ARv7, and AKT signaling, promoting aggressive phenotypes. We also provide a new link between NKX3.1 and PTEN, both of which are downregulated by LIMK2. PTEN loss is strongly linked with NKX3.1 downregulation. As NKX3.1 is a prostate-specific tumor suppressor, preserving its levels by LIMK2 inhibition provides a tremendous opportunity for developing targeted therapy in CRPC. Further, as NKX3.1 downregulates AR transcription and inhibits AKT signaling, restoring its levels by inhibiting LIMK2 is expected to be especially beneficial by co-targeting two driver pathways in tandem, a highly desirable requisite for developing effective PCa therapeutics.

Engineered BcZAT12 gene mitigates salt stress in tomato seedlings.

In salt-prone areas, plant growth and productivity is adversely affected. In the present study, the ZT1-ZT6 transgenic tomato lines having BcZAT12 gene under the regulatory control of the stress inducible Bclea1 promoter were exposed to three salinity levels (50, 100 and 200 mM) at the four leaf stage for 10 days. The transgenic lines showed improved growth in stem height, leaf area, root length and shoot length under saline conditions, as compared to control. Moreover, ZT1 and ZT5 lines showed lower electrolyte leakage and decreased hydrogen peroxide formation, in combination with elevated relative water content, proline and chlorophyll levels. The enzyme activity of catalase was also enhanced in ZT1 and ZT5. These results poses the present lines as an attractive alternative for tomato cultivation in salinity-affected areas.

Phosphorylation-dependent regulation of SPOP by LIMK2 promotes castration-resistant prostate cancer.

BACKGROUND: SPOP, an E3 ubiquitin ligase adaptor, can act either as a tumour suppressor or a tumour promoter. In prostate cancer (PCa), it inhibits tumorigenesis by degrading several oncogenic substrates. SPOP is the most altered gene in PCa (~15%), which renders it ineffective, promoting cancer. The remaining PCa tumours, which retain WT-SPOP, still progress to castration-resistant (CRPC) stage, indicating that other critical mechanisms exist for downregulating SPOP. SPOP is reduced in ~94% of WT-SPOP-bearing prostate tumours; however, no molecular mechanism is known for its downregulation. METHODS: SPOP was identified as a direct target of LIMK2 using an innovative technique. The reciprocal relationship between SPOP and LIMK2 and its consequences on oncogenicity were analysed using a variety of biochemical assays. To probe this relationship in vivo, xenograft studies were conducted. RESULTS: LIMK2 degrades SPOP by direct phosphorylation at three sites. SPOP promotes LIMK2's ubiquitylation, creating a feedback loop. SPOP's degradation stabilises AR, ARv7 and c-Myc promoting oncogenicity. Phospho-resistant SPOP completely suppresses tumorigenesis in vivo, indicating that LIMK2-mediated SPOP degradation is a key event in PCa progression. CONCLUSIONS: While genomically altered SPOP-bearing tumours require gene therapy, uncovering LIMK2-SPOP relationship provides a powerful opportunity to retain WT-SPOP by inhibiting LIMK2, thereby halting disease progression.

Negative cross talk between LIMK2 and PTEN promotes castration resistant prostate cancer pathogenesis in cells and in vivo.

Androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are front-line treatments for highly aggressive prostate cancer. However, prolonged inhibition of AR triggers a compensatory activation of PI3K pathway, most often due to the genomic loss of tumor suppressor PTEN, driving progression to the castration-resistant prostate cancer (CRPC) stage, which has very poor prognosis. We uncovered a novel mechanism of PTEN downregulation triggered by LIMK2, which contributes significantly to CRPC pathogenesis. LIMK2 is a CRPC-specific target. Its depletion fully reverses tumorigenesis in vivo. LIMK2 phosphorylates PTEN at five sites, degrading and inhibiting its activity, thereby driving highly aggressive oncogenic phenotypes in cells and in vivo. PTEN also degrades LIMK2 in a feedback loop, which was confirmed in prostates from PTEN-/- and PTEN+/+ mice. LIMK2 is also the missing link between hypoxia and PTEN degradation in CRPC. This is the first study to show a feedback loop between PTEN and its regulator. Uncovering the LIMK2-PTEN loop provides a powerful therapeutic opportunity to retain the activity and stability of PTEN protein by inhibiting LIMK2, thereby halting the progression to CRPC, ADT-resistance and drug-resistance.

Examining the uptake and bioaccumulation of molybdenum nanoparticles and their effect on antioxidant activities in growing rice seedlings.

The synthesized α-MoO3 and MoS2 NPs had nanosheet and nanoflower-like structures with crystallite size of 21.34 nm and 4.32 nm, respectively. The uptake, bioaccumulation, and impact of these two Mo-NPs were studied in rice (Oryza sativa L) cv. HUR 3022 seedlings exposed to 100, 500, and 1000 ppm concentrations in hydroponics for 10 days in the growth medium. The uptake of α-MoO3 and MoS2 NPs by rice exposed to 100 ppm concentrations of NPs led to the accumulation of 7.32 ppm/4.55 ppm and 1.84 ppm/1.19 ppm in roots/shoots, respectively, as compared to controls. Unlike MoO3, more accumulation of MoS2 in roots reflect less translocation of this NP from roots to shoots. Results suggest tissue-specific distribution of NPs in rice seedlings. The increased growth and elevated protein levels in rice seedlings at 100 ppm concentrations of nanoparticles imply a stimulation in the repair mechanism at low doses indicating hormesis. MoS2 NPs treatments led to increased chlorophyll a levels suggesting it to be non-compromising with photosynthetic process in rice. The high malondialdehyde levels and altered activities of antioxidant enzymes GPX, APX, and CAT in rice seedlings exposed to α-MoO3 or MoS2 NPs indicate oxidative imbalance. Between α-MoO3 and MoS2 NPs, the former shows toxic effects as reflected from the decreased levels of photosynthetic pigments at all concentrations; however, an activation of chloroplast ROS detoxification is evident in the presence of MoS2 NPs. The BCF > 1 for both α-MoO3 and MoS2 NPs and TF of 0.6-2.0 and 0.42-0.65 suggest the latter to be more environmentally safe. In conclusion, a100 ppm MoS2 NPs concentration has low translocation and less accumulation with no significant impact on growth of rice cv. HUR 3022 seedlings and appears to be environmentally safe for future applications.

Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor.

SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis. Importantly, 85% of tumors that retain wild-type SPOP show reduced protein levels, indicating that SPOP downregulation is an essential step in CRPC progression. However, the underlying molecular mechanism remains unknown. This study uncovered the first mechanism of SPOP regulation in any type of cancer. We identified SPOP as a direct substrate of Aurora A (AURKA) using an innovative technique. AURKA directly phosphorylates SPOP at three sites, causing its ubiquitylation. SPOP degradation drives highly aggressive oncogenic phenotypes in cells and in vivo including stabilizing AR, ARv7 and c-Myc. Further, SPOP degrades AURKA via a feedback loop. SPOP upregulation is one of the mechanisms by which enzalutamide exerts its efficacy. Consequently, phospho-resistant SPOP fully abrogates tumorigenesis and EMT in vivo, and renders CRPC cells sensitive to enzalutamide. While genomic mutations of SPOP can be treated with gene therapy, identification of AURKA as an upstream regulator of SPOP provides a powerful opportunity for retaining WT-SPOP in a vast majority of CRPC patients using AURKA inhibitors ± enzalutamide, thereby treating the disease and inhibiting its progression.

Aurora Kinase A-YBX1 Synergy Fuels Aggressive Oncogenic Phenotypes and Chemoresistance in Castration-Resistant Prostate Cancer.

Multifunctional protein YBX1 upregulation promotes castration-resistant prostate cancer (CRPC). However, YBX1 protein abundance, but not its DNA status or mRNA levels, predicts CRPC recurrence, although the mechanism remains unknown. Similarly, the mechanism by which YBX1 regulates androgen receptor (AR) signaling remains unclear. We uncovered the first molecular mechanism of YBX1 upregulation at a post-translational level. YBX1 was identified as an Aurora Kinase-A (AURKA) substrate using a chemical screen. AURKA phosphorylates YBX1 at two key residues, which stabilizes it and promotes its nuclear translocation. YBX1 reciprocates and stabilizes AURKA, thereby initiating a synergistic loop. Notably, phospho-resistant YBX1 is dominant-negative and fully inhibits epithelial to mesenchymal transition, chemoresistance, drug-resistance and tumorigenesis in vivo. Unexpectedly, we further observed that YBX1 upregulates AR post-translationally by preventing its ubiquitylation, but not by increasing its transcription as reported before. Uncovering YBX1-mediated AR stabilization is highly significant due to AR's critical role in both androgen-sensitive prostate cancer and CRPC. As YBX1 inhibitors are unknown, AURKA inhibitors provide a potent tool to degrade both YBX1 and AR simultaneously. Finally, this is the first study to show a reciprocal loop between YBX1 and its kinase, indicating that their concomitant inhibition will be act synergistically for CRPC therapy.