ABSTRACT
Estrogen receptor-positive breast cancer represents itself as the most prevalent malignancy among postmenopausal women. One of the promising therapeutic approaches involves the use of Aromatase inhibitors, which competitively bind to Aromatase, reducing estrone and estradiol levels. While current drugs have improved survival rates, they are not without adverse effects. Consequently, this study explores the computational screening of medicinally relevant compounds derived from okra (Abelmoschus esculentus) for potential Aromatase inhibition. Molecular docking employing AMDock v1.5.2 was utilized to assess binding affinities with Aromatase (PDB:3EQM). Subsequently, in-depth molecular interactions were examined using Discovery Studio Visualizer v4.5, and the stability of docked complexes was evaluated via molecular dynamics with the GROMACS package, focusing on RMSD, RMSF, H-bond count, SASA, Free energy landscape, Principal Component Analysis and binding affinity assessment. The pharmacokinetic properties of the okra compounds were predicted using admetSAR v2.0. Our findings highlight Quercetin 3-gentiobioside as a standout candidate, demonstrating superior binding affinity (-10 kcal/mol) and an estimated Ki of 46.77 nM compared to letrozole and other okra compounds. Molecular dynamic analysis confirms the stability of Quercetin 3-gentiobioside binding in terms of H-bonds and conformational integrity. In conclusion, our computational investigation identifies Quercetin 3-gentiobioside, along with Quercetin 3-O-rutinoside and Hyperin, as promising candidates for preclinical studies in the pursuit of potential Aromatase inhibitors.Communicated by Ramaswamy H. Sarma.
ABSTRACT
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies.
Subject(s)
Endometrial Neoplasms , Societies, Medical , Child , Female , Humans , Asia , Endometrial Neoplasms/diagnosis , Medical OncologyABSTRACT
The title com-pound, C15H11NO5, is relatively planar, with the planes of the two aromatic rings being inclined to each other by 3.09â (5)°. In the crystal, mol-ecules are linked by a pair of C-Hâ¯O hydrogen bonds, forming inversion dimers, which enclose an R 2 2(16) ring motif. The dimers are linked by a further pair of C-Hâ¯O hydrogen-bonds forming ribbons enclosing R 4 4(26) ring motifs. The ribbons are linked by offset π-π inter-actions [centroid-centroid distances = 3.6754â (6)-3.7519â (6)â Å] to form layers parallel to the ac plane. Through Hirshfeld surface analyses, the d norm surfaces, electrostatic potential and two-dimensional fingerprint (FP) plots were examined to verify the contributions of the different inter-molecular contacts within the supra-molecular structure. The shape-index surface shows that two sides of the mol-ecule are involved with the same contacts in neighbouring mol-ecules, and the curvedness plot shows flat surface patches that are characteristic of planar stacking.
ABSTRACT
The title compound, C15H10ClNO5, is relatively planar with the two aromatic rings being inclined to each other by 3.56â (11)°. The central -C(=O)-C-O-C(=O)- bridge is slightly twisted, with a C-C-O-C torsion angle of 164.95â (16)°. In the crystal, mol-ecules are linked by C-Hâ¯O and C-Hâ¯Cl hydrogen bonds, forming layers parallel to the (101) plane. The layers are linked by a further C-Hâ¯O hydrogen bond, forming a three-dimensional supra-molecular structure. There are a number of offset π-π inter-actions present between the layers [inter-centroid distances vary from 3.8264â (15) to 3.9775â (14)â Å]. Hirshfeld surface analyses, the d norm surfaces, electrostatic potential and two-dimensional fingerprint plots were examined to verify the contributions of the different inter-molecular contacts within the supra-molecular structure. The shape-index surface shows that two sides of the mol-ecule are involved in the same contacts with neighbouring mol-ecules, and the curvedness plot shows flat surface patches that are characteristic of planar stacking.
ABSTRACT
The mol-ecular structure of the title compound, C17H14ClFO3, consists of a 4-chloro-3-fluoro-phenyl ring and a 3,4-di-meth-oxy-phenyl ring linked via a prop-2-en-1-one spacer. The mol-ecule has an E configuration about the C=C bond and the carbonyl group is syn with respect to the C=C bond. The F and H atoms at the meta positions of the 4-chloro-3-fluoro-phenyl ring are disordered over two orientations, with an occupancy ratio of 0.785â (3):0.215â (3). In the crystal, mol-ecules are linked via pairs of C-Hâ¯O inter-actions with an R 2 2(14) ring motif, forming inversion dimers. The dimers are linked into a tape structure running along [10] by a C-Hâ¯π inter-action. The inter-molecular contacts in the crystal were further analysed using Hirshfield surface analysis, which indicates that the most significant contacts are Hâ¯H (25.0%), followed by Câ¯H/Hâ¯C (20.6%), Oâ¯H/Hâ¯O (15.6%), Clâ¯H/Hâ¯Cl (10.7%), Fâ¯H/Hâ¯F (10.4%), Fâ¯C/Câ¯F (7.2%) and Câ¯C (3.0%).
ABSTRACT
Catharanthus roseus is a commercial source for anti-cancer terpenoid indole alkaloids (TIAs: vincristine and vinblastine). Inherent levels of these TIAs are very low, hence research studies need to focus on enhancing their levels in planta. Since primary metabolism provides precursors for specialized-metabolism, elevating the former can achieve higher amounts of the latter. Cell Wall Invertase (CWIN), a key enzyme in sucrose-metabolism catalyses the breakdown of sucrose into glucose and fructose, which serve as carbon-skeleton for specialized-metabolites. Understanding CWIN regulation could unravel metabolic-engineering approaches towards enhancing the levels of TIAs in planta. Our study is the first to characterize CWIN at gene-expression level in the medicinal plant, C. roseus. The CWINs and their inter-relationship with sucrose and TIA metabolism was studied at gene and metabolite levels. It was found that sucrose-supplementation to C. roseus leaves significantly elevated the monomeric TIAs (vindoline, catharanthine) and their corresponding genes. This was further confirmed in cross-species, wherein Nicotiana benthamiana leaves transiently-overexpressing CrCWIN2 showed significant upregulation of specialized-metabolism genes: NbPAL2, Nb4CL, NbCHS, NbF3H, NbANS, NbHCT and NbG10H. The specialized metabolites- cinnamic acid, coumarin, and fisetin were significantly upregulated. Thus, the present study provides a valuable insight into metabolic-engineering approaches towards augmenting the levels of therapeutic TIAs.
Subject(s)
Catharanthus/enzymology , Catharanthus/metabolism , Cell Wall/enzymology , Stress, Physiological , beta-Fructofuranosidase/genetics , Antioxidants/metabolism , Catharanthus/cytology , Catharanthus/genetics , Computer Simulation , Gene Expression Profiling , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Plant , Genes, Plant , Isoenzymes/genetics , Isoenzymes/metabolism , Metabolome , Organ Specificity/genetics , Phylogeny , Plant Leaves/metabolism , Solubility , Stress, Physiological/genetics , Nicotiana , beta-Fructofuranosidase/metabolismABSTRACT
In the mol-ecule of the title compound, C17H14BrFO3, the aromatic rings are tilted with respect to the enone bridge by 13.63â (14) and 4.27â (15)°, and form a dihedral angle 17.91â (17)°. In the crystal, centrosymmetrically related mol-ecules are linked by pairs of C-Hâ¯O hydrogen bonds into dimeric units, forming rings of R22(14) graph-set motif. The dimers are further connected by weak C-Hâ¯O hydrogen inter-actions, forming layers parallel to (10). Hirshfeld surface analysis shows that van der Waals inter-actions constitute the major contribution to the inter-molecular inter-actions, with Hâ¯H contacts accounting for 29.7% of the surface.
ABSTRACT
In title compound, C17H15ClO3, the dihedral angle between the benzene and chloro-phenyl rings is 18.46â (7)°. In the crystal, mol-ecules are linked by C-Hâ¯O hydrogen contacts, enclosing an R22(14) ring motif, and by a further C-Hâ¯O hydrogen contact, forming a two-dimensional supra-molecular structure extending along the direction parallel to the ac plane. Hirshfeld surface analysis shows that van der Waals inter-actions constitute the major contribution to the inter-molecular inter-actions, with Hâ¯H contacts accounting for 36.2% of the surface.
ABSTRACT
In the cation of the title salt, C20H19N2O+·Br-, the phenyl rings are inclined to one another by 38.38â (8)°, whereas the central phenyl ring and the pyridiniminium ring are almost perpendicular with a dihedral angle of 87.37â (9)°. The N+=C cationic double bond was verified by the shortened bond length of 1.337â (2)â Å. In the crystal, the Br- anion is linked to the cation by an N-Hâ¯Br hydrogen bond. C-Hâ¯O hydrogen bonds link adjacent pyridiniminium cations into inversion dimers with an R22(18) graph-set motif. These dimers are stacked in a phen-yl-phenyl T-shaped geometry through C-Hâ¯π inter-actions. A Hirshfeld surface analysis was conducted to verify the contributions of the different inter-molecular inter-actions.
ABSTRACT
The role of Melatonin in influencing diverse genes in plants has gained momentum in recent years and many reports have employed qRT-PCR for their quantification. Relative quantification of gene expression relies on accurate normalization of qRT-PCR data against a stably-expressing internal reference-gene. Although researchers have been using commonly available reference-genes to assess Melatonin-induced gene expression, but to-date, there have been no attempts to validate the reference-gene stability under Melatonin-supplementation in planta. In this study, we performed stability assessment of common reference-genes under Melatonin-supplementation and abiotic stress in leaves and seedlings of Catharanthus roseus using geNorm, NormFinder, BestKeeper, ΔCt and RefFinder algorithms. Nine candidate reference-genes were tested for stability in C. roseus (FBOX, CACS, TIP, RSP9, EXP, EXPR, SAND, F17M5, ACT) and our study inferred that while EXP and EXPR were the most-stable, F17M5 was the lowest-stable gene in the leaf-fed samples. Among seedlings of C. roseus, F17M5 and TIP were the most, while ACT was the least-stable gene. The suitability of selected stable reference-gene pairs was demonstrated by assessing the transcript levels of the Melatonin-biosynthesis gene SNAT under same conditions. Our study is the first to comprehensively analyze the stability of commonly-used reference-genes under Melatonin-induced conditions in C. roseus.
Subject(s)
Antioxidants/pharmacology , Catharanthus/metabolism , Gene Expression Regulation, Plant/drug effects , Melatonin/pharmacology , Plant Proteins/chemistry , Plant Proteins/metabolism , Catharanthus/drug effects , Gene Expression Profiling , Plant Leaves/drug effects , Plant Leaves/metabolism , Plant Proteins/genetics , Reference Standards , Seedlings/drug effects , Seedlings/metabolismABSTRACT
Plant secondary metabolites are widely used in human disease treatment; though primary metabolism provides precursors for secondary metabolism, not much has been studied to unravel the link connecting both the processes. Most common form of gene regulation interconnecting diverse metabolism occurs at the transcriptional and/or posttranscriptional level mediated by regulatory cis-elements. The present study aims at understanding the common cis-elements network connecting the major primary metabolic enzyme, cell wall invertase (CWIN) and secondary metabolism genes in Nicotiana benthamiana (N. benthamiana). The CWIN and thirty one other gene sequences were extracted from N. benthamiana genome, followed by cis-element analysis of their 5' upstream and 3' downstream region using different programs (Genomatix software suite; PLACE and PlantCARe). Comparative cis-element analysis of CWIN (N. benthamiana and other plant species) and other primary, secondary metabolism and transcription factor genes (N. benthamiana) revealed the occurrence of common stress associated cis-elements. Predominantly, AHBP, L1BX, MYBL, MADS, MYBS, GTBX, DOFF and CCAF were found in the 5' upstream region of all genes, whereas AHBP, MYBL, L1BX, HEAT, CCAF and KAN1 were largely occurring in the 3' downstream region of all genes; indicating common function of these elements in transcriptional and posttranscriptional gene regulation. Further, genomic analysis using FGENESH, GenScan and homology based methods (BlastX and BlastN) was performed on the N. benthamiana contigs harboring CWIN and PAL, in an attempt to identify genomic neighborhood genes. The 5' upstream and 3' downstream region of genes in the genomic neighborhood of CWIN and PAL were also subjected to similar cis-element analysis, and the results indicated cis-elements profile similar to CWIN, PAL and other primary, secondary metabolism and transcription factor genes. The results of evolutionary studies confirmed that the 5' upstream region of NbCWINs significantly showed more proximity to secondary metabolism genes 4CL and the redox gene SOD, followed by the phenylpropanoid pathway gene CHI. The 3' downstream regions of NbCWINs were more closely related to other plant CWINs, followed by the redox gene, SOD and primary metabolism gene FBA. Thus, the commonly found stress responsive cis-elements in our study can play a vital role in modulating key pathways of both primary and secondary metabolism; thereby postulating their role in regulating plant growth and metabolisms under unfavourable growth conditions.
Subject(s)
Genes, Plant/genetics , Phenylalanine Ammonia-Lyase/genetics , Plant Proteins/genetics , Regulatory Elements, Transcriptional , beta-Fructofuranosidase/genetics , Computer Simulation , Evolution, Molecular , Nicotiana/enzymologyABSTRACT
Plant specialized metabolites are being used worldwide as therapeutic agents against several diseases. Since the precursors for specialized metabolites come through primary metabolism, extensive investigations have been carried out to understand the detailed connection between primary and specialized metabolism at various levels. Stress regulates the expression of primary and specialized metabolism genes at the transcriptional level via transcription factors binding to specific cis-elements. The presence of varied cis-element signatures upstream to different stress-responsive genes and their transcription factor binding patterns provide a prospective molecular link among diverse metabolic pathways. The pattern of occurrence of these cis-elements (overrepresentation/common) decipher the mechanism of stress-responsive upregulation of downstream genes, simultaneously forming a molecular bridge between primary and specialized metabolisms. Though many studies have been conducted on the transcriptional regulation of stress-mediated primary or specialized metabolism genes, but not much data is available with regard to cis-element signatures and transcription factors that simultaneously modulate both pathway genes. Hence, our major focus would be to present a comprehensive analysis of the stress-mediated interconnection between primary and specialized metabolism genes via the interaction between different transcription factors and their corresponding cis-elements. In future, this study could be further utilized for the overexpression of the specific transcription factors that upregulate both primary and specialized metabolism, thereby simultaneously improving the yield and therapeutic content of plants.
ABSTRACT
The title compound, C16H26NO2 (+)·C7H5O2 (-), is a benzoate salt of the painkiller Tramadol. The six-membered cyclo-hexane ring of the cation adopts a slightly distorted chair conformation and carries OH and 3-meth-oxy-phenyl substituents at the 2-position and a protonated methyl-aza-niumylmethyl group at the 3-position. In addition, a weak intra-molecular C-Hâ¯O hydrogen bond is observed in the cation. In the crystal, weak O-Hâ¯O, N-Hâ¯O and C-Hâ¯O hydrogen bonds link the components into chains along [010]. A C-Hâ¯π contact is also observed.
ABSTRACT
The metabolic alterations caused by hyperaldosteronism are being increasingly recognized and have generated considerable interest among the medical fraternity. Hyperaldosteronism is suspected to have a pivotal role in the patho-physiology of congestive cardiac failure where it has been studied extensively. But its effects on calcium metabolism, parathyroid metabolism and renal handling of calcium are less well described. Recent experimental models have shed light into the roles played by previously unknown mechanisms in causing these metabolic alterations. We hereby report a case of primary hyperaldosteronism due to adrenal adenoma (Conn's syndrome) who presented with a myriad of clinical features including symptomatic hypocalcemia, significant weight loss along with uncontrolled hypertension for a prolonged period before eventually detected to have primary hyperaldosteronism. Surgical removal of the causative tumor resulted in prompt disappearance of all the symptoms and signs and regain of lost weight.
Subject(s)
Adrenal Cortex Neoplasms/complications , Adrenocortical Adenoma/complications , Hyperaldosteronism , Hypocalcemia/etiology , Adrenal Cortex Neoplasms/diagnosis , Adrenal Cortex Neoplasms/pathology , Adrenal Cortex Neoplasms/surgery , Adrenocortical Adenoma/diagnosis , Adrenocortical Adenoma/pathology , Adrenocortical Adenoma/surgery , Adult , Female , Humans , Hyperaldosteronism/complications , Hyperaldosteronism/etiology , Hyperaldosteronism/physiopathology , Pregnancy , Treatment OutcomeABSTRACT
OBJECTIVES: To estimate the lifetime prevalence of bipolar II disorder in children and adolescents presenting with DSM-IV major depressive disorder (MDD). METHODS: Sixty-one consecutive subjects aged < or =18 years attending the outpatient services of the Child and Adolescent Psychiatric (CAP) services of the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India with a diagnosis of MDD were evaluated using the Missouri Assessment of Genetics Interview for children (MAGIC). Two psychiatrists, one of whom was a child psychiatrist diagnosed hypomania by consensus. RESULTS: Twelve children had a past episode of hypomania (20%), which was hitherto undiagnosed clinically. LIMITATIONS: We recruited subjects from a psychiatric hospital, thus limiting the generalizability of the finding. Sample size was relatively small and assessments were cross-sectional. CONCLUSIONS: : Our study shows that bipolar II disorder is often misdiagnosed as MDD in children. The study also highlights that the chance of diagnosing bipolarity is enhanced by using semi-structured interview in routine clinical practice.
Subject(s)
Bipolar Disorder/diagnosis , Depressive Disorder, Major/diagnosis , Diagnostic Errors , Adolescent , Child , Cross-Sectional Studies , Demography , Diagnosis, Differential , Diagnostic and Statistical Manual of Mental Disorders , Female , Humans , Interviews as Topic , Male , Time FactorsABSTRACT
OBJECTIVE: To study the long-term course and outcome of juvenile obsessive-compulsive disorder (OCD). METHOD: Two to 9-year follow-up of largely self-referred, drug-naïve subjects (n = 58) by employing catch-up longitudinal design. RESULTS: The mean follow-up period was 5 years. Nearly three-fourth of the sample was adequately treated with medications. Only 21% of the subjects had clinical OCD at follow-up and 48% were in true remission (no OCD and not on treatment). Earlier age-at-onset was associated with better course and outcome. CONCLUSION: Juvenile OCD has favorable outcome. Our findings are applicable to psychiatric hospital settings in India and perhaps to the general psychiatric settings in the Western countries. Whether the better outcome in this sample is the result of differing clinical characteristics or because of true cross-cultural variation in the course needs further exploration. It is speculated that early onset OCD could be a subtype of juvenile OCD with better outcome.
Subject(s)
Cultural Characteristics , Obsessive-Compulsive Disorder/drug therapy , Obsessive-Compulsive Disorder/ethnology , Adolescent , Adult , Age of Onset , Child , Female , Follow-Up Studies , Hospitals, Psychiatric , Humans , India/ethnology , Male , Obsessive-Compulsive Disorder/psychology , Psychotherapy, Group , Treatment OutcomeABSTRACT
We report on an elderly lady in the sixth decade of life with congenital Gerbode's defect who refused surgery. She has atrial fibrillation, massive cardiomegaly and repeated episodes of lower respiratory tract infection.
Subject(s)
Heart Septal Defects, Ventricular/diagnosis , Cardiomegaly/etiology , Diagnosis, Differential , Dyspnea/etiology , Echocardiography, Transesophageal , Female , Heart Septal Defects, Ventricular/complications , Heart Sounds , Humans , Middle AgedABSTRACT
Emphysematous pyelonephritis is a rare life-threatening suppurative necrotising infection of the renal parenchyma and perirenal tissue producing abscess formation and intrarenal gas. It is almost always seen in diabetics, making it a concern of the physician. A high index of suspicion is required for diagnosis and a combined approach has significantly reduced the mortality.
Subject(s)
Emphysema , Kidney Papillary Necrosis , Diabetes Complications , Emphysema/diagnosis , Emphysema/etiology , Emphysema/mortality , Emphysema/therapy , Humans , Kidney Papillary Necrosis/diagnosis , Kidney Papillary Necrosis/etiology , Kidney Papillary Necrosis/mortality , Kidney Papillary Necrosis/therapy , PrognosisABSTRACT
The present study attempts to find a correlation between low serum B-12 levels and dementias. A total of 178 patients of dementia were seen at the cognitive disorder clinic from 1996 to 1998. Serum B-12 levels were studied in 100 patients. 15 patients (39.5%) of Alzheimer's dementia had reduced B-12 levels, while only 5 patients (13.9%) with vascular dementias and 3 patients (11.5%) with other types of dementias had reduced levels. The incidence of low serum B-12 was statistically significant in the Alzheimer's group when compared with the other groups, individually as well as combined together (p<0.05). The aetiopathogenesis and significance of these findings is discussed and the literature is reviewed.