The Pharmacological Implications of Flavopiridol: An Updated Overview.

Flavopiridol is a flavone synthesized from the natural product rohitukine, which is derived from an Indian medicinal plant, namely Dysoxylum binectariferum Hiern. A deeper understanding of the biological mechanisms by which such molecules act may allow scientists to develop effective therapeutic strategies against a variety of life-threatening diseases, such as cancer, viruses, fungal infections, parasites, and neurodegenerative diseases. Mechanistic insight of flavopiridol reveals its potential for kinase inhibitory activity of CDKs (cyclin-dependent kinases) and other kinases, leading to the inhibition of various processes, including cell cycle progression, apoptosis, tumor proliferation, angiogenesis, tumor metastasis, and the inflammation process. The synthetic derivatives of flavopiridol have overcome a few demerits of its parent compound. Moreover, these derivatives have much improved CDK-inhibitory activity and therapeutic abilities for treating severe human diseases. It appears that flavopiridol has potential as a candidate for the formulation of an integrated strategy to combat and alleviate human diseases. This review article aims to unravel the potential therapeutic effectiveness of flavopiridol and its possible mechanism of action.

Identification and validation of reference genes in vetiver (Chrysopogon zizanioides) root transcriptome.

Vetiver [Vetiveria zizanioides (L.) Roberty] is a perennial C-4 grass traditionally valued for its aromatic roots/root essential oil. Owing to its deep penetrating web-forming roots, the grass is now widely used across the globe for phytoremediation and the conservation of soil and water. This study has used the transcriptome data of vetiver roots in its two distinct geographic morphotypes (North Indian type A and South Indian type B) for reference gene(s) identification. Further, validation of reference genes using various abiotic stresses such as heat, cold, salt, and drought was carried out. The de novo assembly based on differential genes analysis gave 1,36,824 genes (PRJNA292937). Statistical tests like RefFinder, NormFinder, BestKeeper, geNorm, and Delta-Ct software were applied on 346 selected contigs. Eleven selected genes viz., GAPs, UBE2W, RP, OSCam2, MUB, RPS, Core histone 1, Core histone 2, SAMS, GRCWSP, PLDCP along with Actin were used for qRT-PCR analysis. Finally, the study identified the five best reference genes GAPs, OsCam2, MUB, Core histone 1, and SAMS along with Actin. The two optimal reference genes SAMS and Core histone 1 were identified with the help of qbase + software. The findings of the present analyses have value in the identification of suitable reference gene(s) in transcriptomic and molecular data analysis concerning various phenotypes related to abiotic stress and developmental aspects, as well as a quality control measure in gene expression experiments. Identifying reference genes in vetiver appears important as it allows for accurate normalization of gene expression data in qRT-PCR experiments. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-023-01315-7.

Correction to: Identification and validation of reference genes in vetiver (Chrysopogon zizanioides) root transcriptome.

[This corrects the article DOI: 10.1007/s12298-023-01315-7.].

STAT signaling as a target for intervention: from cancer inflammation and angiogenesis to non-coding RNAs modulation.

As a landmark, scientific investigation in cytokine signaling and interferon-related anti-viral activity, signal transducer and activator of transcription (STAT) family of proteins was first discovered in the 1990s. Today, we know that the STAT family consists of several transcription factors which regulate various molecular and cellular processes, including proliferation, angiogenesis, and differentiation in human carcinoma. STAT family members play an active role in transducing signals from cell membrane to nucleus through intracellular signaling and thus activating gene transcription. Additionally, they are also associated with the development and progression of human cancer by facilitating inflammation, cell survival, and resistance to therapeutic responses. Accumulating evidence suggests that not all STAT proteins are associated with the progression of human malignancy; however, STAT3/5 are constitutively activated in various cancers, including multiple myeloma, lymphoma, breast cancer, prostate hepatocellular carcinoma, and non-small cell lung cancer. The present review highlights how STAT-associated events are implicated in cancer inflammation, angiogenesis and non-coding RNA (ncRNA) modulation to highlight potential intervention into carcinogenesis-related cellular processes.

Surfactant pollution, an emerging threat to ecosystem: Approaches for effective bacterial degradation.

The use of surfactants in households and industries is inevitable and so is their discharge into the environment, especially into the water bodies as effluents. Being surface-active agents, their utilization is mostly seen in soaps, detergents, personal care products, emulsifiers, wetting agents, etc. Anionic surfactants are the most used class. These surfactants are responsible for the foam and froth in the water bodies and cause potential adverse effects to both biotic and abiotic components of the ecosystem. Surfactants are capable of penetrating the cell membrane and thus cause toxicity to living organisms. Accumulation of these compounds has been known to cause significant gill damage and loss of sight in fish. Alteration of physiological and biochemical parameters of water decreases the amount of dissolved oxygen and thus affecting the entire ecosystem. Microbes utilizing surfactants as substrates for energy form the basis of the biodegradation of these compounds. The main organisms for surfactant biodegradation, both in sewage and natural waters, are bacteria. Several Pseudomonas and Bacillus spp. have shown efficient degradation of anionic surfactants namely: sodium dodecyl sulphate (SDS), linear alkylbenzene sulphonate (LAS), sodium dodecylbenzenesulphonate (SDBS). Also, several microbial consortia constituting Alcaligenes spp., Citrobacter spp., etc. have shown efficacy in the degradation of surfactants. The biodegradation efficiency studies of these microbes/microbial consortia would be of immense help in formulating better solutions for the bioremediation of surfactants and help to reduce their potential environmental hazards.

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions.

Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.

Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds.

Antibiotic resistance is one of the major growing concerns for public health. Conventional antibiotics act on a few predefined targets and, with time, several bacteria have developed resistance against a large number of antibiotics. The WHO has suggested that antibiotic resistance is at a crisis stage and identification of new antibiotics and targets could be the only approach to bridge the gap. Filamentous Temperature Sensitive-Mutant Z (Fts-Z) is one of the promising and less explored antibiotic targets. It is a highly conserved protein and plays a key role in bacterial cell division by introducing a cytokinetic Z-ring formation. In the present article, the potential of over 165 cyanobacterial compounds with reported antibiotic activity against the catalytic core domain in the Fts-Z protein of the Bacillus subtilis was studied. The identified cyanobacterial compounds were screened using the GLIDE module of Maestro v-2019-2 followed by 100-ns molecular dynamics (MD) simulation. Ranking of the potential compound was performed using dock score and MMGBSA based free energy. The study reported that the docking score of aphanorphine (-6.010 Kcalmol-1) and alpha-dimorphecolic acid (ADMA) (-6.574 Kcalmol-1) showed significant role with respect to the reported potential inhibitor PC190723 (-4.135 Kcalmol-1). A 100 ns MD simulation infers that Fts-Z ADMA complex has a stable conformation throughout the progress of the simulation. Both the compounds, i.e., ADMA and Aphanorphine, were further considered for In-vitro validation by performing anti-bacterial studies against B. subtilis by agar well diffusion method. The results obtained through In-vitro studies confirm that ADMA, a small molecule of cyanobacterial origin, is a potential compound with an antibacterial activity that may act by inhibiting the novel target Fts-Z and could be a great drug candidate for antibiotic development.

Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure-Activity Relationship.

The increase in the number of cases of type 2 diabetes mellitus (T2DM) and the complications associated with the side effects of chemical/synthetic drugs have raised concerns about the safety of the drugs. Hence, there is an urgent need to explore and identify natural bioactive compounds as alternative drugs. Protein tyrosine phosphatase 1B (PTP1B) functions as a negative regulator and is therefore considered as one of the key protein targets modulating insulin signaling and insulin resistance. This article deals with the screening of a database of polyphenols against PTP1B activity for the identification of a potential inhibitor. The research plan had two clear objectives. Under first objective, we conducted a quantitative structure-activity relationship analysis of flavonoids with PTP1B that revealed the strongest correlation (R2 = 93.25%) between the number of aromatic bonds (naro) and inhibitory concentrations (IC50) of PTP1B. The second objective emphasized the binding potential of the selected polyphenols against the activity of PTP1B using molecular docking, molecular dynamic (MD) simulation and free energy estimation. Among all the polyphenols, silydianin, a flavonolignan, was identified as a lead compound that possesses drug-likeness properties, has a higher negative binding energy of -7.235 kcal/mol and a pKd value of 5.2. The free energy-based binding affinity (ΔG) was estimated to be -7.02 kcal/mol. MD simulation revealed the stability of interacting residues (Gly183, Arg221, Thr263 and Asp265). The results demonstrated that the identified polyphenol, silydianin, could act as a promising natural PTP1B inhibitor that can modulate the insulin resistance.

Root system architecture, physiological analysis and dynamic transcriptomics unravel the drought-responsive traits in rice genotypes.

Drought is the major abiotic factors that limit crop productivity worldwide. To withstand stress conditions, plants alter numerous mechanisms for adaption and tolerance. Therefore, in the present study, 106 rice varieties were screened for drought tolerance phenotype via exposing different concentrations of polyethylene glycol 6000 (PEG) in the hydroponic nutrient medium at the time interval of 1, 3, and 7 days to evaluate the changes in their root system architecture. Further, based on root phenotype obtained after PEG-induced drought, two contrasting varieties drought-tolerant Heena and -sensitive Kiran were selected to study transcriptional and physiological alterations at the same stress durations. Physiological parameters (photosynthesis rate, stomatal conductance, transpiration), and non-enzymatic antioxidants (carotenoids, anthocyanins, total phenol content) production indicated better performance of Heena than Kiran. Comparatively higher accumulation of carotenoid and anthocyanin content and the increased photosynthetic rate was also observed in Heena. Root morphology (length, numbers of root hairs, seminal roots and adventitious roots) and anatomical data (lignin deposition, xylem area) enable tolerant variety Heena to better maintain membrane integrity and relative water content, which also contribute to comparatively higher biomass accumulation in Heena under drought. In transcriptome profiling, significant drought stress-associated differentially expressed genes (DEGs) were identified in both the varieties. A total of 1033 and 936 uniquely upregulated DEGs were found in Heena and Kiran respectively. The significant modulation of DEGs that were mainly associated with phytohormone signaling, stress-responsive genes (LEA, DREB), transcription factors (TFs) (AP2/ERF, MYB, WRKY, bHLH), and genes involved in photosynthesis and antioxidative mechanisms indicate better adaptive nature of Heena in stress tolerance. Additionally, the QTL-mapping analysis showed a very high number of DEGs associated with drought stress at AQHP069 QTL in Heena in comparison to Kiran which further distinguishes the drought-responsive traits at the chromosomal level in both the contrasting varieties. Overall, results support the higher capability of Heena over Kiran variety to induce numerous genes along with the development of better root architecture to endure drought stress.

Metastatic malignant peripheral nerve sheath tumor. A diagnostic surprise.

Malignant peripheral nerve sheath tumours (MPNSTs) are rare soft tissue tumors that arise from pre-existing plexiform neurofibromas or within a normal peripheral nerve. They are aggressive tumors with high rates of recurrence and distant metastases, the most common sites of metastasis being the lung followed by bone. A 46 year old gentleman presented with breathlessness and chest pain three years after post amputation of left thumb for an ulcerative growth. CECT thorax showed a left upper lobe mass with pleural and pericardial effusion. Within a month of presentation he worsened and succumbed to the disease. Antemortem biopsy of the left hand ulcerative growth showed features suggestive of malignant peripheral nerve sheath tumour- epithelioid variant and post mortem liver and lung biopsy showed metastasis of MPNST. The diagnosis was a malignant peripheral nerve sheath tumor with lung, liver and cardiac metastasis. This case report aims to highlight the importance of upfront aggressive multimodality local therapy for achieving local disease control in patients presenting with localised MPNST and regular follow up for early detection of relapse and metastasis.