Physiological and Molecular Mechanisms Associated with Potato Tuber Dormancy.

Tuber dormancy is an important physiological trait that impacts postharvest storage and end use qualities of potatoes. Overall, dormancy regulation of potato tuber is a complex process driven by genetic as well as environmental factors. Elucidation of the molecular and physiological mechanisms that influence different dormancy stages of tuber has wider potato breeding and industry relevant implications. Therefore, the primary objective of this review is to present the current knowledge on the diversity in tuber dormancy traits among wild relatives of potatoes and discuss how genetic and epigenetic factors contribute to the tuber dormancy. Advancements in understanding of key physiological mechanisms involved in tuber dormancy regulations, such as apical dominance, phytohormone metabolism, and oxidative stress responses were also discussed. This review highlights the impacts of common sprout suppressors on the molecular and physiological mechanisms associated with tuber dormancy and other storage qualities. Collectively, the literature suggests that significant changes in expressions of genes associated with cell cycle, phytohormone metabolism, and oxidative stress response influence initiation, maintenance, and termination of dormancy in potato tubers. Commercial sprout suppressors mainly alter the expressions of genes associated with cell cycle and stress responses and suppress sprout growth rather than prolonging the tuber dormancy.

Discovery and Development of Quinazolinones and Quinazolinediones for Ameliorating Nonalcoholic Fatty Liver Disease (NAFLD) by Modulating COP1-ATGL Axis.

E3 ubiquitin ligase, Constitutive Photomorphogenic 1 (COP1) regulates turnover of Adipose Triglyceride Lipase (ATGL), the rate-limiting lipolytic enzyme. Genetic perturbation in the COP1-ATGL axis disrupts lipid homeostasis, leading to liver steatosis. Using drug development strategies, we herein report quinazolinone and quinazolinedione based modulators for COP1-ATGL axis. Systematic SAR studies and subsequent optimization were performed by incorporating relevant functional groups at the N1, N3, C5, and C6 positions of both scaffolds. Compounds' efficacy was evaluated by multiple biological assays and ADME profiling. The lead compound 86 could increase ATGL protein expression, reduce ATGL ubiquitination and COP1 autoubiquitination, and diminish lipid accumulation in hepatocytes in the nanomolar range. Oral administration of 86 abrogated triglyceride accumulation and resolved fibrosis in preclinical Nonalcoholic Fatty Liver Disease (NAFLD) model. The study thus establishes quinazolinedione as a viable chemotype to therapeutically modulate the activity of COP1 and ATGL in relevant clinical contexts.

Catalyzing the Future of Medicinal Chemistry Research in India.

The present publication provides a comprehensive look at more than a decade (2010 to midyear of 2023) of medicinal chemistry research in India, focusing on contributions to medicinal chemistry and drug discovery from both Indian academia and industries. The work provides an overview of cutting-edge medicinal chemistry research along with the organic-transformation-based chemical research scenarios in India in the past decade. It also distinguishes areas of research as well as contributions from different federal research institutes, state universities, central universities, and private universities by their geographical locations around India. The paper takes broader stock of the situation by comparing the articles published in the two internationally acclaimed journals in the field, viz. Journal of Medicinal Chemistry and Organic Letters, which highlights the current research trends as well as the thrust needed at the grass-roots level to boost medicinal chemistry and drug discovery research in India. Finally, we believe that this discussion may create a pathway for policymakers and funding agencies to focus their efforts to motivate lesser inclined institutions as well as provide incentives to the institutions primarily involved in medicinal chemistry research, as they already have built capacity for such research.

Three new yeast species from flowers of Camellia sinensis var. assamica collected in Northern Thailand and their tannin tolerance characterization.

Our recent research study focused on Miang fermentation revealed that tannin-tolerant yeasts and bacteria play vital roles in the Miang production process. A high proportion of yeast species are associated with plants, insects, or both, and nectar is one of the unexplored sources of yeast biodiversity. Therefore, this study aimed to isolate and identify yeasts of tea flowers of Camellia sinensis var. assamica and to investigate their tannin tolerance, which is a property essential to Miang production processes. A total of 82 yeasts were recovered from a total of 53 flower samples in Northern Thailand. It was found that two and eight yeast strains were distinct from all other known species within the genera Metschnikowia and Wickerhamiella, respectively. These yeast strains were described as three new species, namely, Metschnikowia lannaensis, Wickerhamiella camelliae, and W. thailandensis. The identification of these species was based on phenotypic (morphological, biochemical, and physiological characteristics) and phylogenetic analyses of a combination of the internal transcribed spacer (ITS) regions and the D1/D2 domains of the large subunit (LSU) ribosomal RNA gene. The yeast diversity in tea flowers acquired from Chiang Mai, Lampang, and Nan provinces had a positive correlation with those acquired from Phayao, Chiang Rai, and Phrae, respectively. Wickerhamiella azyma, Candida leandrae, and W. thailandensis were the species uniquely found in tea flowers collected from Nan and Phrae, Chiang Mai, and Lampang provinces, respectively. Some of the tannin-tolerant and/or tannase-producing yeasts were associated with yeasts in the commercial Miang process and those found during Miang production, i.e., C. tropicalis, Hyphopichia burtonii, Meyerozyma caribbica, Pichia manshurica, C. orthopsilosis, Cyberlindnera fabianii, Hanseniaspora uvarum, and Wickerhamomyces anomalus. In conclusion, these studies suggest that floral nectar could support the formation of yeast communities that are beneficial for Miang production.

Topoisomerase I inhibitors: Challenges, progress and the road ahead.

Topoisomerase IB (Top1), a subcategory of DNA topoisomerase enzymes is expressed much higher in several tumor cells. Therefore, modulating the activity of Top1 in tumor cells to prevent DNA replication and subsequent cell division made it an important drug target for anticancer therapy. FDA-approved camptothecin (CPT) derivatives topotecan and irinotecan exert anticancer activity through stabilization of enzyme-mediated DNA cleavage complex forming a ternary complex between DNA-Top1-drug. However, CPT derivatives suffer from several limitations which prompted interest in the development of 'non-camptothecin' Top1 poisons as anticancer agents. This review aims to provide chronological development of different classes of Top1 poisons from both natural and synthetic sources through strategic structure-activity relationship (SAR) analysis with insight into the important structural features in different chemotypes that imparted Top1 inhibition along with the understanding of the structural basis of inhibition. This review also provides a snapshot of the application of Top1 poisons in various combination therapies in recent times. We believe such a comprehensive review is going to be beneficial for the medicinal chemistry community to design efficient drug development strategies using existing knowledge.

Elicitation of Stress-Induced Phenolic Metabolites for Antimicrobial Applications against Foodborne Human Bacterial Pathogens.

Foodborne bacterial pathogens in consumed foods are major food safety concerns worldwide, leading to serious illness and even death. An exciting strategy is to use novel phenolic compounds against bacterial pathogens based on recruiting the inducible metabolic responses of plant endogenous protective defense against biotic and abiotic stresses. Such stress-inducible phenolic metabolites have high potential to reduce bacterial contamination, and particularly improve safety of plant foods. The stimulation of plant protective response by inducing biosynthesis of stress-inducible phenolics with antimicrobial properties is among the safe and effective strategies that can be targeted for plant food safety and human gut health benefits. Metabolically driven elicitation with physical, chemical, and microbial elicitors has shown significant improvement in the biosynthesis of phenolic metabolites with antimicrobial properties in food and medicinal plants. Using the above rationale, this review focuses on current advances and relevance of metabolically driven elicitation strategies to enhance antimicrobial phenolics in plant food models for bacterial-linked food safety applications. Additionally, the specific objective of this review is to explore the potential role of redox-linked pentose phosphate pathway (PPP) regulation for enhancing biosynthesis of stress-inducible antibacterial phenolics in elicited plants, which are relevant for wider food safety and human health benefits.

Phenolic Bioactives From Plant-Based Foods for Glycemic Control.

Plant-based foods containing phenolic bioactives have human health protective functions relevant for combating diet and lifestyle-influenced chronic diseases, including type 2 diabetes (T2D). The molecular structural features of dietary phenolic bioactives allow antioxidant functions relevant for countering chronic oxidative stress-induced metabolic breakdown commonly associated with T2D. In addition to antioxidant properties, phenolic bioactives of diverse plant foods have therapeutic functional activities such as improving insulin sensitivity, reducing hepatic glucose output, inhibiting activity of key carbohydrate digestive enzymes, and modulating absorption of glucose in the bloodstream, thereby subsequently improving post-prandial glycemic control. These therapeutic functional properties have direct implications and benefits in the dietary management of T2D. Therefore, plant-based foods that are rich in phenolic bioactives are excellent dietary sources of therapeutic targets to improve overall glycemic control by managing chronic hyperglycemia and chronic oxidative stress, which are major contributing factors to T2D pathogenesis. However, in studies with diverse array of plant-based foods, concentration and composition of phenolic bioactives and their glycemic control relevant bioactivity can vary widely between different plant species, plant parts, and among different varieties/genotypes due to the different environmental and growing conditions, post-harvest storage, and food processing steps. This has allowed advances in innovative strategies to screen and optimize whole and processed plant derived foods and their ingredients based on their phenolic bioactive linked antioxidant and anti-hyperglycemic properties for their effective integration into T2D focused dietary solutions. In this review, different pre-harvest and post-harvest strategies and factors that influence phenolic bioactive-linked antioxidant and anti-hyperglycemic properties in diverse plant derived foods and derivation of extracts with therapeutic potential are highlighted and discussed. Additionally, novel bioprocessing strategies to enhance bioavailability and bioactivity of phenolics in plant-derived foods targeting optimum glycemic control and associated T2D therapeutic benefits are also advanced.

Development of a metabolically stable topoisomerase I poison as anticancer agent.

We have recently reported a new chemotype of a potent topoisomerase I poison with compound 1 as a potential anticancer chemotherapeutic agent. During further optimization, it has been observed that compound 1 suffers from high intrinsic clearance in human liver microsomes. To overcome the metabolic instability of compound 1, we report design and synthesis of metabolically stable Top1 poison 3. Newly identified Top1 poison 3 exhibits t1/2 of 69.1 min in human liver microsomes in comparison to compound 1 with t1/2 of 9.9 min. Molecular dynamic study of the newly optimized Top1 poison 3 was performed to get the insight into the stability of the binding pose in the active site. Compound 3 was able to trap DNA-Top1 cleavage complex and found to be less cytotoxic in non-cancerous cell line as compared to compound 1.

Food Diversity and Indigenous Food Systems to Combat Diet-Linked Chronic Diseases.

Improving food and nutritional diversity based on the diversity of traditional plant-based foods is an important dietary strategy to address the challenges of rapidly emerging diet- and lifestyle-linked noncommunicable chronic diseases (NCDs) of indigenous communities worldwide. Restoration of native ecosystems, revival of traditional food crop cultivation, and revival of traditional knowledge of food preparation, processing, and preservation are important steps to build dietary support strategies against an NCD epidemic of contemporary indigenous communities. Recent studies have indicated that many traditional plant-based foods of Native Americans provide a rich source of human health-relevant bioactive compounds with diverse health benefits. Based on this rationale of health benefits of traditional plant-based foods, the objective of this review is to present a state-of-the-art comprehensive framework for ecologically and culturally relevant sustainable strategies to restore and integrate the traditional plant food diversity of Native Americans to address the NCD challenges of indigenous and wider nonindigenous communities worldwide.

Metabolic stimulation of phenolic biosynthesis and antioxidant enzyme response in dark germinated barley (Hordeum vulgare L.) sprouts using bioprocessed elicitors.

Sprouting and seed elicitor treatments stimulate the biosynthesis of health relevant phenolic bioactives in plants partly by upregulating proline-associated pentose phosphate pathway (PAPPP). This study investigated the upregulation of PAPPP-linked and antioxidant enzyme associated metabolic responses in elicitor-treated barley (Hordeum vulgare L.) sprouts previously established with stimulation of health relevant phenolic bioactives. Barley seeds were treated with bioprocessed elicitors marine protein hydrolysates (GroPro®, GP) and soluble chitosan oligosaccharide and germinated under dark conditions. Upregulation of PAPPP and subsequent stimulation of phenolic biosynthesis and antioxidant enzyme responses were monitored at day 2, 4, and 6 of sprouting. High PAPPP-linked antioxidant enzyme responses were observed at early stages of germination with selected doses of GP treatments, especially in cv. Pinnacle. Total soluble phenolic content remained at higher level, while guaiacol peroxidase activity increased over the course of sprouting indicating increased phenolic polymerization to support structural needs of sprouts.

Evaluation of phenolic antioxidant-linked in vitro bioactivity of Peruvian corn (Zea mays L.) diversity targeting for potential management of hyperglycemia and obesity.

Peruvian corn biodiversity is one of the highest in the world and may represent an important natural source of health relevant phenolic bioactive compounds whose potential needs to be investigated. This study investigated twenty-two Peruvian corn samples corresponding to five corn races (Arequipeño, Cabanita, Kculli, Granada and Coruca) in relation to their total phenolic contents (TPC), anthocyanin contents, Ultra-Performance Liquid Chromatography (UPLC) phenolic profiles and antioxidant capacity (ABTS and ORAC methods). Subsequently using both free and cell-wall bound phenolic fractions their health relevance targeting hyperglycemia (α-glucosidase and α-amylase inhibition) and obesity (lipase inhibition) potentials was evaluated using in vitro assay models. Antioxidant capacity and TPC were high in bound fractions from yellow-colored races in contrast to the purple-colored race (Kculli) which had high TPC (mainly anthocyanins) and antioxidant capacity in the free form. The major phenolic acids detected by UPLC were ferulic and p-coumaric acids. High α-glucosidase (32.5-76.1%, 25 mg sample dose) and moderate α-amylase inhibitory activities (13.6-29.0%, 250 mg sample dose) were found in all free fractions, but only samples from the Kculli race had lipase inhibitory activity (58.45-92.16%, 12.5 mg sample dose). Principal component analysis revealed that the variability of data was affected by the race and the α-glucosidase and lipase inhibitory activities positively correlated with anthocyanins and antioxidant capacity. Some accessions of Kculli, Granada and Cabanita races are promising for future breeding strategies focused on the development of improved corn varieties targeted for the design of functional foods relevant for hyperglycemia and obesity prevention.

Discovery and Mechanistic Study of Tailor-Made Quinoline Derivatives as Topoisomerase 1 Poison with Potent Anticancer Activity.

To overcome chemical limitations of camptothecin (CPT), we report design, synthesis, and validation of a quinoline-based novel class of topoisomerase 1 (Top1) inhibitors and establish that compound 28 ( N-(3-(1 H-imidazol-1-yl)propyl)-6-(4-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine) exhibits the highest potency in inhibiting human Top1 activity with an IC50 value of 29 ± 0.04 nM. Compound 28 traps Top1-DNA cleavage complexes (Top1ccs) both in the in vitro cleavage assays and in live cells. Point mutation of Top1-N722S fails to trap compound 28-induced Top1cc because of its inability to form a hydrogen bond with compound 28. Unlike CPT, compound 28 shows excellent plasma serum stability and is not a substrate of P-glycoprotein 1 (permeability glycoprotein) advancing its potential anticancer activity. Finally, we provide evidence that compound 28 overcomes the chemical instability of CPT in human breast adenocarcinoma cells through generation of persistent and less reversible Top1cc-induced DNA double-strand breaks as detected by γH2AX foci immunostaining after 5 h of drug removal.

Understanding the riboflavin biosynthesis pathway for the development of antimicrobial agents.

Life on earth depends on the biosynthesis of riboflavin, which plays a vital role in biological electron transport processes. Higher mammals obtain riboflavin from dietary sources; however, various microorganisms, including Gram-negative pathogenic bacteria and yeast, lack an efficient riboflavin-uptake system and are dependent on endogenous riboflavin biosynthesis. Consequently, the inhibition of enzymes in the riboflavin biosynthesis pathway would allow selective toxicity to a pathogen and not the host. Thus, the riboflavin biosynthesis pathway is an attractive target for designing novel antimicrobial drugs, which are urgently needed to address the issue of multidrug resistance seen in various pathogens. The enzymes involved in riboflavin biosynthesis are lumazine synthase (LS) and riboflavin synthase (RS). Understanding the details of the mechanisms of the enzyme-catalyzed reactions and the structural changes that occur in the enzyme active sites during catalysis can facilitate the design and synthesis of suitable analogs that can specifically inhibit the relevant enzymes and stop the generation of riboflavin in pathogenic bacteria. The present review is the first compilation of the work that has been carried out over the last 25 years focusing on the design of inhibitors of the biosynthesis of riboflavin based on an understanding of the mechanisms of LS and RS. This review aimed to address the fundamental advances in our understanding of riboflavin biosynthesis as applied to the rational design of a novel class of inhibitors. These advances have been aided by X-ray structures of ligand-enzyme complexes, rotational-echo, double-resonance nuclear magnetic resonance spectroscopy, high-throughput screening, virtual screenings, and various mechanistic probes.

Natural preservatives for superficial scald reduction and enhancement of protective phenolic-linked antioxidant responses in apple during post-harvest storage.

Superficial scald during post-harvest storage is a serious problem for long-term preservation and shelf-life of some apple and pear cultivars. Development of superficial scald and related physiological disorders such as enzymatic and non-enzymatic browning are associated in part with oxidative breakdown and redox imbalance. Therefore, targeting natural antioxidants from food-grade sources as post-harvest treatment to reduce superficial scald has merit. Such natural antioxidants can potentially counter oxidation-linked damages associated with superficial scald through stimulation of antioxidant enzyme responses and biosynthesis of less-oxidized phenolics involving protective redox-linked pathway such as proline-associated pentose phosphate pathway. Based on this rationale, bioprocessed food-grade oregano extract (OX) and soluble chitosan oligosaccharide (COS) were targeted as post-harvest treatment (2 and 4 g L-1) and were compared with diphenylamine (DPA) (1 and 2 g L-1) to reduce superficial scald and to improve protective phenolic-linked antioxidant responses in "Cortland" cultivar stored at 4 °C for 15 weeks. Overall, significant reduction of superficial scald and conjugated triene was observed with DPA and OX (2 g L-1) post-harvest treatments. Furthermore, stimulation of antioxidant enzyme responses such as increases in superoxide dismutase and guaiacol peroxidase activity was also observed, but was more evident with DPA and COS treatment. Overall, results of this study indicated that critical balance of less-oxidized phenolics and antioxidant enzymes and associated anabolic PPP-linked redox regulation is essential for improving post-harvest preservation and reduction of superficial scald in apple.

Phenolic Composition and Evaluation of the Antimicrobial Activity of Free and Bound Phenolic Fractions from a Peruvian Purple Corn (Zea mays L.) Accession.

Beneficial effects on overall gut health by phenolic bioactives-rich foods are potentially due to their modulation of probiotic gut bacteria and antimicrobial activity against pathogenic bacteria. Based on this rationale, the effect of the free and bound phenolic fractions from a Peruvian purple corn accession AREQ-084 on probiotic lactic acid bacteria such as Lactobacillus helveticus and Bifidobacterium longum and the gastric cancer-related pathogen Helicobacter pylori was evaluated. The free and bound phenolic composition was also determined by ultra-performance liquid chromatography. Anthocyanins were the major phenolic compounds (310.04 mg cyanidin-3-glucoside equivalents/100 g dry weight, DW) in the free phenolic fraction along with hydroxycinnamic acids such as p-coumaric acid derivatives, followed by caffeic and ferulic acid derivatives. The bound phenolic form had only hydroxycinnamic acids such as ferulic acid, p-coumaric acid, and a ferulic acid derivative with ferulic acid being the major phenolic compound (156.30 mg/100 g DW). These phenolic compounds were compatible with beneficial probiotic lactic acid bacteria such as L. helveticus and B. longum as these bacteria were not inhibited by the free and bound phenolic fractions at 10 to 50 mg/mL and 10 mg/mL of sample doses, respectively. However, the pathogenic H. pylori was also not inhibited by both purple corn phenolic forms at same above sample doses. This study provides the preliminary base for the characterization of phenolic compounds of Peruvian purple corn biodiversity and its potential health benefits relevant to improving human gut health. PRACTICAL APPLICATION: This study provides insights that Peruvian purple corn accession AREQ-084 can be targeted as a potential source of health-relevant phenolic compounds such as anthocyanins along with hydroxycinnamic acids linked to its dietary fiber fraction. Additionally, these phenolic fractions did not affect the gut health associated beneficial bacteria nor the pathogenic H. pylori. Purple corn can be targeted for design of probiotic functional foods integrated with their anthocyanin linked-coloring properties.

Improving phenolic bioactive-linked anti-hyperglycemic functions of dark germinated barley sprouts (Hordeum vulgare L.) using seed elicitation strategy.

Sprouts of cereal grains, such as barley (Hordeum vulgare L.), are a good source of beneficial phenolic bioactives. Such health relevant phenolic bioactives of cereal sprouts can be targeted to manage chronic hyperglycemia and oxidative stress commonly associated with type 2 diabetes (T2D). Therefore improving phenolic bioactives by stimulating plant endogenous defense responses such as protective pentose phosphate pathway (PPP) during sprouting has significant merit. Based on this metabolic rationale, this study aimed to enhance phenolic bioactives and associated antioxidant and anti-hyperglycemic functions in dark germinated barley sprouts using exogenous elicitor treatments. Dark-germinated sprouts of two malting barley cultivars (Pinnacle and Celebration), treated with chitosan oligosaccharide (COS) and marine protein hydrolysate (GP), were evaluated. Total soluble phenolic content (TSP), phenolic acid profiles, total antioxidant activity (TA) and in vitro inhibitory activities of hyperglycemia relevant α-amylase and α-glucosidase enzymes of the dark germinated barley sprouts were evaluated at day 2, 4, and 6 post elicitor treatments. Overall, TSP content, TA, and α-amylase inhibitory activity of dark germinated barley sprouts decreased, while α-glucosidase inhibitory activity and gallic acid content increased from day 2 to day 6. Among barley cultivars, high phenolic antioxidant-linked anti-hyperglycemic bioactives were observed in Celebration. Furthermore, GP and COS seed elicitor treatments in selective doses improved T2D relevant phenolic-linked anti-hyperglycemic bioactives of barley spouts at day 6. Therefore, such seed elicitation approach can be strategically used to develop bioactive enriched functional food ingredients from cereal sprouts targeting chronic hyperglycemia and oxidative stress linked to T2D.

Neuropsychiatric Manifestation of Hashimoto's Encephalopathy in an Adolescent and Treatment.

Hashimoto's encephalopathy is usually underdiagnosed and untreated because of complex neuropsychiatric manifestation. We report a case of an adolescent female with Hashimoto's encephalopathy who responded well to a combination of aspirin and levothyroxine. A 16-year-old girl presented at psychiatric emergency services with a depressive episode, menstrual irregularities, and a 5-month past history of thyroid swelling. On clinical examination, she was in a euthyroid state with insignificant neurological history. However, her previous investigation revealed a hypothyroid state. Her magnetic resonance imaging findings demonstrated infarcts in the bilateral gangliocapsular region and left frontal periventricular deep white matter lesion. Ultrasonography of the thyroid and fine needle aspiration cytology confirmed lymphocytic thyroiditis. Anti-thyroid peroxidase (289 IU/ml) antibody titer was elevated (289 IU/mL). Her depressive symptoms responded well to antidepressants, mood stabilizers, nonsteroidal anti-inflammatory drugs, and levothyroxine. She remained in the euthyroid state and then in the euthymic state for 3 years. Hashimoto's encephalopathy is steroid-responsive encephalopathy. Most researchers have observed a dramatic response to steroids with or without levothyroxine. A clinician may consider aspirin as an alternative to a steroid in long-term management to avoid steroid-related side effects and contraindications.

Metabolic stimulation of plant phenolics for food preservation and health.

Plant phenolics as secondary metabolites are key to a plant's defense response against biotic and abiotic stresses. These phytochemicals are also increasingly relevant to food preservation and human health in terms of chronic disease management. Phenolic compounds from different food crops with different chemical structures and biological functions have the potential to act as natural antioxidants. Plant-based human foods are rich with these phenolic phytochemicals and can be used effectively for food preservation and bioactive enrichments through metabolic stimulation of key pathways. Phenolic metabolites protect against microbial degradation of plant-based foods during postharvest storage. Phenolics not only provide biotic protection but also help to counter biochemical and physical food deteriorations and to enhance shelf life and nutritional quality. This review summarizes the role of metabolically stimulated plant phenolics in food preservation and their impact on the prevention of oxidative stress-induced human diseases.