Total Synthesis and Determination of the Absolute Configuration of Berkeleylactone I.

Herein, we report the first total synthesis of berkeleylactone I and its 12S diastereomer. Consequently, this chemical synthesis allowed us to establish the unknown absolute stereochemistry at the C-12 center as 12R, which was unidentified by the isolation group. This synthetic approach includes several critical reactions, such as the Sharpless asymmetric dihydroxylation, Baran's Ni-catalyzed alkyl-alkyl cross-coupling reaction, Brown allylation, Mitsunobu reaction, and ring-closing metathesis, as key steps.

Shaping the Future of Obesity Treatment: In Silico Multi-Modeling of IP6K1 Inhibitors for Obesity and Metabolic Dysfunction.

Recent research has uncovered a promising approach to addressing the growing global health concern of obesity and related disorders. The inhibition of inositol hexakisphosphate kinase 1 (IP6K1) has emerged as a potential therapeutic strategy. This study employs multiple ligand-based in silico modeling techniques to investigate the structural requirements for benzisoxazole derivatives as IP6K1 inhibitors. Firstly, we developed linear 2D Quantitative Structure-Activity Relationship (2D-QSAR) models to ensure both their mechanistic interpretability and predictive accuracy. Then, ligand-based pharmacophore modeling was performed to identify the essential features responsible for the compounds' high activity. To gain insights into the 3D requirements for enhanced potency against the IP6K1 enzyme, we employed multiple alignment techniques to set up 3D-QSAR models. Given the absence of an available X-ray crystal structure for IP6K1, a reliable homology model for the enzyme was developed and structurally validated in order to perform structure-based analyses on the selected dataset compounds. Finally, molecular dynamic simulations, using the docked poses of these compounds, provided further insights. Our findings consistently supported the mechanistic interpretations derived from both ligand-based and structure-based analyses. This study offers valuable guidance on the design of novel IP6K1 inhibitors. Importantly, our work exclusively relies on non-commercial software packages, ensuring accessibility for reproducing the reported models.

A conserved nutrient responsive axis mediates autophagic degradation of miRNA-mRNA hybrids in blood cell progenitors.

In animals, microRNAs are amongst the primary non-coding RNAs involved in regulating the gene expression of a cell. Most mRNAs in a cell are targeted by one or many miRNAs. Although several mechanisms can be attributed to the degradation of miRNA and mRNA within a cell, but the involvement of autophagy in the clearance of miRNA and its target mRNA is not known. We discover a leucine-responsive axis in blood cell progenitors that can mediate an autophagy-directed degradation of miRNA-bound mRNA in Drosophila melanogaster and Homo sapiens. This previously unknown miRNA clearance axis is activated upon amino acid deprivation that can traffic miRNA-mRNA-loaded Argonaute for autophagic degradation in a p62-dependent manner. Thus, our research not only reports a novel axis that can address the turnover of a catalytically active miRISC but also elucidates a slicer-independent mechanism through which autophagy can selectively initiate the clearance of target mRNA.

Total Synthesis, Revised Structure, and Biological Evaluation of Elgonene B and Analogues.

Herein, we report the first total synthesis of elgonene B and its congeners, thus resulting in a revision of the configuration at the C-6 carbon of the originally proposed structure of elgonene B. This synthetic approach demonstrates the utility of several important reactions such as the chiral oxazaborolidinium ion-catalyzed Diels-Alder reaction, Ando's Horner-Wadsworth-Emmons olefination, and the intermolecular Nozaki-Hiyama-Kishi reaction as key steps. Additionally, the study explores the cytotoxic and antibacterial activities of elgonene B and its congeners (1-4).

A Case of Naevoid Blaschkoid Psoriasis in a Two-Year-Old Child.

Psoriasis is a chronic, immune-mediated skin disorder characterised by well-demarcated erythematous plaque with micaceous scale. Naevoid Blaschkoid psoriasis is an unusual subtype that occurs along Blaschko lines. A two-year-old boy presented with erythematous scaly lesions distributed along the lines of Blaschko over the bilateral upper limb, the front of the chest, back, and the right lower limb. The lesions appeared four months ago and slowly progressed. There was no history of trauma, no skin lesions in other parts of the body, and no significant family history. Nail and mucosa were normal. Histopathology showed psoriasiform dermatitis with characteristics of psoriasis. The child was treated with topical clobetasol propionate 0.05% cream. Naevoid Blaschkoid psoriasis, in the absence of psoriatic lesion elsewhere on the body, is a rare manifestation. It has striking similarity with inflammatory linear verrucous epidermal nevus (ILVEN), both clinically and histologically. Naevoid psoriasis usually presents late, is asymptomatic or mildly pruritic, progresses rapidly, and responds favourably to antipsoriatic treatment. In contrast, ILVEN presents early, is intensely pruritic, slowly progressive, and is usually refractory to antipsoriatic treatment. Histologically, ILVEN demonstrates abruptly alternating areas of hypergranulosis with orthokeratosis, and parakeratosis with agranulosis. An inflammatory infiltrate is present in the upper dermis. Psoriasis presents with papillomatosis, acanthosis, and parakeratosis with absent or minimal granular layer. Immunohistochemical staining can be done in such doubtful cases. Involucrin would be detectable in psoriasis, but it is absent in ILVEN. Pathogenesis of linear psoriasis is unknown but might be explained by the concept of genetic mosaicism. Although rare, there have been a few reported cases of linear psoriasis occurring in early childhood.

Evaluation of morphine, methadone, digoxin, and dronabinol poisoning during the years 2017 to 2019 in Ilam, Iran.

Background: Every year, drug poisoning is the most prevalent reason for referring patients to medical centers. This study aimed to evaluation of morphine, methadone, digoxin, and dronabinol poisoning in Shahid Mostafa Khomeini Hospital in Ilam. Methods: In this In this Cross-sectional study, patient samples suspected of morphine, methadone, digoxin, and dronabinol poisoning referred to the toxicology laboratory of Ilam University of Medical Sciences were analyzed using the HPLC method, and the results were analysed using SPSS software. Results: Results showed that the percentage of drug use is greater in men than in women. The highest percentage of morphine and methadone poisonings were detected in those under the age of 40, whereas the highest percentage of digoxin poisonings were recorded in those over the age of 80. As a result, the average age of digoxin users was substantially greater in men than in women. Methadone consumers showed significantly greater blood levels than others. In addition, there was a significant difference (P<0.01) in blood levels between men and women who used morphine. Conclusion: In general, it is important to understand the status of drug poisoning with drugs such as morphine, methadone, digoxin, and dronabinol, as well as the prognosis associated with the treatment process of such poisoning.

Smart bio-nano interface derived from zein protein as receptors for biotinyl moiety.

Proteinaceous, tunable nanostructures of zein (prolamine of corn) were developed as biotinyl-specific receptors using a molecular imprinting technique. Sacrificial templates, such as latex beads (LB3) and anodized alumina membrane (AAM), have been used to control nanostructural patterns in biotin-imprinted zein (BMZ). Briefly, a methanolic solution of the zein-biotin complex was drop cast upon a self-organized LB3 and AAM templates on Au/quartz surfaces. Subsequent dissolution of these sacrificial templates affords highly oriented, predetermined, and uniformly grown hyperporous (300 nm) and nanowires (150 nm) motifs of zein (BMZ-LB3 and BMZ-AAM), as shown by scanning electron microscopy (SEM). Selective extraction of biotin molecular template cast-off site-selective biotin imprints within these zein nanostructures complementary to biotinyl moieties. Alternatively, biotin-imprinted zein nanoparticles (BMZ-Np) and thin film (BMZ-MeOH) were prepared by coacervation and drop casting methods, respectively. Density functional theoretical (DFT) studies reveal strong hydrogen-bonded interaction of biotin with serine and glutamine residues of zein. Quartz crystal microbalance (QCM) studies show remarkable sensitivity of the hyperporous-BMZ-LB3 and nanowires of BMZ-AAM towards biotin derivative (biotin methyl ester) by five (24.75 ± 1.34 Hz/mM) and four (18.19 ± 0.75 Hz/mM) times, respectively, higher than the BMZ-MeOH. Enhanced permeability features of the zein nanostructures, when templated with LB3, enable the QCM detection of biotin- or its derivatives down to 12.9 ng mL-1 from dairy products (Kefir). The outcome of this study shall be a key aspect in interfacing biological materials with micro-/nano-sensors and electronic devices for detecting pertinent analytes using sustainably developed biopolymer-based nanostructures.

Capsicum annuum L. and its bioactive constituents: A critical review of a traditional culinary spice in terms of its modern pharmacological potentials with toxicological issues.

Capsicum annuum L., commonly known as chili pepper, is used as an important spice globally and as a crude drug in many traditional medicine systems. The fruits of C. annuum have been used as a tonic, antiseptic, and stimulating agent, to treat dyspepsia, appetites, and flatulence, and to improve digestion and circulation. The article aims to critically review the phytochemical and pharmacological properties of C. annuum and its major compounds. Capsaicin, dihydrocapsaicin, and some carotenoids are reported as the major active compounds with several pharmacological potentials especially as anticancer and cardioprotectant. The anticancer effect of capsaicinoids is mainly mediated through mechanisms involving the interaction of Ca2+ -dependent activation of the MAPK pathway, suppression of NOX-dependent reactive oxygen species generation, and p53-mediated activation of mitochondrial apoptosis in cancer cells. Similarly, the cardioprotective effects of capsaicinoids are mediated through their interaction with cellular transient receptor potential vanilloid 1 channel, and restoration of calcitonin gene-related peptide via Ca2+ -dependent release of neuropeptides and suppression of bradykinin. In conclusion, this comprehensive review presents detailed information about the traditional uses, phytochemistry, and pharmacology of major bioactive principles of C. annuum with special emphasis on anticancer, cardioprotective effects, and plausible toxic adversities along with food safety.

Polarization-Multiplexed Incoherent Broadband Surface Plasmon Resonance: A New Analytical Strategy for Plasmonic Sensing.

Surface plasmon resonance (SPR) is an interfacial phenomenon, and the plasmonic sensors are based on the optical excitation of the collective oscillations of free electrons at a metal-dielectric interface. Here, we present the new development of an incoherent broadband (IBB)-SPR probe combining the wavelength interrogation technique with polarization-multiplexing (PM). The performance characteristics of the so-called PMIBB-SPR strategy was validated for the detection of nonenzymatic aqueous urea samples as a representative example for plasmonic sensing with an excellent wavelength and phase sensitivities of 0.1363 nm/mM and 10.34597 mM/deg, respectively. We further explored the missing link between plasmonic polariton resonance (PPR) and polarization modulation via the measurements of the Stokes parameters of the reflected light. This deepens our understanding of the fundamentals of polarization-multiplexed SPR phenomenon at the interface. This study thus paves the way to develop a new-generation analytical technique with the aim of tracking various real-time chemical and biological molecular interactions occurring at the interfaces.

Total synthesis of proposed elgonene C and its (4R,5R)-diastereomer.

The total synthesis of the proposed elgonene C (1) and its (4R,5R)-diastereomer (1a) has been achieved using a second-generation oxazaborolidinium ion-catalysed Diels-Alder reaction, Sharpless asymmetric dihydroxylation, and a Ni-catalysed cross-carboxyl coupling reaction via redox-active ester (RAE) formation as key reactions. The spectral and analytical data for our synthetic compounds 1 and 1a do not match the isolation data provided by Stadler et al. which indicates that structural revision is required for the proposed elgonene C.

Physiological ROS controls Upd3-dependent modeling of ECM to support cardiac function in Drosophila.

Despite their highly reactive nature, reactive oxygen species (ROS) at the physiological level serve as signaling molecules regulating diverse biological processes. While ROS usually act autonomously, they also function as local paracrine signals by diffusing out of the cells producing them. Using in vivo molecular genetic analyses in Drosophila, we provide evidence for ROS-dependent paracrine signaling that does not entail ROS release. We show that elevated levels of physiological ROS within the pericardial cells activate a signaling cascade transduced by Ask1, c-Jun N-terminal kinase, and p38 to regulate the expression of the cytokine Unpaired 3 (Upd3). Upd3 released by the pericardial cells controls fat body-specific expression of the extracellular matrix (ECM) protein Pericardin, essential for cardiac function and healthy life span. Therefore, our work reveals an unexpected inter-organ communication circuitry wherein high physiological levels of ROS regulate cytokine-dependent modulation of cardiac ECM with implications in normal and pathophysiological conditions.

Traditional uses, phytochemistry, and pharmacology of genus Vitex (Lamiaceae).

Vitex, the genus of the family Lamiaceae, comprises of about 230 species mostly distributed in the warm regions of Europe and temperate regions of Asia. Several Vitex species have been used as folk medicine in different countries for the treatment of various kinds of diseases and ailments. The main aim of this review is to collect and analyze the scientific information available about the Vitex species regarding their chemical constituents and pharmacological activities. The phytochemical investigation of various Vitex species has resulted in the isolation of about 556 chemical constituents belong to various chemical category viz. iridoids, diterpenoids, triterpenoids, flavonoids, lignans, sesquiterpenoids, monoterpenoids, ecdysteroids, and others. The crude extracts of different Vitex species as well as pure phytochemicals exhibited a wide spectrum of in-vitro and in-vivo pharmacological activities. In the present review, the scientific literature data on the ethnopharmacological, phytochemical, and pharmacological investigations on the genus Vitex are summarized. More attention should be given in future research to evaluate the pharmacological potential with detailed mechanism of actions for the pure compounds, extracts of plants from this genus. Moreover, their clinical study is needed to justify their use in modern medicine and to further exploring this genus for new drug discovery.

Ubx-Collier signaling cascade maintains blood progenitors in the posterior lobes of the Drosophila larval lymph gland.

Drosophila larval hematopoiesis occurs in a specialized multi-lobed organ called the lymph gland. Extensive characterization of the organ has provided mechanistic insights into events related to developmental hematopoiesis. Spanning from the thoracic to the abdominal segment of the larvae, this organ comprises a pair of primary, secondary, and tertiary lobes. Much of our understanding arises from the studies on the primary lobe, while the secondary and tertiary lobes have remained mostly unexplored. Previous studies have inferred that these lobes are composed of progenitors that differentiate during pupation; however, the mechanistic basis of this extended progenitor state remains unclear. This study shows that posterior lobe progenitors are maintained by a local signaling center defined by Ubx and Collier in the tertiary lobe. This Ubx zone in the tertiary lobe shares several markers with the niche of the primary lobe. Ubx domain regulates the homeostasis of the posterior lobe progenitors in normal development and an immune-challenged scenario. Our study establishes the lymph gland as a model to tease out how the progenitors interface with the dual niches within an organ during development and disorders.

Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection.

Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland of Drosophila senses immune challenge and reacts to it quickly through the nuclear factor-κB (NF-κB), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche cells in a Jun Kinase-dependent manner, resulting in the trapping of Hh implicated in progenitor maintenance. Notably, during infection, downregulation of Relish in the niche tilts the maintenance program toward precocious differentiation, thereby bolstering the cellular arm of the immune response.

Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila.

Over the years, Drosophila has served as a wonderful genetically tractable model system to unravel various facets of tissue-resident stem cells in their microenvironment. Studies in different stem and progenitor cell types of Drosophila have led to the discovery of cell-intrinsic and extrinsic factors crucial for stem cell state and fate. Though initially touted as the ATP generating machines for carrying various cellular processes, it is now increasingly becoming clear that mitochondrial processes alone can override the cellular program of stem cells. The last few years have witnessed a surge in our understanding of mitochondria's contribution to governing different stem cell properties in their subtissular niches in Drosophila. Through this review, we intend to sum up and highlight the outcome of these in vivo studies that implicate mitochondria as a central regulator of stem cell fate decisions; to find the commonalities and uniqueness associated with these regulatory mechanisms.

Marine Cyanobacteria and Microalgae Metabolites-A Rich Source of Potential Anticancer Drugs.

Cancer is at present one of the utmost deadly diseases worldwide. Past efforts in cancer research have focused on natural medicinal products. Over the past decades, a great deal of initiatives was invested towards isolating and identifying new marine metabolites via pharmaceutical companies, and research institutions in general. Secondary marine metabolites are looked at as a favorable source of potentially new pharmaceutically active compounds, having a vast structural diversity and diverse biological activities; therefore, this is an astonishing source of potentially new anticancer therapy. This review contains an extensive critical discussion on the potential of marine microbial compounds and marine microalgae metabolites as anticancer drugs, highlighting their chemical structure and exploring the underlying mechanisms of action. Current limitation, challenges, and future research pathways were also presented.

Goldenseal (Hydrastis canadensis L.) and its active constituents: A critical review of their efficacy and toxicological issues.

Goldenseal (Hydrastis canadensis L.) is a medicinal plant widely used in various traditional systems of medicine and as a food supplement. It has been traditionally used by Native Americans as a coloring agent and as medicinal remedy for common diseases and conditions like wounds, digestive disorders, ulcers, skin and eye ailments, and cancer. Over the years, goldenseal has become a popular food supplement in the USA and other regions. The rhizome of this plant has been used for the treatment of a variety of diseases including, gastrointestinal disorders, ulcers, muscular debility, nervous prostration, constipation, skin and eye infections, cancer, among others. Berberine is one of the most bioactive alkaloid that has been identified in different parts of goldenseal. The goldenseal extract containing berberine showed numerous therapeutic effects such as antimicrobial, anti-inflammatory, hypolipidemic, hypoglycemic, antioxidant, neuroprotective (anti-Alzheimer's disease), cardioprotective, and gastrointestinal protective. Various research finding suggest the health promoting effects of goldenseal components and their extracts. However, few studies have also suggested the possible neurotoxic, hepatotoxic and phototoxic activities of goldenseal extract and its alkaloids. Thus, large randomized, double-blind clinical studies need to be conducted on goldenseal supplements and their main alkaloids to provide more evidence on the mechanisms responsible for the pharmaceutical activity, clinical efficacy and safety of these products. Thus, it is very important to review the scientific information about goldenseal to understand about the current scenario.