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Background: Heart failure is a clinical syndrome characterized by decreased cardiac output, leading to systemic organ hypoxia and resulting in dyspnea, pulmonary edema, organ congestion, and pleural effusion. Owing to the diverse clinical manifestations of heart failure, early diagnosis can be challenging, and misdiagnosis may occur occasionally. The use of echocardiography and blood brain natriuretic peptide can aid in obtaining a more accurate diagnosis. Case presentation: This article presents two case reports of patients who were misdiagnosed with acute cholecystitis. Both patients were young Mongolia males (age 26 and 39 years) who presented to the emergency department with acute upper abdominal pain, abdominal ultrasound revealed gallbladder enlargement, and blood tests suggested mild elevation of bilirubin levels. However, despite the absence of procalcitonin and C-reactive protein elevation, the patients were admitted to the general surgical department with a diagnosis of "acute cholecystitis." Both patients were given treatment for cholecystitis, but their vital signs did not improve, while later examinations confirmed heart failure. After treatment with diuretics and cardiac glycosides, both patients' symptoms were relieved. Conclusion: We aim to highlight the clinical manifestations of heart failure and differentiate it from rare conditions such as acute cholecystitis. Physicians should make accurate diagnoses on the basis of physical examinations, laboratory testing and imaging, and surveys while avoiding diagnostic heuristics or mindsets. By sharing these two case reports, we hope to increase awareness to prevent potential complications and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Secondary metabolites of several plants, including esculin and digitoxin, which are cardiac glycosides, were previously employed for their therapeutic effects. The current study aims to investigate the functions of the main Na+ /K+ transport inhibitor digitoxin and the antioxidant esculin for enhancing flax plant growth and production under salinity. Methodology: Flax plants were irrigated with distilled water supplemented with 0.0 and 5000 mg/L salt solution starting from 15 DAS from sowing. Then exogenous treatment with digitoxin and esculin with 50 mg L− 1 and 100 mg L− 1 were used for this work. Results: According to the results of this work, foliar spraying of esculin or digitoxin increased the salinity tolerance of flax plants.The foliar application of either esculin or digitoxin induced an elevation in the contents of photosynthetic pigments, osmolytes including soluble sugar and proline as well as the total phenols in salt-stressed flax plants. Moreover, esculin and digitoxin in particular counteract oxidative stress by increasing the activity of antioxidant enzymes including superoxide dismutase, catalase, peroxidase, phenylalanine ammonia-lyase, and tyrosine ammonia lyase, leading to a decrease in reactive oxygen species and lipid peroxidation levels and electrolyte leakage. The efficiency of esculin and digitoxin to sustain ion homeostasis by inhibiting Na+ absorption and increasing potassium, calcium, and phosphorus in flax plants may be the reason for their protective actions towards salinity.As a consequence, esculin and digitoxin increased yield quantity and quality as shown by increases in all investigated yield criteriaas shoot height, root length, their fresh and dry weights as well asseed yield/plant (g), and 1000 seeds weight, especially those that improved the desired oil properties. Conclusion: In conclusion, this study concluded that digitoxin was more effective in inhibiting Na+ build-up and increasing flax salinity tolerance, particularly at the high investigated dose as compared to esculin. In this study, we reported the recent findings of exogenousapplication of either digitoxin or esculin glycosides which are new investigated salt alleviators never used before for improving the salt tolerance in flax plants. [ABSTRACT FROM AUTHOR]

Nanotechnology is becoming a promise for scientific advancement nowadays in areas like medicine, consumer products, energy, materials, and manufacturing. Copper oxide nanoparticles (CuO NPs) were synthesized using Ocimum lamiifolium Hochst. ex Benth and Withana somnifera (L) Dunal leaf extract via green synthetic pathway. The leaf of O. lamiifolium and W. somnifera were known to have strong antibiotic and antioxidant properties arising due to the presence of various secondary metabolites, including, flavonoids, alkaloids, saponins, tannins, cardiac glycosides, and phenolic compounds which serve as reducing, stabilizing, and capping agents for the CuO-Nanoparticles (NPs) synthesized. The biosynthesized CuO NPs were characterized based on Fourier transform infrared spectroscopy, X-ray diffraction spectroscopy, and scanning electron microscopy. O. lamiifolium and W. somnifera leaf extract mediated synthesis could produce CuO NPs with average crystallite size of 15 nm and 19 nm, respectively. The biosynthesized CuO-NPs were further examined for antibacterial activity with Gram-positive (S. aureus) and Gram-negative bacteria (E. coli and P. aeruginosa). The GZDK-CuO NPs synthesized using W. somnifera leaf extract inhibited the growth of E. coli. and P. aeruginosa largely in comparison to S. aureus. Whereas the DMAZ-CuO NPs synthesized with the help of O. lamiifolium leaf extract showed higher bacterial inhibition on E. coli compared to S. aureus and P. aeruginosa. The minimum inhibitory concentration (MIC) values of both types of NPs are also assessed on all three pathogens. The newly biosynthesized nanoparticles, thus, were found to be optional materials for inhibiting the growth of drug- resistant bacterial pathogens. [ABSTRACT FROM AUTHOR]

Na+-K+ ATPase is an integral component of cardiac sarcolemma and consists of three major subunits, namely the α-subunit with three isoforms (α1, α2, and α3), β-subunit with two isoforms (β1 and β2) and γ-subunit (phospholemman). This enzyme has been demonstrated to transport three Na and two K ions to generate a trans-membrane gradient, maintain cation homeostasis in cardiomyocytes and participate in regulating contractile force development. Na+-K+ ATPase serves as a receptor for both exogenous and endogenous cardiotonic glycosides and steroids, and a signal transducer for modifying myocardial metabolism as well as cellular survival and death. In addition, Na+-K+ ATPase is regulated by different hormones through the phosphorylation/dephosphorylation of phospholemman, which is tightly bound to this enzyme. The activity of Na+-K+ ATPase has been reported to be increased, unaltered and depressed in failing hearts depending upon the type and stage of heart failure as well as the association/disassociation of phospholemman and binding with endogenous cardiotonic steroids, namely endogenous ouabain and marinobufagenin. Increased Na+-K+ ATPase activity in association with a depressed level of intracellular Na+ in failing hearts is considered to decrease intracellular Ca2+ and serve as an adaptive mechanism for maintaining cardiac function. The slight to moderate depression of Na+-K+ ATPase by cardiac glycosides in association with an increased level of Na+ in cardiomyocytes is known to produce beneficial effects in failing hearts. On the other hand, markedly reduced Na+-K+ ATPase activity associated with an increased level of intracellular Na+ in failing hearts has been demonstrated to result in an intracellular Ca2+ overload, the occurrence of cardiac arrhythmias and depression in cardiac function during the development of heart failure. Furthermore, the status of Na+-K+ ATPase activity in heart failure is determined by changes in isoform subunits of the enzyme, the development of oxidative stress, intracellular Ca2+-overload, protease activation, the activity of inflammatory cytokines and sarcolemmal lipid composition. Evidence has been presented to show that marked alterations in myocardial cations cannot be explained exclusively on the basis of sarcolemma alterations, as other Ca2+ channels, cation transporters and exchangers may be involved in this event. A marked reduction in Na+-K+ ATPase activity due to a shift in its isoform subunits in association with intracellular Ca2+-overload, cardiac energy depletion, increased membrane permeability, Ca2+-handling abnormalities and damage to myocardial ultrastructure appear to be involved in the progression of heart failure. [ABSTRACT FROM AUTHOR]

Since ancient times, people have used medicinal plants to treat various diseases. Nerium oleander is a toxic plant due to the presence of various cardiac glycosides. Oleander, at a dose of 50 mg kg-1 inhibits Na+/K+ ATPase pump in mice. Despite being toxic, it is used in traditional medicine. Almost all of the parts of oleander plant contain various phytochemicals such as phenols, tannins, flavonoids, coumarins, sterols, triterpenes, alkaloids, and different types of cardenolides. Oleander extract has neuroprotective, sedative, and anticonvulsant properties, especially against ischemic stroke. Cardenolides like nerizoside, neritaloside, odoroside-H, and neridiginoside offer advantages when used as CNS depressants. CNS depressant action of oleander is primarily due to a rise in GABA levels. At low to moderate dose, it shows depressant activity but in high doses, body became motionless inducing tremors and lethargy. Oleanderʼs dual role of toxic and therapeutic activity raises concerns about its application. Yet due to presence of vast constituents, it can be used for modern medicine. Cardenolides showing antidepressant activity on mice. [Display omitted] • Nerium oleander is considered to be a poisonous plant. • But it contains various phytochemicals, including antioxidants, anticancer agents, CNS depressants, and anticonvulsants. • This review aims to identify the therapeutic benefits of the plant and its toxicity. [ABSTRACT FROM AUTHOR]

Background and Aims: Cardiac glycosides (CGs), traditionally used for heart failure, have shown potential as anti‐cancer agents. This study aims to explore their multifaceted mechanisms in cancer cell biology using proteome integral solubility alteration (PISA), focusing on the interaction with key proteins implicated in cellular metabolism and mitochondrial function. Methods: We conducted lysate‐based and intact‐cell PISA assays on cancer cells treated with CGs (Digoxin, Digitoxin, Ouabain) to analyze protein solubility changes. This was followed by mass spectrometric analysis and bioinformatics to identify differentially soluble proteins (DSPs). Molecular docking simulations were performed to predict protein‐CG interactions. Public data including gene expression changes upon CG treatment were re‐analyzed for validation. Results: The PISA assays revealed CGs' broad‐spectrum interactions, particularly affecting proteins like PKM2, ANXA2, SLC16A1, GOT2 and GLUD1. Molecular docking confirmed stable interactions between CGs and these DSPs. Re‐analysis of public data supported the impact of CGs on cancer metabolism and cell signaling pathways. Conclusion: Our findings suggest that CGs could be repurposed for cancer therapy by modulating cellular processes. The PISA data provide insights into the polypharmacological effects of CGs, warranting further exploration of their mechanisms and clinical potential. [ABSTRACT FROM AUTHOR]

Cardiotonic steroids are known to bind to Na+/K+-ATPase and regulate several biological processes, including the immune response. The synthetic cardiotonic steroid γ-Benzylidene Digoxin 8 (BD-8) is emerging as a promising immunomodulatory molecule, although it has remained largely unexplored. Therefore, we tested the immunomodulatory potential of BD-8 both in vitro and in vivo. Hence, primary mouse macrophages were incubated with combinations of BD-8 and the pro-inflammatory fungal protein zymosan (ZYM). Nitric oxide (NO) production was determined by Griess reagent and cytokines production was assessed by enzyme-linked immunosorbent assay. Inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), p-nuclear factor kappa B p65 (NF-κB p65), p-extracellular signal-regulated kinase (p-ERK), and p-p38 were evaluated by flow cytometry. Macrophages exposed to BD-8 displayed reduced phagocytic activity, NO levels, and production of the proinflammatory cytokine IL-1β induced by ZYM. Furthermore, BD-8 diminished the expression of iNOS and phosphorylation of NF-κB p65, ERK, and p38. Additionally, BD-8 exhibited anti-inflammatory capacity in vivo in a carrageenan-induced mouse paw edema model. Taken together, these findings demonstrate the anti-inflammatory activity of BD-8 and further reinforce the potential of cardiotonic steroids and their derivatives as immunomodulatory molecules. [ABSTRACT FROM AUTHOR]

Background: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. Results: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. Conclusion: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19. [ABSTRACT FROM AUTHOR]

Objective: Nepal's medicinal herbs are rich in cultural importance and have several uses. Senna alata, a plant belonging to the Leguminosae family, is prized for its aesthetic and therapeutic qualities. The goal of the study was to extract Senna alata leaves using several solvent macerations. Methods: The study aims to evaluate the phytochemistry, total phenolic and flavonoid levels, antioxidant qualities in vitro, anti-inflammatory effects, cytotoxicity, anti-thrombolytic potential, and antibacterial activity, a variety of methodologies were employed. Results: The extractive values of Senna alata were determined as 1.58%, 0.78%, and 5.92% in hexane, ethyl acetate, and methanol, respectively. GC-MS analysis revealed major compounds such as 3-Methylmannoside, Neophytadiene, Campesterol, and Vitamin E in the leaf extract. Qualitative phytochemical screening confirmed the presence of tannins, carbohydrates, flavonoids, cardiac glycosides, glycosides, and saponins in the methanol extract. The total phenolic and flavonoid contents were 46.36±4.5 mg GAE/g and 480.4±3.055 QE/g of dried extract, respectively. The extract exhibited significant antioxidant and anti-inflammatory activities, with IC50 values of 29.81 and 9.93, respectively. Additionally, it demonstrated cytotoxic activity with an LC50 value of 767.85 in the brine shrimp bioassay. In terms of thrombolytic activity, the extract showed clot lysis percentages of 7.89% and 10.13% at concentrations of 10 mg/ml and 25 mg/ml, respectively. Conclusion: The methanolic extract of Senna alata leaves displayed therapeutic potential, including antioxidant, anti-inflammatory, cytotoxic, thrombolytic, and antibacterial effects. The presence of several bioactive compounds, as confirmed by GC-MS analysis, further supports the plant's potential for therapeutic use. [ABSTRACT FROM AUTHOR]

Thevetia thevetioides is a species within the Apocynaceae family known for containing cardenolide-glycosides, commonly referred to as cardiac glycosides, which are characteristic of this genus. The seeds of the Thevetia species are frequently used as a model source for studying cardiac steroids, as these glycosides can be more readily extracted from the oil-rich seeds than from the plant's green tissues. In this work, the cardenolide profile of ripe and immature seeds was determined and compared to establish the main differences. Ripe seeds contain six related cardenolides and triosides, with thevetin B being the predominant component. In contrast, immature seeds exhibit a total of thirteen cardiac glycosides, including monoglycosides such as neriifolin and peruvosides A, B, and C, as well as diglycosides like thevebiosides A, B, and C. Some of these compounds have previously been identified as degradation products of more complex cardiac glycosides; however, their presence in immature seeds, as described in this study, suggests that they may serve as biosynthetic precursors to the triosides observed in mature seeds. The glycoside patterns observed via HPTLC are associated with specific chemical structures characteristic of this genus, typically featuring thevetose or acetyl-thevetose at the first position, followed by glucose or gentibiose in di- or trisaccharides, independent of the trioside aglycones identified: digitoxigenin, cannogenin, or yccotligenin. Ripe seeds predominantly contain triosides, including thevetin B, C, and A, the latter of which has not been previously reported. [ABSTRACT FROM AUTHOR]

Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro , followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC 50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types. • Patient-derived 3D models of dedifferentiated endometrial carcinoma (DDEC) were subjected to drug repurposing screen. • The drug screen identified digoxin as an effective anti-cancer drug in suppressing DDEC tumor growth. • DDEC displayed greater sensitivity to digoxin compared to non-DDEC endometrial cancer cells in vitro. • Digoxin significantly inhibited patient-derived DDEC tumor growth in vivo. • These results provide compelling preclinical evidence for the use of digoxin as systemic therapy for DDEC. [ABSTRACT FROM AUTHOR]

Euphorbia tirucalli, commonly known as the pencil cactus or milk bush plant, is used as an alternative medicine. The current study evaluated the phytochemical contents, antibacterial, anticandidal, and antisporicidal potential of the E. tirucalli methanolic extract. The antibacterial and anticandidal activity of E. tirucalli methanolic extract was determined by performing a disc diffusion assay, MIC, MBC, and MCC. The sporicidal activity was tested at different concentrations of extract and exposure times. Phytochemical analyses revealed the presence of alkaloids, saponins, cardiac glycosides, terpenoids, and tannins in E. tirucalli methanolic extract. Results demonstrated inhibition zones of the extract against Gram-positive bacteria were in range of 22.00-7.00 mm. Meanwhile, inhibition zones of the extract against Gram-negative bacteria were in range of 13.00-7.00 mm. All bacteria were inhibited with MIC values at 1.56-25.0 mg/ml and can be completely killed with MBC values of 20-200 mg/ml. Inhibition zones of E. tirucalli methanolic extract against Candida spp. were in the range of 20.00-8.00 mm. All Candida spp. were inhibited with MIC values at 1.56-100.00 mg/ml and MBC values of 100-300 mg/ml. All concentrations of the extract inhibited all Bacillus spp. spores at different exposure times. In conclusion, the methanolic extract of E. tirucalli exhibits antibacterial, anticandidal, and sporicidal activities. The findings indicated that the methanolic extract of E. tirucalli has good potential for prospective nature-based antimicrobial agents. [ABSTRACT FROM AUTHOR]

• Metabolite screening was achieved by using standard qualitative tests. • Bioactive metabolites were separated and identified by De-replication approach, coupling HPLC-ESI-QTOF-MS with MZmine 3, global natural products social molecular networking (GNPS) and METLIN Gen2. • Microwave digestion was used to extract metals for inductively coupled plasma optical emission spectroscopy (ICP-OES) analysis. • Health risk assessment was achieved by determining estimated daily intake (EDI), hazard quotients (HQ), and carcinogenic risk (CR). The bark of Entandrophragma delevoyi De Wild (E. delevoyi) is widely used in the Zambian traditional health care system as a very effective medicinal plant. Nevertheless, little is known about the phytochemicals affiliated with the ethno-pharmacological uses of the plant. Further, the heavy metals safety of consuming the plant for medicinal purposes remains unknown. In this study, metabolite profiling of the methanolic stem bark extract of E. delevoyi was performed using a de-replication approach by coupling HPLC-ESI-QTOF-MS with MZmine 3 based two molecular networking approaches, that is, GNPS (global natural products social molecular networking) and METLIN Gen2. Varieties of metabolites were tentatively identified for the first time in E. delevoyi. Health risk assessment was achieved by analysing the presence and concentration of heavy metals such as Ag, Al, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, Si, Sn, U and Zn using inductively coupled plasma optical emission spectroscopy (ICP-OES). Further, estimated daily intake (EDI), hazard quotients (HQ), and carcinogenic risk were determined. The utilization of qualitative tests to screen metabolite classes and the molecular networking tools revealed a detailed phytochemical profile of this medicinal plant species. Qualitative metabolite screening tests revealed the presence of flavonoids, alkaloids, phenolics, saponins, anthraquinones, terpenoids, steroids, cardiac glycosides, anthocyanins, and tannins in the methanol extract. LCMS2 coupled to mzmine3.6 revealed the presence of thirty-five metabolites from MoNA database. In addition, LCMS2-GNPS revealed the presence of twenty-six metabolites, and LCMS-METLIN Gen2 revealed a further sixteen compounds. Furthermore, total polyphenolic content and antioxidant (1,1-diphenyl-2-picryl-hydrazylhydrate - DPPH) capacities were assayed. Total phenolic content was 169.46 ± 0.71 mg GAE/g and total flavonoid content was 53.14 ± 1.78 mg QE/g. The crude extract had significant total polyphenolic content and antioxidant potential (IC 50 = 48.91 µg/mL) compared to the standard, ascorbic acid (IC 50 = 74.47 µg/mL). This plant, full of bioactive compounds and significant antioxidant properties, offers unique health solutions and robust possibilities for future drug development and pharmacology research. Although the bark of E. delevoyi possesses many health-promoting bioactive metabolites, the heavy metals evaluated in the bark of E. delevoyi in this study have carcinogenic risk (Al, 0.096; Cd, 0.002; Cr, 1.271; Ni, 0.024). Based on the non-carcinogenic health risk evaluation, E. delevoyi bark may be safe. However, its safety can only be determined if the plant's health risks are fully described in extensive chronic toxicity tests. E. delevoyi should therefore be used with caution in medicinal preparations. [ABSTRACT FROM AUTHOR]

INTRODUCTION. The safe use of lily-of-the-valley medicinal products requires adequately controlling the content of cardiac glycosides. The State Pharmacopoeia of the Russian Federation stipulates that the content of cardiac glycosides in lily-of-the-valley medicinal products should be quantified using bioassays and spectrophotometry. However, the determination of cardiac glycosides needs more accurate and selective physicochemical methods, such as high-performance liquid chromatography (HPLC).AIM. This study aimed to develop and validate an HPLC analytical procedure for the quantitative determination of cardiac glycosides (convallatoxin) in lily-of-the-valley herbal medicinal products.MATERIALS AND METHODS. The study examined the Lily-of-the-Valley Tincture, Zelenin Drops, Valocormid, Carniland®, and Lily-of-the-Valley Extract Reference Standard samples. The content of cardiac glycosides was determined by comparison with a reference standard for convallatoxin by HPLC and spectrophotometry. The samples were prepared as outlined in Monograph 3.4.0003.18 Lily-of-the-Valley Herb Tincture of the State Pharmacopoeia of the Russian Federation. Mixed cardiac glycosides were separated on a Luna 5 µm C18(2) column by gradient elution with 0.1% orthophosphoric acid in water and acetonitrile. The analysis was performed using an autoinjector with sample cooling to 5 °C.RESULTS. The developed analytical procedure met the acceptance criteria for specificity, intermediate precision, linearity (correlation coefficient of 0.99985), and repeatability (relative standard deviation of convallatoxin measurements of 1.61%). The analytical procedure is suitable for the quantitative determination of convallatoxin in lily-of-the-valley herbal medicinal products because it produces reliable and repeatable results.CONCLUSIONS. The authors developed a highly sensitive and selective HPLC analytical procedure for the quantitative determination of convallatoxin in lily-of-the-valley herbal medicinal products. The content of convallatoxin ranged from 0.012 to 0.018 mg/mL in the liquid active substance Lily-of-the-Valley Tincture, from 0.004 to 0.013 mg/mL in the medicinal product Zelenin Drops, and from 0.005 to 0.007 mg/mL in the medicinal products Carniland® and Valocormid. For the Lily-of-the-Valley Extract Reference Standard, the content of convallatoxin amounted to 0.029 mg/mL.

Abstract Background Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. Results Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. Conclusion Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

Four alpine goats developed diarrhea soon after the owner placed plant clippings believed to be yellow oleander (Thevetia peruviana) into their pen on a suburban property near Palm Desert, CA, USA. A 1-y-old female goat died suddenly ~1 h after eating the plant clippings and was submitted to the San Bernardino Branch of the California Animal Health and Food Safety Laboratory System for postmortem examination. The main autopsy and histopathologic findings were myocardial hemorrhage and necrosis, consistent with cardiac glycoside intoxication. Rumen contents were analyzed by LC-MS/MS; peruvoside, a cardiac glycoside, was detected, but oleandrin, the cardiac glycoside of common oleander (Nerium oleander), was not. An LC-high-resolution MS (LC-HRMS) analysis revealed the presence of peruvoside and neriifolin in the rumen contents and in a tested plant fragment, indicating that the plant was a member of the Thevetia genus. A clipping from the plant fed to the goats and submitted by the owner was identified as yellow oleander, Thevetia peruviana (also known as Cascabela thevetia).

Introduction:Rakta and Shveta Karavira, a Upavisha (semi-poisonous), botanically identified as Nerium indicum Mill., is being used in different ayurvedic therapeutics, after proper shodhana (purification) with some specific media. Media such as Godugdha (cow’s milk) and Gomutra (cow’s urine) have been mentioned in Ayurvedic literature for shodhana of Karavira root bark.Methods:Shodhana of Karavira root barks was carried out using Godugdha (cow’s milk), Gomutra (cow’s urine), and water media. Standard procedures were followed for performing the physicochemical and phytochemical analysis. To rule out the impact of the shodhana, a high-performance thin-layer chromatography study involved the extraction of total cardiac glycosides (TCGs) fractions.Results:Gross alterations in the drug’s appearance, smell, and touch were noticed. Various physicochemical parameters underwent changes. All raw and Shodhita samples contained metabolites such as carbohydrates, alkaloids, glycosides, tannins, and flavonoids. All raw, shodhita, and media had a common value of 0.03 Rf. On spectral comparison, peaks of raw samples coincide with peaks of their respective media samples but none of the shodhita samples.Conclusion:The effect of shodhana on the bark of the Karavira root is confirmed by changes in physicochemical parameters compared to their raw samples. The presence of similar phenotypic molecules, their adsorption behavior, and their spectral characteristics are suggested by samples having a common value of 0.03 Rf. A spectral comparison suggests that TCGs were transferred from the raw samples to the respective media samples.

Marinobufagenin (MBG) is implicated in chronic kidney disease, where it removes Fli1-induced inhibition of the collagen-1. We hypothesized that (i) in nephrectomized rats, aortic fibrosis develops due to elevated plasma MBG and inhibited Fli1, and (ii) that the antibody to MBG reduces collagen-1 and improves vasodilatation. A partial nephrectomy was performed in male Sprague-Dawley rats. Sham-operated animals comprised the control group. At 5 weeks following nephrectomy, rats were administered the vehicle (n = 8), or the anti-MBG antibody (n = 8). Isolated aortic rings were tested for their responsiveness to sodium nitroprusside following endothelin-1-induced constriction. In nephrectomized rats, there was an increase in the intensity of collagen staining in the aortic wall vs. the controls. In antibody-treated rats, the structure of bundles of collagen fibers had ordered organization. Western blots of the aorta had lower levels of Fli1 (arbitrary units, 1 ± 0.05 vs. 0.2 ± 0.01; p < 0.001) and greater collagen-1 (arbitrary units, 1 ± 0.01 vs. 9 ± 0.4; p < 0.001) vs. the control group. Administration of the MBG antibody to rats reversed the effect of the nephrectomy on Fli1 and collagen-1 proteins. Aortic rings pretreated with endothelin-1 exhibited 50% relaxation following the addition of sodium nitroprusside (EC50 = 0.28 μmol/L). The responsiveness of the aortic rings obtained from nephrectomized rats was markedly reduced (EC50 = 3.5 mol/L) compared to the control rings. Treatment of rats with the antibody restored vasorelaxation. Thus, the anti-MBG antibody counteracts the Fli1-collagen-1 system and reduces aortic fibrosis. [ABSTRACT FROM AUTHOR]

The present work deals with the establishment of hairy root cultures from different explants of C.procera using Agrobacteriumrhizogenes strain A4. A high transformation frequency (95%) was obtained from leaves followed by cotyledons (81.6%) and hypocotyls (38.3%). Genetic transformation of hairy roots was confirmed through PCR by amplifying a 400 bp fragment of the rolB gene. Hairy roots were highly branched, possessed plagiotropic and rapid growth on hormone-free ½ B5 medium. Ten cardiac glycosides, including calotropagenin, calotoxin, frugoside, coroglaucigenin, calotropin, calactin, uzarigenin, asclepin, uscharidin, and uscharin, based on their specific masses and fragmentation properties were identified in ethanolic extracts of hairy roots by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry UHPLC/QTOF-MS. This protocol could be used as a powerful tool for large-scale in vitro production of highly valued cardiac glycosides and for further transcriptomics or metabolomics studies. [ABSTRACT FROM AUTHOR]

Cardiac glycosides (CGs) are well known for treating congestive heart failure, and several CGs like digoxin, digitoxin, and ouabain are marketed as drugs. In the present study, we have biosynthesized two CGs (CGCL520/227 and CGCL534/209) and elicited them up to 537- and 357-fold respectively in response to methyl jasmonate (MJ) treatment. For identification of the key enzyme involved in its biosynthesis, a comparative transcriptome sequencing of control and MJ elicited (75.0 mg L−1 for 3 d) callus culture was done. A total of 17,898 transcripts were expressed across all samples. Annotated unigenes were functionally categorized based on gene ontology. A total of 7625 unigenes were significantly matched in the KEGG database involved in 151 different plant metabolism pathways. Upon digital expression analysis, 2924 MJ-responsive transcripts were identified, and among them 166 were unique for MJ-treated samples. A majority of upregulated transcripts were categorized under hydrolase activity, oxido-reductase activity, metabolic processes, and carbohydrate metabolic process. Based on their role in terpenoid, steroid, and cardenolide pathways, 295 putative unigenes representing 24 gene families involved in CG biosynthesis were identified. Expression analysis revealed that 12 transcripts involved in steroid and cardenolide biosynthetic pathways were upregulated in response to MJ. The highest expression was recorded for squalene monooxygenase (SMO) with 43-fold upregulation, followed by sterol delta7 reductase (DWF5) with 22.2-fold. C-5 sterol desaturase (STE1), 4-diphosphocytidyl-2-C-methyl-D-erythritolkinase/4diphosphocytidyl-2C-methyl-D-erythritol synthase (CMK), 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR), acetyl-CoA C-acetyltransferase (AACT), mono-oxygenases (MO), and progesterone 5β-reductase (PBR) showed high and significant expressions of 16.4-, 16.1-, 14.8-, 14.7-, 13.4-, and 11.3-fold, respectively. This study not only identifies MJ-responsive CGs and related transcripts involved in CG biosynthesis, but also provides scope for the development of biotechnological process for biosynthesis and enrichment of targeted CGs using identified rate-limiting key enzymes. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancers are aggressive and challenging to treat due to the severe side effects and toxicity of current treatments. Bufalin, a natural compound from the Chinese toad, has shown promise in fighting various cancers but has not been thoroughly studied for head and neck cancers. Our research aims to explore how bufalin works against these specific cancer cells. By using different techniques, we discovered that bufalin could reduce cancer cell growth, induce cell death, and enhance the body's immune response against tumors. These findings suggest that bufalin could become a new, effective treatment option with potentially fewer side effects for patients with head and neck cancers. This research could pave the way for developing better therapies and improving outcomes for patients facing this difficult disease. Bufalin, a cardiotonic steroid derived from the Chinese toad (Bufo gargarizans), has demonstrated potent anticancer properties across various cancer types, positioning it as a promising therapeutic candidate. However, comprehensive mechanistic studies specific to head and neck cancers have been lacking. Our study aimed to bridge this gap by investigating bufalin's mechanisms of action in head and neck cancer cells. Using several methods, such as Western blotting, immunofluorescence, and flow cytometry, we observed bufalin's dose-dependent reduction in cell viability, disruption of cell membrane integrity, and inhibition of colony formation in both HPV-positive and HPV-negative cell lines. Bufalin induces apoptosis through the modulation of apoptosis-related proteins, mitochondrial function, and reactive oxygen species production. It also arrests the cell cycle at the G2/M phase and attenuates cell migration while affecting epithelial–mesenchymal transition markers and targeting pivotal signaling pathways, including Wnt/β-catenin, EGFR, and NF-κB. Additionally, bufalin exerted immunomodulatory effects by polarizing macrophages toward the M1 phenotype, bolstering antitumor immune responses. These findings underscore bufalin's potential as a multifaceted therapeutic agent against head and neck cancers, targeting essential pathways involved in proliferation, apoptosis, cell cycle regulation, metastasis, and immune modulation. Further research is warranted to validate these mechanisms and optimize bufalin's clinical application. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is a significant planetary health challenge with its high morbidity and mortality rate, not to mention the marked interindividual variability in treatment outcomes and side effects. There is an urgent need for robust systems biomarkers that can help with early cancer diagnosis, prediction of treatment outcomes, and design of precision/personalized medicines for LUAD. The present study aimed at systems biomarkers of LUAD and deployed integrative bioinformatics and machine learning tools to harness gene expression data. Predictive models were developed to stratify patients based on prognostic outcomes. Importantly, we report here several potential key genes, for example, PMEL and BRIP1, and pathways implicated in the progression and prognosis of LUAD that could potentially be targeted for precision/personalized medicine in the future. Our drug repurposing analysis and molecular docking simulations suggested eight drug candidates for LUAD such as heat shock protein 90 inhibitors, cardiac glycosides, an antipsychotic agent (trifluoperazine), and a calcium ionophore (ionomycin). In summary, this study identifies several promising leads on systems biomarkers and drug candidates for LUAD. The findings also attest to the importance of integrative bioinformatics, structural biology and machine learning techniques in biomarker discovery, and precision oncology research and development. [ABSTRACT FROM AUTHOR]

Green medicine, the drugs derived from plants attained a wide spread interest, as believed to be safe and dependable, compared with costly synthetic drugs that have adverse effects. In this study, Annona Squamosa (A. squamosa) have been investigated for their phytochemical, antioxidant, antimutagenic activities. Qualitative analysis of various phytochemical constituents and quantitative analysis of total phenol were determined by the well-known test protocol available in the literature. The extraction yield was found in the order: methanol>water>ethyl acetate>hexane. The extracts found to possess saponin glycosides, cardiac glycosides, phenolics, terpenoids, sterols, and flavonoids. The total phenolic content of hexane, ethyl acetate, methanolic and aqueous extract of A. squamosa were 3.04±0.37, 5.83±0.29, 31.42±2.35, and 27.21±1.06 GAE mg/g, respectively. The methanolic extracts exhibited highest amount of total polyphenol content compared to all other solvent extracts. The ethyl acetate, methanolic and aqueous extracts were evaluated for their antioxidant potential in terms of DPPH radical scavenging capabilities. The scavenging was found to dose dependent with IC50 value of 185.24, 103.09 and 160.17 µg/ml for the ethyl acetate, methanol and aqueous extracts respectively. The antimutagenic potential of the methanolic extract was studied using Ames test using T98 strain of Salmonella typhimurium applying NPD as the mutagen. The number of reverant colonies were counted using a digital colony counter and the reduction in colonies was calculated as the activity (%) of the extract at four doses. The reverent colonies were visible as lawn like structures on the surface of the plate and were significantly lower compared to positive control in the extract plate and the negative control. The extract was able to control the growth of reverant colonies upto 79.30% in comparison to the mutagenic control. The results show that the methanolic extract of A. squamosa leaf was able to exhibit a dose regulated antimutagenic activity by inhibiting the growth of His+ reverant colonies of Salmonella typhimurium. [ABSTRACT FROM AUTHOR]

Cardiac glycosides are chemical defence toxins known to fatally inhibit the Na,K‐ATPase (NKA) throughout the animal kingdom. Several animals, however, have evolved target‐site insensitivity through substitutions in the otherwise highly conserved cardiac glycoside binding pocket of the NKA. The large milkweed bug, Oncopeltus fasciatus, shares a long evolutionary history with cardiac glycoside containing plants that led to intricate adaptations. Most strikingly, several duplications of the bugs' NKA1α gene provided the opportunity for differential resistance‐conferring substitutions and subsequent sub‐functionalization of the enzymes. Here, we analysed cardiac glycoside resistance and ion pumping activity of nine functional NKA α/β‐combinations of O. fasciatus expressed in cell culture. We tested the enzymes with two structurally distinct cardiac glycosides, calotropin, a host plant compound, and ouabain, a standard cardiac glycoside. The identity and number of known resistance‐conferring substitutions in the cardiac glycoside binding site significantly impacted activity and toxin resistance in the three α‐subunits. The β‐subunits also influenced the enzymes' characteristics, yet to a lesser extent. Enzymes containing the more ancient αC‐subunit were inhibited by both compounds but much more strongly by the host plant toxin calotropin than by ouabain. The sensitivity to calotropin was diminished in enzymes containing the more derived αB and αA, which were only marginally inhibited by both cardiac glycosides. This trend culminated in αAβ1 having higher resistance against calotropin than against ouabain. These results support the coevolutionary escalation of plant defences and herbivore tolerance mechanisms. The possession of multiple paralogs additionally mitigates pleiotropic effects by compromising between ion pumping activity and resistance. see also the Perspective by Franziska Beran and David G. Heckel [ABSTRACT FROM AUTHOR]

Introduction: Capsicum species are known in food and trado-medicinal uses for maladies management due their rich content of phytochemicals, but with little work done on in silico bioprospection of its volatilome. Objectives: This study targeted chemometric profiling, virtual bioprospection of potential lead metabolites in 2 Capsicum annuum L. fruit variants' (green and red) to identify lead gyrase B inhibitors (GBIs) and provide new mechanistic insights. Methods: Metabolites were profiled using Gas Chromatography-Mass Spectrometry (GC-MS), and quantitative phytochemical assays. Extracts antioxidant (DPPH, ABTS, FRAP) and antibacterial (susceptibility testing) activities were also determined. In silico [docking, pharmacokinetics, DFT] analyses were used to identify and predict chemical features of potential lead GBIs key to extracts molecular mechanism of action. Results: Mass spectral analysis identified hydrocarbons, fatty acid and other derivatives. Quantitative phytochemical analysis showed flavonoids, cardiac glycosides and alkaloids. The green C. annuum extract had better antioxidative action, while extracts of both green and red variant showed similar antimicrobial profiles against resistant bacterial pathogens. In silico highest docking scores were observed for [1-Ethyloctyl) cyclohexane (-6.6 kcal/mol)] and dibutyl phthalate (-6.4 kcal/mol). All lead GBIs had desirable pharmacokinetics in line with the Lipinski rule of 5, and chemical reactivity properties. Conclusion: In silico and in vitro methods combination provided robust metabolomic profiling. The identified lead C. annuum-based natural GBIs contribute to the bioactivity profile and molecular mechanism of action of fractions. The study provided a first-hand report on natural GBIs derivable from Capsicum fruits which could be exploited in formulations for non-food and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

This study investigates the bioactivities of the leaf extract of Acalypha godseffiana (Muell Arg.) and the stem bark extract of Alstonia boonei (De Wild) against Sitophilus oryzae (Linnaeus) and Sitophilus zeamais (Motschulsky) at different concentrations (2.5, 5.0, 7.5, 10.0, and 12.5% %). The relative growth rate (RGR), relative consumption rate (RCR), and efficiency of conversion of ingested food (ECI) of both Sitophilus species were assessed using extract-treated wheat flour discs. The contact toxicity and effects of both extracts on the adult emergence of both weevils were also determined. Control experiments were set up for all the bioassays. Phytochemical compounds (tannins, saponins, anthraquinones, cardiac glycosides, flavonoids, and alkaloids) in each botanical extract were checked. Except for anthraquinones, which was lacking in A. boonei but marginally present in A. godseffiana, both extracts contain all the tested phytochemicals in either low, moderate, or high amounts. The LC50 values showed that both extracts had higher toxicity to S. zeamais at 24 and 48 h and to S. oryzae at 72 and 96 h. Both extracts at 12.5% significantly decreased adult emergence and evoked higher inhibition in adult emergence of both Sitophilus species relative to controls. RGR, RCR, and ECI generally decreased as extract concentrations increased. At 12.5%, A. boonei and A. godseffiana considerably decreased the RCR of S. oryzae and S. zeamais, respectively. Additionally, the ECI of both species was significantly lower relative to controls. Conclusively, the two extracts evoked insecticidal, anti-nutritional, and significantly reduced adult emergence of both Sitophilus species relative to controls. [ABSTRACT FROM AUTHOR]

Psoralea corylifolia, locally known as Bakuchi, is a well-known medicinal plant noted for its myriad healthcare benefits. Every part of the plant encompasses several phyto-chemical constituents whose potential application is explored by many researchers in recent times. Though profound research is done on assessment of benefits of seeds and fruits of P. corylifolia, investigation of phyto-chemical constituents and beneficial properties of leaves remained an untouched area. Therefore, the present study focused on unveiling the bio-molecules in the leaves and callus grown using leaf explants in tissue culture. The optimum concentration for callus induction utilizing NAA and BAP hormones was determined to be 5.0 mg/L NAA combined with 0.5 mg/L BAP and 5.0 mg/L NAA combined with 0.5 mg/L KN with green friable callus. Using methanol as solvent, soxhlet extractor was used to extract phyto-chemical constituents from the dried callus powder. The phyto-chemical screening of the plant extract was carried out using standard protocols. Further, anti-microbial properties against bacteria and fungi were carried out. The presence of several phyto-chemical constituents like alkaloids, steroids, terpenoids, cardiac glycosides, anthraquinone glycosides, and flavonoids in both leaves and callu was observed in the present study. Both leaves and callus shown remarkable anti-bacterial properties, especially against Staphylococcus aureus, and MDR strains such as MRSA and VRE. In addition, significant anti-fungal activity was also witnessed against Candida albicans, Candida aureus, Cryptococcus neoformans, and Cryptococcus gattii by extracts of leaves and callus. As both leaves and callus having almost similar properties, micro-propagation using tissue culture can be exploited as a potential tool in preparation of healthcare products and this is especially useful in P. corylifolia because of its slow growing nature. [ABSTRACT FROM AUTHOR]

Background and Objectives: Acute kidney injury (AKI) remains a significant complication following major cardiac surgery. Marinobufagenin (MBG), a cardiotonic steroid involved in sodium balance and blood pressure regulation, has been linked to organ damage after ischemia–reperfusion events. This pilot, prospective study investigates the utility of circulating MBG to improve AKI risk assessment in cardiac surgery patients as a stand-alone biomarker and after inclusion in a validated risk model (STS-AKI score). Materials and Methods: We included 45 patients undergoing elective cardiac surgery. The MBG levels were measured preoperatively and at 4, 8, and 12 h post-surgery. The AKI was defined according to the KDIGO guidelines. Statistical analyses assessed the diagnostic and prognostic utility of MBG and its integration with the STS-AKI score. Results: An AKI occurred in 26.7% of the patients. The STS-AKI score performed well in this cohort (AUC: 0.736). The MBG levels displayed a decreasing trend in the whole population after surgery (p = 0.02). However, in the AKI patients, MBG increased at 4 and 8 h before decreasing at 12 h post-surgery. The MBG changes from the baseline to 8 h and from 8 to 12 h post-surgery showed a remarkable diagnostic accuracy for an AKI (AUCs: 0.917 and 0.843, respectively). Integrating these MBG changes with the STS-AKI score significantly improved the model performance, including discrimination, calibration, and risk reclassification. Conclusions: The MBG measurement, particularly any dynamic changes post-surgery, enhances AKI risk stratification in cardiac surgery patients. Integrating MBG with the STS-AKI score offers more accurate risk predictions, potentially leading to better patient management and outcomes. [ABSTRACT FROM AUTHOR]

Summary: The chemical arms race between plants and insects is foundational to the generation and maintenance of biological diversity. We asked how the evolution of a novel defensive compound in an already well‐defended plant lineage impacts interactions with diverse herbivores. Erysimum cheiranthoides (Brassicaceae), which produces both ancestral glucosinolates and novel cardiac glycosides, served as a model.We analyzed gene expression to identify cardiac glycoside biosynthetic enzymes in E. cheiranthoides and characterized these enzymes via heterologous expression and CRISPR/Cas9 knockout. Using E. cheiranthoides cardiac glycoside‐deficient lines, we conducted insect experiments in both the laboratory and field.EcCYP87A126 initiates cardiac glycoside biosynthesis via sterol side‐chain cleavage, and EcCYP716A418 has a role in cardiac glycoside hydroxylation. In EcCYP87A126 knockout lines, cardiac glycoside production was eliminated. Laboratory experiments with these lines revealed that cardiac glycosides were highly effective defenses against two species of glucosinolate‐tolerant specialist herbivores, but did not protect against all crucifer‐feeding specialist herbivores in the field. Cardiac glycosides had lesser to no effect on two broad generalist herbivores.These results begin elucidation of the E. cheiranthoides cardiac glycoside biosynthetic pathway and demonstrate in vivo that cardiac glycoside production allows Erysimum to escape from some, but not all, specialist herbivores. See also the Commentary on this article by Agosto-Ramos et al., 242: 2388–2390. [ABSTRACT FROM AUTHOR]

Some microorganisms known as endophytes live in symbiotic relationships in the living tissues of plants without posing a health risk. As a result, they synthesize many metabolites which are helpful for the plants in many ways. So, these metabolites are known to exhibit many biological properties like antioxidant, antidiabetic anti-inflammatory, etc. Currently, many drugs are used to control inflammatory diseases like arthritis and, irritable bowel disease; however, they pose a lot of side effects. The present study was taken up to explore the anti-inflammatory properties along with the phytochemicals present, its quantification, and other in vitro biological activities of the less reported Aspergillus melleus, an endophytic fungus, isolated from Premna serratifolia L., a medicinal plant. The results of the investigation demonstrated the presence of alkaloids, phenols, terpenoids, flavonoids, tannins, cardiac glycosides and amino acids in the methanolic extract of endophytic fungus. It yielded 25.28 µg GAE/g and 19.465 µg GAE/g of total phenolic and flavonoid content, respectively. The results of anti-inflammatory activity showed 84.69+0.82% protein inhibition by BSA and also showed IC50 values of 68.53 µg/mL and 43.34 µg/mL for COX1 and COX 2, respectively. It exhibited 63.91+0.08% of radical scavenging activity by DPPH. The IC50 values of 181.41 µg/mL and 190.62 µg/mL were found for the in vitro antidiabetic activity. This study shows that the endophytic fungus A. melleus has exhibited considerably good results with respect to its in vitro biological activities. Yet, there is a scope for future researchers to isolate the bioactive metabolites to explore for future needs. [ABSTRACT FROM AUTHOR]

The sodium pump, or Na+/K+-ATPase (NKA), is an essential enzyme found in the plasma membrane of all animal cells. Its primary role is to transport sodium (Na+) and potassium (K+) ions across the cell membrane, using energy from ATP hydrolysis. This transport creates and maintains an electrochemical gradient, which is crucial for various cellular processes, including cell volume regulation, electrical excitability, and secondary active transport. Although the role of NKA as a pump was discovered and demonstrated several decades ago, it remains the subject of intense research. Current studies aim to delve deeper into several aspects of this molecular entity, such as describing its structure and mode of operation in atomic detail, understanding its molecular and functional diversity, and examining the consequences of its malfunction due to structural alterations. Additionally, researchers are investigating the effects of various substances that amplify or decrease its pumping activity. Beyond its role as a pump, growing evidence indicates that in various cell types, NKA also functions as a receptor for cardiac glycosides like ouabain. This receptor activity triggers the activation of various signaling pathways, producing significant morphological and physiological effects. In this report, we present the results of a comprehensive review of the most outstanding studies of the past five years. We highlight the progress made regarding this new concept of NKA and the various cardiac glycosides that influence it. Furthermore, we emphasize NKA's role in epithelial physiology, particularly its function as a receptor for cardiac glycosides that trigger intracellular signals regulating cell–cell contacts, proliferation, differentiation, and adhesion. We also analyze the role of NKA β-subunits as cell adhesion molecules in glia and epithelial cells. [ABSTRACT FROM AUTHOR]

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment. [ABSTRACT FROM AUTHOR]

Parthenium hysterophorus L. is a family member of Asteraceae and is a notorious weed with a few different names as congress weed, carrot weed (Gajarghas), and wild feverfew. It poses significant threats to human health, agriculture, and biodiversity in regions like Australia and India. This harmful plant is associated with a range of health issues including mutagenicity, skin rashes, Diarrhea, allergy-related respiratory issues, dermatitis through contact, and skin allergies, as well as animal and human dehydration. Efforts to manage Parthenium weed have often been ineffective due to its rapid re-infestation. Despite its acknowledged toxicity, Parthenium is still used in traditional medicine for treating fevers, headaches, wounds, diabetes, diarrhea, anemia, heart problems, and malaria. Studies have indicated that P. hysterophorus L. extract contains a diverse range of compounds including proteins, amino acids, terpenoids, quinones, alkaloids, carbohydrates, cardiac glycosides, flavonoids, phenols, and coumarins. Essential oils from this plant contain compounds such as germacrene-D, β-myrcene, and trans-β-ocimene, which are responsible for its anti-inflammatory, anti-oxidant, insecticidal, larvicidal, anti-microbial, hypoglycemic, and anticancer properties. This review paper's objective is to furnish a thorough summary encompassing the phytochemistry, ethnobotanical applications, toxicology, and biological activities linked with P. hysterophorus. [ABSTRACT FROM AUTHOR]

Background: Medicinal plants play a major role in the delivery of healthcare, particularly among the rural population of Ethiopia. Plant extracts and their bioactive compounds have been utilized for the treatment of several diseases. This study was aimed at evaluating the antibacterial activity, antioxidant capacity, and phytochemical content of selected medicinal plants used in Dibatie district, western Ethiopia. Methods: Study plants were collected, shade dried, pulverized, extracted by maceration in 80% ethanol, and subjected to antibacterial, antioxidant, and phytochemical tests. Minimum inhibitory concentration (MIC) was determined using 96-well microplates and nutrient broth microdilution. Antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Phytochemical screening was conducted using standard test methods. Results: The ethanolic extract of Polystachya steudneri Rchb.f. pseudobulbs was the most active against gram-negative Proteus mirabilis, Salmonella typhimurium, Klebsiella pneumoniae, Escherichia coli, and Shigella flexneri, with MIC values of 8 ± 0, 11 ± 5, 3 ± 1, 3 ± 1, and 2 ± 0 mg/mL, respectively. The ethanolic extract of P. steudneri was also the most effective against gram-positive Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus agalactiae, and Enterococcus faecalis, with MIC values of 8 ± 0, 8 ± 0, 3 ± 1, and 16 ± 0 mg/mL, respectively. Ethanolic extracts of Gnidia involucrata Steud. ex A.Rich. stems and roots were effective antioxidants, with respective 50% DPPH free radical inhibitory concentrations (IC50) of 168.68 and 181.79 µg/mL, followed by that of P. steudneri (IC50 = 203.11 µg/mL). The study plants contained alkaloids, anthocyanins, anthraquinones, cardiac glycosides, coumarins, flavonoids, phenols, saponins, steroids, tannins, and terpenoids. Conclusions: This study confirmed the antibiotic, antioxidant, and phytochemical constituents of the investigated plants and suggested further investigations that may lead to bioactive lead compounds. [ABSTRACT FROM AUTHOR]

Aleurites moluccanus (candlenut) and Bertholletia excelsa (Brazil nut) are marketed as dietary supplements for weight loss. These dietary supplements have been found to sometimes be adulterated with toxic nuts/seeds from Cascabela thevetia, commonly known as yellow oleander or lucky nut. This study emphasizes the key identification parameters to differentiate the genuine and adulterated nuts. Samples were obtained from authenticated sources of the nuts and from commercial sources of dietary supplements. This study examined 38 samples, including voucher and commercial samples. All eight commercial candlenut dietary supplement samples were adulterated. Additionally, two samples sold as Brazil nuts were also found to be adulterated. Other nuts were screened for the presence of Cardiac Glycosides, but none were found to be positive. The presence of yellow oleander was confirmed in all commercial dietary supplement samples marketed as candlenut as well as in commercial samples of Brazil nut. This study provides simple key identification characters using micro-morphology and histochemical localization of cardiac glycosides in the commercial nuts, HPTLC fingerprints, and LC-DAD-Q-ToF analytical parameters to detect and identify adulteration in commercial products. [ABSTRACT FROM AUTHOR]

Simple Summary: Orb-weaving spiders can learn to avoid eating unpalatable prey, but what happens when they encounter one that they have never seen before? In the United States, a spider from East Asia has become established (the "jorō spider") in recent years, and their webs are most prominent during the late-summer and fall, which is also when migrating monarch butterflies are in abundance. Since monarch butterflies are unpalatable (because of developing on toxic milkweeds), we wondered if jorō spiders would recognize this and avoid eating them, given that these species do not coexist in East Asia. Using field observations of butterflies deposited into jorō spider webs, we found that these spiders do avoid eating monarchs, and even remove them from their webs in some cases. They readily attack other butterflies, even those that are similarly colored to monarchs. This raises many questions about how they perceive the "distastefulness" of monarchs, even without tasting the butterflies first. An invasive spider from East Asia has established in the U.S. southeast (the "jorō spider," Trichonephila clavata) and is rapidly expanding its range. Studies assessing the impact of this species are needed, including how expansive its diet is. An open question is whether monarch butterflies, Danaus plexippus, are a potential prey item for this spider, given that jorō spiders do not coexist with monarchs in their native range. Since monarch larvae feed on milkweed, they sequester cardiac glycosides into their adult tissues, rendering them unpalatable to many predators. At sites within northeast Georgia, we staged a series of trials (n = 61) where we tossed monarchs into jorō spider webs and, for comparison, performed similar trials with another aposematic species, gulf fritillary (Agraulis vanilla), and a palatable species, tiger swallowtail (Papilio glaucus). We recorded the outcome of the trials, which included whether the spider attacked or did not attack the prey. We also conducted a visual survey during the same fall season to look for evidence of jorō spiders consuming monarchs naturally. Our findings revealed that jorō spiders avoided eating monarchs; spiders only attacked monarchs 20% of the time, which was significantly less than the attack rates of similarly sized or larger butterflies: 86% for gulf fritillaries and 58% for tiger swallowtails. Some jorō spiders even removed monarchs from their webs. From our visual surveys of the surrounding area, we found no evidence of natural monarch consumption and, in general, butterflies made up only a fraction of the jorō spider diet. We conclude that jorō spiders appear to recognize monarch butterflies as being unpalatable, even without having a prior history with the species. This invokes questions about how these spiders can immediately recognize their unpalatability without touching the butterflies. [ABSTRACT FROM AUTHOR]

Thevetia peruviana plant, a member of the Apocynaceae family, has a long history in traditional medicine for treating various ailments such as amenorrhea, malaria, jaundice, hemorrhoids, constipation, headaches, and skin issues. It contains significant amounts of cardiac glycosides in both its roots and seeds, which are known for their cytotoxic effects similar to digoxin. Given its potential toxicity and widespread use, current research is focused on assessing the antimitotic properties of the methanolic extract derived from the fruits of Thevetia peruviana. In the pursuit of potential pharmaceutical findings from plants, the antimitotic properties of the extracts were investigated through the Allium cepa assay. The findings indicated a noteworthy decrease in the mitotic index of root tips compared to the control, with the degree of mitotic suppression escalating alongside the concentration of the extracts. Therefore, the study suggests that the methanol extract derived from T. peruviana fruit has notable inhibitory and mitodepressive impacts on cell division in Allium cepa L. meristems. [ABSTRACT FROM AUTHOR]

Background: Syzygium aromaticum has been used for over a century because it has biological qualities for several health-related problems, and the crude essential oils are known to contain several components that could be responsible for synergistic or antagonistic potentials in relation to their biological uses. The study was designed to compare the biological activities of the crude essential oil from the bud of Syzygium aromaticum and fractions obtained from column chromatography. Materials and methods: The essential oil was extracted by hydrodistillation, and two prominent fractions, C1 and C2, were obtained from the column chromatography separation of the crude essential oil. The quantitative phytochemical analysis was done by standard methods, the antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) scavenging assays. The antifungal activities were assessed by the agar diffusion method, while the anti-inflammatory activity was done using a lipoxygenase inhibitory assay. The major component observed in the crude and fractions was determined by gas chromatography–mass spectrometry (GC–MS) analysis. Results: The phytochemical analysis showed that phenolic acid, tannin, saponin, flavonoids, alkaloids, cardiac glycosides, and terpenoids were present in variable quantities in all of the fractions and crude essential oil. The half-maximal inhibitory concentration (IC50) value for DPPH scavenging activity ranged from 226.1 to 301.2 µg/mL while that of ABTS scavenging activity ranged from 211.0 to 316.0 µg/mL. The lowest value of IC50 for both DPPH and ABTS was observed in fraction C1. The crude essential oil with a minimum inhibitory concentrations (MIC) value of 8.00 mg/mL was the most efficient against Candida albicans, Aspergillus penicillum, and Aspergillus niger. The anti-inflammatory assay showed C1 to have the lowest value of IC50 for the lipoxygenase assay. The major component observed in the crude essential oil as well as fraction C1 was eugenol, while fraction C2 had β-caryophyllene as the major component. Conclusions: The result showed that all fractions as well as the crude essential oil exhibited antioxidant, antifungal, and anti-inflammatory activities, and the crude essential oil was synergic only with respect to its antifungal activity, while fraction C1 was more efficient as an anti-inflammatory and antioxidant agent. [ABSTRACT FROM AUTHOR]

Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain–blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs' applicability in the clinic and decrease the risk of side effects on the CNS. This study aimed to investigate the tissue distribution of the CTS ouabain following intraperitoneal injection and whether ouabain passes through the BBB. After intraperitoneal injection (1.25 mg/kg), ouabain concentrations were measured at 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, and 24 h using HPLC–MS in brain, heart, liver, and kidney tissues and blood plasma in C57/black mice. Ouabain was undetectable in the brain tissue. Plasma: Cmax = 882.88 ± 21.82 ng/g; Tmax = 0.08 ± 0.01 h; T1/2 = 0.15 ± 0.02 h; MRT = 0.26 ± 0.01. Cardiac tissue: Cmax = 145.24 ± 44.03 ng/g (undetectable at 60 min); Tmax = 0.08 ± 0.02 h; T1/2 = 0.23 ± 0.09 h; MRT = 0.38 ± 0.14 h. Kidney tissue: Cmax = 1072.3 ± 260.8 ng/g; Tmax = 0.35 ± 0.19 h; T1/2 = 1.32 ± 0.76 h; MRT = 1.41 ± 0.71 h. Liver tissue: Cmax = 2558.0 ± 382.4 ng/g; Tmax = 0.35 ± 0.13 h; T1/2 = 1.24 ± 0.7 h; MRT = 0.98 ± 0.33 h. Unlike digoxin, ouabain does not cross the BBB and is eliminated quicker from all the analyzed tissues, giving it a potential advantage over digoxin in systemic administration. However, the inability of ouabain to pass though the BBB necessitates intracerebral administration when used to investigate its effects on the CNS. [ABSTRACT FROM AUTHOR]

This study was carried out to evaluate the in vitro effect of crude methanol extracts of root of Sarcocephallus latifolius (SL) on Plasmodium falciparum. Powdered root of Sarcocephallus latifolius was subjected to cold maceration using 99.8% methanol. The crude extract was sequentially fractionated using four solvents of increasing polarity. P. falciparum field isolate was cultivated in vitro using the Trager and Jensen Candle jar method. The plant extracts were tested against the ring staged synchronous P. falciparum field isolates by incubation in 96-well micro titre plate for 48 h. Preliminary Phytochemical screening of the crude methanol plant extracts revealed the presence of Saponins, Tannins, Flavonoids, Alkaloids, Anthraquinone and cardiac glycosides Results also showed that Sarcocephalus latifolius extracts have moderate activity when against P. falciparum with its crude methanol extract having IC50 of 14.78 µg/mL, chloroform fraction with 19.95 µg/mL, Benzene fraction with IC50 of 33.00 µg/mL and ethylacetate fraction with IC50 of 49 µg/mL. the Aqueous fraction had the lowest antiplasmodial activity with IC50 of 72 µg/mL. Statistical analysis reveals increasing activity with increasing concentration which shows significant antiplasmodial activity at P value = 0.01. The findings in this studies have shown that the crude methanol extracts of SL and its fractions have moderate activity on the cultured field isolate of Plasmodium falciparum, Therefore the findings in this research will serve as a stepping stone to avert some of the challenges posed by parasite resistance to the existing antimalarial drugs. [ABSTRACT FROM AUTHOR]

Sodium-potassium-ATPase (Na+K+-ATPase), a target to treat congestive heart failure, is the only known receptor for cardiac glycosides implicated in intracellular signaling and additionally functions enzymatically in ion transport. Spermatozoa need transmembrane ion transport and signaling to fertilize, and Na+K+-ATPase is identified here for the first time in boar spermatozoa. Head plasma membrane (HPM) isolated from boar spermatozoa was confirmed pure by marker enzymes acid and alkaline phosphatase (218 ± 23% and 245 ± 38% enrichment, respectively, versus whole spermatozoa). Western immunoblotting detected α and β subunits (isoforms α1, α3, β1, β2, and β3) in different concentrations in whole spermatozoa and HPM. Immunofluorescence of intact sperm only detected α3 on the post-equatorial exterior membrane; methanol-permeabilized sperm also had α3 post-equatorially and other isoforms on the acrosomal ridge and cap. Mass spectrometry confirmed the presence of all isoforms in HPM. Incubating boar sperm in capacitating media to induce the physiological changes preceding fertilization significantly increased the percentage of capacitated sperm compared to 0 h control (33.0 ± 2.6% vs. 19.2 ± 2.6% capacitated sperm, respectively; p = 0.014) and altered the β2 immunofluorescence pattern. These results demonstrate the presence of Na+K+-ATPase in boar sperm HPM and that it changes during capacitation. [ABSTRACT FROM AUTHOR]