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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]

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]

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]

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]

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]

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]

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.

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]

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]

Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950s and 1960s, we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, subnanomolar ouabain sometimes stimulates NKA while higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcomes in patients with HF. Fourth, cloning of NKA in 1985 revealed multiple NKA α and β subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent, e.g., ouabain induces hypertension in rodents while digoxin is antihypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous phenomena are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain-binding site on physiology and pathophysiology. [ABSTRACT FROM AUTHOR]

Background: The prevalent utilization of medicinal plants in communities underscores their promise as antimicrobial agents amid rising antibiotic resistance. This study assesses five medicinal plants; Bambusa vulgaris, Hibiscus sabdariffa, Heteropogon contortus, Moringa oleifera, and Carica papaya against clinical isolates of Salmonella Typhi and Shigella dysenteriae. Methodology: Five medicinal plants were chosen based on traditional knowledge and ethnobotanical practices. Phytochemical analysis followed standard methods. Plant extracts were prepared using ethanol, ethyl acetate, dichloromethane, and hexane. Various concentrations (R conc., D1 conc., D2 conc, D3 conc, and D4 conc) of the extracts were evaluated using Kirby-Bauer disk diffusion and broth dilution methods to ascertain antimicrobial properties, including minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC). Results: Phytochemical analysis revealed abundant saponins, cardiac glycosides, terpenoids, steroids, flavonoids, phenolics, and tannins, notably higher with ethanol extraction. Hibiscus sabdariffa demonstrated potent activity against S. Typhi with inhibition zone diameters of 29.00 mm (R conc), 27.00 mm (D1 conc), 14.00 mm (D2 conc), and 4.00 mm (D3 conc). Heteropogon contortus exhibited activity against S. dysenteriae with inhibition zone diameter of 25.05 mm (R conc), 15.00 mm (D1 conc), 10.00 mm (D2 conc), and 5.00 mm (D3 onc). The inhibition zone diameters of B. vulgaris were 18.50 mm (R conc), 17.00 mm (D1 conc), and 10.00 mm (D2 conc) against S. dysenteriae. The MIC and MBC were similar for both organisms, with H. sabdariffa (MIC: D3-4.27 mg/mL, MBC: D1-68.25 mg/mL) and H. contortus (MIC: D3-4.69 mg/mL, MBC: R-75.00 mg/mL), while M. oleifera, C. papaya, and B. vulgaris had negligible antimicrobial activity. Conclusion: Hibiscus sabdariffa and H. contortus exhibited potent antimicrobial effects against Salmonella, with MICs of 4.27 mg/mL and 4.69 mg/mL, and MBCs of 68.25 mg/mL and 75.00 mg/mL respectively. Their consistent low MICs against Shigella suggest their potentials for antibiotic production. [ABSTRACT FROM AUTHOR]

Background: A study carried out by World Health Organization revealed that around 80% of individuals globally depends on herbal forms of medication with 40% of pharmaceutical products being sourced from medicinal plants. The study objective was to evaluate the phytochemicals composition, in vitro antimicrobial and antioxidant properties of the leaves of Terminalia catappa L. aqueous and methanolic extracts. Methods: Antimicrobial activity was analyzed by disk diffusion, the minimum inhibitory concentration in-vitro assays with ciprofloxacin as the standard for antibacterial assay while nystatin for antifungal assay. Ferric reducing antioxidant power and 2,2-diphenyl-1-picryl-hydrazyl-hydrate assays were used for the evaluation of antioxidant properties of the crude extracts while the groups responsible for this activity identified using Fourier transform infrared spectrophotometer. Results: The study found that the leaves of Terminalia catappa contained alkaloids, tannins, steroids, cardiac glycosides, flavonoids, phenols, saponins, and coumarins, but terpenoids were absent. Presence of functional groups associated with this class of compounds such as OH vibrational frequencies were observed in IR spectrum of the crude extracts. Methanolic extract from Terminalia catappa exhibited greater antibacterial properties against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus, whereas aqueous extract displayed greater antibacterial activity against Bacillus subtilis for all concentrations tested. The amount of the sample that scavenged 50 percent of DPPH (IC50) was found to be 8.723, 13.42 and 13.04 µg/mL for L-ascorbic acid, Terminalia catappa L. methanolic and aqueous extracts respectively. The antimicrobial and antioxidant activities varied with the extract concentration and solvent used in extractions. Conclusion: Terminalia catappa L. leaves are prospective for use as a source of therapeutic agents that could lead to the advancement of new antimicrobial and antioxidant products. [ABSTRACT FROM AUTHOR]

Bersama (Melianthaceae) has been used in traditional medicine for a wide range of ailments, including blood purifier, immune booster, psychotropic medication, and treatment for malaria, hepatitis, infertility, diabetes, impotency, meningitis, and stroke. This review gathers fragmented information from the literature on ethnomedicinal applications, phytochemistry, pharmacology, and toxicology of the Bersama genus. It also explores the therapeutic potential of the Bersama genus in ethnophytopharmacology, allowing for further investigation. All the available information published in the English language on Bersama genus was compiled from electronic databases such as Academic Journals, Ethnobotany, Google Scholar, PubMed, Science Direct, Web of Science, and library search using the following keywords: "Bersama genus," "traditional use," "phytochemistry," "pharmacological effects," and "toxicology". The ethnomedical applications of the Bersama genus have been recorded, and it has been used traditionally for more than 30 different types of ailments. Thus far, more than 50 compounds have been isolated from the genus. Cardiac glycosides and terpenoids are the main compounds isolated from the Bersama genus. Different plant parts of Bersama genus extracts demonstrated a wide range of pharmacological properties, including antioxidant, antimalarial, antidiabetic, antiviral, anti-inflammatory, and cytotoxic activity. Exemplary drug leads from the genus include mangiferin and quercetin-3-O-arabinopyranoside, both of which have antioxidant activities. Bersama genus has long been used to cure a wide range of ailments. Bersama genus extracts and phytochemicals have been found to have promising pharmacological activities. Further study on promising crude extracts and compounds is required to develop innovative therapeutic candidates. [ABSTRACT FROM AUTHOR]

The article discusses guideline-recommended medical therapy (GRMT) for heart failure with reduced ejection fraction (HFrEF). GRMT includes medications such as ACE inhibitors, beta-blockers, and SGLT2 inhibitors. The article emphasizes the importance of initiating GRMT promptly and titrating to target doses within the first 4 weeks following the index heart failure episode. It also discusses the concept of reverse remodeling, which is the process of improving the structure and function of the heart. The article presents a recent study that suggests the 90-day time frame for reassessing left ventricular function may be too short for substantial recovery in some patients. The study also highlights the importance of implementing and optimizing GRMT to unlock the full potential of reverse remodeling. The article concludes by suggesting that further research is needed to explore the impact of GRMT on the need for implantable cardioverter-defibrillator (ICD) devices. [Extracted from the article]

The iconic Monarch butterfly is probably the best‐known example of chemical defence against predation, as pictures of vomiting naive blue jays in countless textbooks vividly illustrate. Larvae of the butterfly take up toxic cardiac glycosides from their milkweed hostplants and carry them over to the adult stage. These compounds (cardiotonic steroids, including cardenolides and bufadienolides) inhibit the animal transmembrane sodium‐potassium ATPase (Na,K‐ATPase), but the Monarch enzyme resists this inhibition thanks to amino acid substitutions in its catalytic alpha‐subunit. Some birds also have substitutions and can feast on cardiac glycoside‐sequestering insects with impunity. A flurry of recent work has shown how the alpha‐subunit gene has been duplicated multiple times in separate insect lineages specializing in cardiac glycoside‐producing plants. In this issue of Molecular Ecology, Herbertz et al. toss the beta‐subunit into the mix, by expressing all nine combinations of three alpha‐ and three beta‐subunits of the milkweed bug Na,K‐ATPase and testing their response to a cardenolide from the hostplant. The findings suggest that the diversification and subfunctionalization of genes allow milkweed bugs to balance trade‐offs between resistance towards sequestered host plant toxins that protect the bugs from predators, and physiological costs in terms of Na,K‐ATPase activity. [ABSTRACT FROM AUTHOR]

Following previous studies that have confirmed the therapeutic potential of medicinal plants, scientists are now focusing on the potential of these medicinal plants in resolving issues associated with adverse drug reactions. Reports have been made on medicinal plants having fewer adverse drug reactions than synthetic drugs though a few medicinal plants have been approved by the Food and Drug Administration for therapeutic uses. The main aim of this research was to investigate the therapeutic properties of the leaves of Eriobotrya japonica (Thunb.) Lindl. The leaf constituents of E. japonica were extracted and quantified using maceration methods. The therapeutic potential of these phytochemicals was then investigated focusing on the antioxidant, anti-inflammatory, and antibacterial properties. The antioxidant properties were investigated using a newly proposed method called the Nitrocellulose Permanganometry assay. The anti-inflammatory and antibacterial assays were investigated using the albumin denaturation assay and broth dilution technique respectively. Alkaloids, flavonoids, and saponins showed anti-inflammatory activity by inhibiting albumin denaturation, with alkaloids having the most anti-inflammatory activity as compared to flavonoids and saponins. The relative intensities representing antioxidant potential showed that tannins had the highest antioxidant potency compared to the other tested phytochemicals. All the phytochemicals showed antibacterial activity against Staphylococcus aureus with cardiac glycosides being the most potent. Thus, E. japonica proved to have therapeutic potential as all the phytochemicals obtained from this plant showed anti-inflammatory, antioxidant, and antibacterial activity. Toxicity studies are therefore required to recommend the use of E. japonica as a natural remedy.

• Low-dose digoxin enhanced ATPase activity in the cerebral cortex. • Low-dose digoxin increased long dendritic spines in the cerebral cortex. • Low-dose digoxin did not affect locomotor activity in open-field tests. • Low-dose digoxin improved motor learning in the rotarod test. • The enhancement of motor learning was more noticeable in mice lacking neurotrypsin. Synapse formation following the generation of postsynaptic dendritic spines is essential for motor learning and functional recovery after brain injury. The C-terminal fragment of agrin cleaved by neurotrypsin induces dendritic spine formation in the adult hippocampus. Since the α 3 subunit of sodium–potassium ATPase (Na/K ATPase) is a neuronal receptor for agrin in the central nervous system, cardiac glycosides might facilitate dendritic spine formation and subsequent improvements in learning. This study investigated the effects of cardiac glycoside digoxin on dendritic spine turnover and learning performance in mice. Golgi-Cox staining revealed that intraperitoneal injection of digoxin less than its IC 50 in the brain significantly increased the density of long spines (≥2 µm) in the cerebral cortex in wild-type mice and neurotrypsin-knockout (NT-KO) mice showing impairment of activity-dependent spine formation. Although the motor learning performance of NT-KO mice was significantly lower than control wild-type mice under the control condition, low doses of digoxin enhanced performance to a similar degree in both strains. In NT-KO mice, lower digoxin doses equivalent to clinical doses also significantly improved motor learning performance. These data suggest that lower doses of digoxin could modify dendritic spine formation or recycling and facilitate motor learning in compensation for the disruption of neurotrypsin-agrin pathway. [ABSTRACT FROM AUTHOR]

Belonging to the Euphorbiaceae family, the Para rubber tree is formally referred to as Hevea brasiliensis in scientific terms. It is commonly known as an important economic commodity in Thailand because the natural rubber primarily originates from the milky latex obtained from the tree. However, the available research on the phytochemicals found in different parts of the rubber tree and their biological effects is quite restricted. This study aimed to determine the phytochemical constituents, antioxidant and antibacterial activity studies on the crude dry leaf extracts of H. brasiliensis. The results indicated the presence of alkaloids, anthraquinones, cardiac glycosides, coumarin, flavonoids, saponin, steroids, tannins, and terpenoids. The total phenolic content was 63.95±4.31 mgGAE/g in the ethanolic leaf extract. The ethanolic extract displayed notable effectiveness in scavenging free radicals (71.2±0.17%) at 500 μg/ml concentration and antioxidant capacity (the lowest IC50 value 42.57±0.91 μg/ml). The ethanol extract of the leaf of H. brasiliensis showed inhibition zone on all of the selected bacteria (gram-positive; Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, and gram-negative; Escherichia coli, Pseudomonas aeruginosa) at 200 mg/ml. In conclusion, the dried leaves of H. brasiliensis compose phytochemicals that exhibit antioxidant and antibacterial activities and possesses the potential to act as a reservoir of plant-derived antibiotics and natural antioxidants. [ABSTRACT FROM AUTHOR]

Cardiac glycosides (CGs) have been used for decades to treat heart failure and arrhythmic diseases. Recent non-clinical and epidemiological findings have suggested that CGs exhibit anti-tumor activities. Therefore, CGs may be repositioned as drugs for the treatment of cancer. A detailed understanding of the anti-cancer mechanisms of CGs is essential for their application to the treatment of targetable cancer types. To elucidate the factors associated with the anti-tumor effects of CGs, we performed transcriptome profiling on human multiple myeloma AMO1 cells treated with periplocin, one of the CGs. Periplocin significantly down-regulated the transcription of MYC (c-Myc), a well-established oncogene. Periplocin also suppressed c-Myc expression at the protein levels. This repression of c-Myc was also observed in several cell lines. To identify target proteins for the inhibition of c-Myc, we generated CG-resistant (C9) cells using a sustained treatment with digoxin. We confirmed that C9 cells acquired resistance to the inhibition of c-Myc expression and cell proliferation by CGs. Moreover, the sequencing of genomic DNA in C9 cells revealed the mutation of D128N in α1-Na/K-ATPase, indicating the target protein. These results suggest that CGs suppress c-Myc expression in cancer cells via α1-Na/K-ATPase, which provides further support for the anti-tumor activities of CGs. [ABSTRACT FROM AUTHOR]

Hyophila involuta (Hook) Jaeg., a sample collected from a natural population in the Biological Garden, Obafemi Awolowo University, Nigeria, was sorted into non-sporophytic and sporophytic gametophytes. This was with a view to investigating the possible influence of sporophyte emergence on the bioactive constituents and the antimicrobial potentials of the moss plant. Aqueous extracts of each of the non-sporophytic and the sporophytic gametophyte samples were prepared, and each was subjected to qualitative and quantitative phytochemical screening, gas chromatography-mass spectrometry (GC-MS) analyses, and antimicrobial potentials tests on selected bacteria and fungi following standard procedures. The results showed both extracts testing positive for alkaloids, cardiac glycosides, saponins, and steroids. Quantitatively, alkaloids and cardiac glycosides concentrations were higher in the non-sporophytic than in the sporophytic gametophytes. Nevertheless, the saponins content was higher in sporophytic gametophytes. GC-MS analyses revealed 40 and 46 bioactive compounds in the non-sporophytic and the sporophytic gametophyte samples respectively. The most prominent compound was 1, 13-tetradecadiene (13.62%) in the non-sporophytic gametophyte but cycloheptasiloxane tetradecamethyl- (13.78%) in the sporophytic game-tophyte. Furthermore, the sporophytic gametophyte extract inhibited the growth of Escherichia coli, Pseudomonas aeruginosa , and Candida pseudotropicalis while the non-sporophytic gametophyte extract only inhibited the growth of P. aeruginosa at a minimum inhibitory concentration of 40 mg/mL except for C. pseudotropicalis (20 mg/mL). This study, therefore, provided insight for investigating the medicinal values of bryophytes and concluded that the emergence of sporophytes on gametophytes of a bryophyte species can vary significantly the synthesis of its biologically active compounds and its antimicrobial activity. [ABSTRACT FROM AUTHOR]

Objective: To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment. Data Sources: A systematic search of the MEDLINE (1946 to April 2023) and EMBASE (1974 to April 2023) databases was conducted for articles that focused on the impact of WT or body size on the PK of drugs of interest used in HF patients. Study Selection and Data Extraction: Articles written in English or French related to the aim of our study were retained for analysis. Data Synthesis: Of 6493 articles, 20 were retained for analysis. Weight was associated with the clearance of digoxin, carvedilol, enalapril, and candesartan as well as the volume of distribution of eplerenone and bisoprolol. There was no documented direct impact of WT on the PK of furosemide, valsartan, and metoprolol, although these studies were limited or confounded by the small sample size, adjustment of PK factors by WT, or the use of the Cockroff-Gault equation for the evaluation of creatinine clearance, which includes WT. Relevance to Patient Care and Clinical Practice: This review highlights and summarizes the available data on the importance of WT on the PK of HF treatment. Conclusion: Considering the significant impact of WT on most HF drugs in this review, it may be important to further investigate it in the context of personalized therapy, particularly in patients presenting extreme WTs. [ABSTRACT FROM AUTHOR]

Reactive oxygen species reacts with numerous molecules in the body system causing oxidative damage, which requires antioxidants to ameliorate. Pleurotus ostreatus, a highly nutritious edible mushroom, has been reported to be rich in bioactive compounds. This study evaluated the comparative antioxidant activity and phytochemical contents of five extracts of P. ostreatus: aqueous (AE), chloroform (CE), ethanol (EE), methanol (ME) and n-hexane (HE). The phytochemical composition and antioxidant activity of the extracts were determined using standard in-vitro antioxidant assay methods. Results showed that the extracts contained alkaloids, tannins, saponins, flavonoids, terpenoids, phenolics, cardiac glycosides, carbohydrates, anthrocyanins, and betacyanins in varied amounts. CE had the highest flavonoid content (104.83 ± 29.46 mg/100 g); AE gave the highest phenol content of 24.14 ± 0.02 mg/100 g; tannin was highest in EE (25.12 ± 0.06 mg/100 g); HE had highest amounts of alkaloids (187.60 ± 0.28 mg/100 g) and saponins (0.16 ± 0.00 mg/100 g). Antioxidant analyses revealed that CE had the best hydroxyl radical activity of 250% at 100 µg/ml and ferric cyanide reducing power of 8495 µg/ml; ME gave the maximum DPPH activity (87.67%) and hydrogen peroxide scavenging activity (65.58%) at 500 µg/ml; EE had the highest nitric oxide radical inhibition of 65.81% at 500 µg/ml and ascorbate peroxidase activity of 1.60 (iU/l). AE had the best total antioxidant capacity (5.27 µg/ml GAE at 500 µg/ml) and ferrous iron chelating activity (99.23% at 100 µg/ml) while HE gave the highest guaiacol peroxidase activity of 0.20(iU/l). The comparative phytochemical and antioxidant characteristics (IC50) of the extracts followed the order: CE > AE > EE > ME > HE. Overall, chloroform was the best extraction solvent for P. ostreatus. The high content of phenolic compounds, flavonoids, and alkaloids in P. ostreatus makes it a rich source of antioxidants and potential candidate for the development of new therapies for a variety of oxidative stress-related disorders. [ABSTRACT FROM AUTHOR]