Pharmaceuticals

The last decades have seen an increase in the isolation and characterization of anticancer compounds derived from marine organisms, especially invertebrates, and their use in clinical trials. In this regard, ascidians, which are included in the subphylum Tunicata, represent successful examples with two drugs, Aplidine(C) and Yondelis(C), that reached the market as orphan drugs against several malignancies. Here, we report that an organic extract prepared from homogenized tissues of the Mediterranean ascidian Ciona robusta inhibited cell proliferation in HT-29, Hep G2, and U2 OS human cells with the former resulting as the most sensitive to the extract (EC50 = 250 {micro}g/ml). We demonstrated that the ascidian organic extract was not cytotoxic on HT-29 cells induced to differentiate with sodium butyrate, suggesting a preference for the mixture for the malignant phenotype. Finally, we reported that the cell death induced by the organic extract was mediated by the activation of a process of cytotoxic autophagy as a result of the increased expression of the LC3-II marker and the number of autophagic vacuoles, which almost doubled in treated HT-29 cells. In summary, although the detailed chemical composition of the Ciona robusta extract is still undetermined, our data suggest the presence in it of bioactive compounds possessing anticancer activity.

Cannabidiol (CBD) and Cannabigerol (CBG) are non-psychoactive cannabinoids known to affect both cancerous and non-cancerous cells. Autophagy is a critical regulator of cell survival and death; however, the impact of CBD and CBG on cell viability through autophagy remains limited. In this study, we show that low-dose combinations of CBD and CBG synergistically enhance Caco-2 cell proliferation, achieving effects comparable to those observed at higher doses. Both cannabinoids--whether applied individually at high concentrations or in low-dose combinations--activate autophagy. Correlation analyses between cell viability and autophagic flux, along with comparative assessments of wild-type and ATG9-deficient Caco-2 cells, demonstrate that the survival-promoting effects of CBD and CBG are closely associated with autophagy activation. Overall, these findings reveal that both individual and combined treatments significantly modulate Caco-2 cell viability under conditions with or without autophagy activation, emphasizing the substantial role of cannabinoid-regulated autophagy in influencing cell survival. HighlightsO_LILow-dose combinations of CBD and CBG synergistically enhance Caco-2 cell proliferation. C_LIO_LIBoth high-dose individual treatments and low-dose combinations of CBD and CBG activate autophagy. C_LIO_LICBD- and CBG-mediated autophagy paly beneficial role in supporting Caco-2 cell survival. C_LI

The rapid development of research on the therapeutic benefits of medicinal cannabis, in parallel with an increased understanding of the endocannabinoid system, has driven research of Cannabis sativa constituents for managing neurological conditions. While most studies have focused on the therapeutic potential of the major components of cannabis plant extract isolated or combined, limited research has explored the pharmacological benefits of whole cannabis plant extract. In this study, we investigated the potential anti-inflammatory and neuroprotective effects of NTI-164, a novel full-spectrum cannabis extract with negligible {Delta}9-tetrahydrocannabinol (THC), compared with cannabidiol (CBD) alone in BV-2 microglial and SHSY-5Y neuronal cells. The inflammation-induced upregulation of microglial inflammatory mediators, being tumour necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible nitric oxide synthase (iNOS), and Arginase-1 (Arg-1), were significantly attenuated by NTI-164. This immunomodulatory effect was not observed upon treatment with isolated CBD. Compared to CBD alone, NTI-164 prevented elevated mitochondrial activity while normalising cell numbers in immune-activated microglia cells. NTI-164 also promoted the proliferation of undifferentiated neurons and the survival of differentiated neurons under excitotoxic conditions. Overall, our work shows that the anti-inflammatory and neuroprotective effects of NTI-164 as a full-spectrum cannabis extract are enhanced relative to that of CBD alone, highlighting the potential therapeutic efficacy of NTI-164 for the treatment of neuropathologies such as autism spectrum disorder (ASD) and related neuropathologies. This study has further shown that understanding the synergistic effect of phytocannabinoids is integral to realising the therapeutic potential of full-spectrum cannabis extract to inform the design of botanical-derived treatments for managing neurological disorders.

Allergic rhinitis (AR), a chronic inflammatory disease associated with comorbidities, adversely affects lifes quality, productivity and increases financial healthcare burden. Herbal medicines are emerging for AR treatment. The presence of two immunomodulatory lectins (jacalin and artinM) in jackfruit (Artocarpus heterophyllus) seeds suggests a probable therapeutic potential of jackfruit seed extract in AR management. A double-blind, placebo-controlled pilot trial of jackfruit seed extract formulation (JaSE) was conducted in 60 AR patients to assess its AR treatment efficacy by evaluating changes in AR symptoms (score-based) over 15 days of treatment. The study was approved by the Institutional Ethics Review Committee and was registered with CTRI (CTRI/2023/08/056311). Out of 60 patients enrolled, 53 completed the trial. No adverse events were reported throughout the study. Post-treatment, both the JaSE and placebo (saline) groups demonstrated statistically significant reduction in AR symptoms. The potential of JaSE in relieving AR symptoms was observed, though non-significant as compared to placebo. Absence of statistically significant difference between two treatment groups may be attributed to the placebo effect and small sample size. Expanding sample size and conducting adequately powered clinical trials in future will be essential to accurately assess the efficacy of the novel candidate JaSE in AR management.

Osteoarthritis (OA) is the most prevalent disorder of articulating joints and a leading cause of disability in humans, affecting half of the worlds population aged 65 years or older. Articular cartilage and synovial tissue from OA patients show an overactivity of the membrane channel protein connexin43 (Cx43) and accumulation of senescent cells associated with disrupted tissue regeneration. We have recently demonstrated the use of the Cx43 as an appropriate therapeutic target to halt OA progression by decreasing the accumulation of senescent cells and by triggering redifferentiation of osteoarthritic chondrocytes (OACs) into a more differentiated state, restoring the fully mature phenotype and cartilage regeneration. In this study we have found that small molecular polyphenols derived by olive extracts target Cx43 and senescence in OACs, synovial and bone cells from patients and in human mesenchymal stem cells (hMSCs). Our results indicate that these small molecules including oleuropein regulate the promoter activity of Cx43 gene. The downregulation of Cx43 expression by oleuropein reduce gap junction intercellular communication, cellular senescence in chondrocytes and enhance the propensity of hMSCs to differentiate into chondrocytes and bone cells, reducing adipogenesis. In concordance with these results, these small molecules reduce Cx43 and decrease Twist-1 activity leading to redifferentiation of OACs, which restores the synthesis of cartilage ECM components (Col2A1 and proteoglycans) and reduces inflammatory and catabolic factors IL-1{beta}, IL-6, COX-2 and MMP-3 and cellular senescence orchestrated by p53/p21 together with the synthesis of SASP via NF-kB. Altogether, our results demonstrate the use of the olive-derived polyphenols such as oleuropein as potentially effective therapeutic agents to enhance the efficacy of hMSC therapy and to induce a pro-regenerative environment in OA patients by restoring cellular phenotype and clearing out senescent cells in joint tissues in order to stop or prevent the progression of the disease.

There is increasing evidence for an autoimmune aetiology in post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). SARS-CoV-2 has now become the main trigger for ME/CFS. We have already conducted two small proof-of-concept studies of IgG depletion by immunoadsorption (IA) in post-infectious ME/CFS, which showed efficacy in most patients. This observational study aims to evaluate the efficacy of IA in patients with post-COVID-19 ME/CFS. The primary objective is to assess the improvement in functional ability. Due to the urgency of finding therapies for post-Covid-Syndrome (PCS), we report here the interim results of the first ten patients with seven responders defined by an increase of between 10 and 35 points in the Short-Form 36 Physical Function (SF36-PF) at week four after IA. The results of this observational study will provide the basis for patient selection for a randomised controlled trial (RTC) including sham apheresis and for a RTC combining IA with B-cell depletion therapy.

BackgroundImmunodaat, a proprietary botanical extract, contains standardized extract of Elderberry (Sambucus Nigra L.). Elderberry is used as an immunity enhancer for prevention and management of various respiratory diseases and as an anti-oxidant. ObjectivesThe present study evaluated the effect of Immunodaat, in Post Covid-19 recovery. MethodsAn open labeled, comparative, randomized, multi-centric, prospective clinical study was conducted on 74 subjects who had post COVID-19 symptoms recovery from mild-moderate COVID-19 within the last 15 days. Subjects were divided equally, with 37 subjects in trial and control groups each, where subjects in trial group were given Immunodaat capsules in a dose of 250 mg Capsules twice daily along with the standard care for COVID-19 for consecutive 30 days while subjects in control group were given only the standard care for Post Covid. Subjects were evaluated for post clinical recovery signs and symptoms (like cough, fatigue, Myalgia, Joint pain, confusion, altered mood, anxiety, insomnia etc.) and lab parameters. Subjects were evaluated for quality of life using WHO QOL BREF. ResultsContinuous 30 days administration of Immunodaat showed a significant difference in reducing physical as well as mental symptoms when compared to the control group. Also, a significant improvement in quality of life was observed on WHO QOL BREF scale with the use of Immunodaat compared to the control group. Overall quality of life, energy levels and stamina levels improved with the use of Immunodaat. Subjects showed excellent tolerability and did not have any adverse effect with the use of Immunodaat. ConclusionThe study concludes that use of Immunodaat over 30 days aided to normalize the physical and mental symptoms that occurred due to Post COVID and long COVID. Immunodaat can be considered as a safe and effective natural ingredient in the management of Post COVID-19 or long COVID condition.

The present study systematically investigated the role of sodium starch glycolate, kollidon CL, and ludiflash in nine (9) formulations (F-1 to F-9) of clonazepam orally fast disintegrating tablets (OFDT) developed via direct compression. Advanced preformulating assessments ensured optimal flow properties and compressibility, facilitating robust tablet manufacturing. In vitro dissolution studies revealed that formulations incorporating different superdisintegrants (F-3, F-6, and F-9) exhibited superior drug release profiles with faster drug release, attributed to the concentration and characteristics of the excipients, with F-5 demonstrating the highest dissolution efficiency (94%). Drug release kinetics followed first-order models with anomalous (non-Fickian) diffusion mechanisms, highlighting the interplay between formulation composition and drug release behavior. Similarity factor (f2) analysis confirmed moderate alignment with the marketed product, identifying key areas for further optimization. Stability testing, conducted under ICH guidelines, demonstrated the long-term integrity of all formulations. This study bridges a critical research gap by providing an in-depth analysis of superdisintegrants selection, dissolution behavior, and stability, offering a strategic approach for optimizing OFDT formulations for improved therapeutic efficacy and patient compliance. Author SummaryOptimization of superdisintegrants in clonazepam orally fast disintegrating tablets : Impact on dissolution, drug release, and stability is based on the pharmaceutical formulation and development of OFDT of clonazepam, a benzodiazepine used for treating epilepsy and panic disorders. The research aims to enhance the disintegration efficiency, dissolution rate, and bioavailability of the drug by incorporating three superdisintegrants: sodium starch glycolate, kollidon CL, and ludiflash through the direct compression method, a widely used pharmaceutical manufacturing process. The study involves preformulation analysis, physicochemical evaluation, in vitro dissolution studies, and stability testing under ICH guidelines, ultimately identifying F-5 as the most effective formulation with 94% dissolution efficiency. The findings contribute to the optimization of excipient selection in fast-dissolving formulations to improve the therapeutic performance and patient compliance of clonazepam.

Several vaccines against SARS-CoV-2 have been granted emergency use authorization from the United States Food and Drug Administration and similar regulatory bodies abroad to combat the COVID-19 pandemic. While these vaccines have been shown to be extremely safe, transient side-effects lasting 24-48 hours post-vaccination have been reported. Here we conducted a retrospective analysis of 50977 subscribers to the WHOOP platform (33119 males, 17858 females; total of 65686 unique responses) who received either the AstraZeneca (AZ, n=2093), Janssen/Johnson & Johnson (J&J&J, n=3888), Moderna (n=23776; M1, 14553 first dose; M2, 9223 second dose), or Pfizer/BioNTech (n=35929; P&B1, 22387 first dose; P&B2, 13542 second dose) vaccines using data collected through April 14, 2021. Subjective reactogenicity was assessed using self-reported surveys. Results from these surveys indicated that the odds of self-reporting an adverse event after vaccination depend on gender, age, and manufacturer. Objectively measured cardiovascular (resting heart rate, RHR; heart rate variability, HRV) and sleep (total sleep duration, % light sleep, and % restorative sleep [a combination of REM and slow wave sleep]) metrics were assessed using a wrist-worn biometric device (Whoop Inc, Boston, MA, USA) and compared to the same day of the week, one week prior. Data are presented as a percent change from baseline {+/-} 95% confidence intervals. On the night after vaccination, RHR was higher (AZ: 13.5{+/-}0.76%; J&J&J: 16.5{+/-}0.64%; M1: 2.86{+/-}0.19%; M2: 9.3{+/-}0.53%; P&B1: 1.18{+/-}0.14%; P&B2: 13.5{+/-}0.36%) and HRV (AZ: -21.8{+/-}1.47%; J&J&J: - 25.6{+/-}1.15%; M1: -4.8{+/-}055%; M2: -19.9{+/-}1.33%; P&B1: -1.7{+/-}0.45%; P&B2: 8.60{+/-}1.10%) was lower than baseline levels. As for sleep metrics, total sleep was lower after the AZ and J&J&J vaccines (AZ: -3.7{+/-}0.98%; J&J&J: -3.8{+/-}0.80%; M1: 0.94{+/-}0.32%; M2: 0.14{+/-}0.80%; P&B1: 1.10{+/-}0.25%; P&B2: 0.35{+/-}0.63%); for AZ, J&J&J and the second dose of Moderna and P&B, a greater percentage of sleep post-vaccination came from light sleep (AZ: 9.24{+/-}1.22%; J&J&J: 13.8{+/-}1.02%; M1: 1.73{+/-}0.40%; M2: 8.02{+/-}0.99%; P&B1: 0.44{+/-}0.31%; P&B2: 2.54{+/-}0.74%) and a lower percentage from restorative sleep (AZ: -9.21{+/-}1.27%; J&J&J: -12.6{+/-}1.00%; M1: 0.16{+/-}0.43%; M2: -8.31{+/-}1.05%; P&B1: 1.27{+/-}0.34%; P&B2: -1.36{+/-}0.83%) than the week prior. Across all objective metrics measured, there were general trends that indicated an attenuated response in older populations and a larger response after the second dose for the Pfizer/BioNTech and Moderna vaccines (AstraZeneca second dose not analyzed). Importantly, the effects of the vaccines on cardiovascular and sleep measures were transient and returned to baseline by the second night following vaccination (P > 0.05 or absolute Cohens d < 0.25). In summary, these results confirm the previously observed subjective symptomatology trends, and for the first time show that objectively measured cardiovascular and sleep parameters are altered the night after vaccination. Moreover, these results suggest that the response may be different between vaccine manufacturers and may be modified by age and larger after the second dose. This information can be used to inform policy makers and employers considering offering paid time off for vaccination, as well as individuals planning their commitments post-vaccination.

The popularity of the specially synthesized cell-penetrating peptides (CPPs) in cancer treatment has grown recently. The main aim of this study was to investigate the effects of four mitochondrially targeted antioxidant CPPs on the viability and bioenergetic function of mitochondria in human adenocarcinoma Caco-2 cells. The number of viable cells was measured by MTT and trypan blue assays. Respirometry and the permeabilized cell technique were applied to measure the mitochondrial function in this cell line. We did not observe any significant effect of CPPs on the mitochondrial reserve respiratory capacity, the function of respiratory chain complexes, and the inclination of these cancer cells to aerobic glycolysis. mtgCPP peptide with the highest antioxidant activity demonstrated improved mitochondrial coupling efficiency. CPPs do not affect mitochondrial function directly but can be considered in therapeutics as a drug-delivery moleculeCompeting Interest StatementThe authors have declared no competing interest.Abbreviations usedAKadenylate kinase;Ap5Adiadenosine pentaphosphate;CATcarboxyatractyloside;CRCcolorectal cancer;CPPscell-penetrating peptides;HKhexokinase;FAM5-(6)-carboxyfluorescein;MTT3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazoliumbromide;OXPHOSoxidative phosphorylation;ROSreactive oxygen species;TMPDN,N,N’,N’-tetramethyl-phenylenediamine;VDACvoltage dependent anion channel.View Full Text

Psychedelics are new, promising candidate molecules for clinical use in psychiatric disorders such as Treatment-Resistant Depression (TRD) and Post Traumatic Stress Disorder (PTSD). They were recently also proposed as molecules supporting neural tissue repair by anti-inflammatory properties. Here we reported that two classic psychedelics, DMT and psilocin, can influence microglial functions by reducing the level of TLR4, p65, CD80 proteins, which are markers of the immune response, and upregulat TREM2 neuroprotective receptor. Psilocin also secured neuronal survival in the neuron-microglia co-culture model by attenuating the phagocytic function of microglia. We conclude that DMT and psilocin regulate the immunomodulatory potential of microglia. Of note, psychedelics were previously reported as a relatively safe treatment approach. The demonstrated regulation of inflammatory molecules and microglia phagocytosis suggests that psychedelics or their analogs are candidates in the therapy of neurological disorders where microglia and inflammation significantly contribute to pathogenic disease mechanisms.

Cannabidiol (CBD) and cannabigerol (CBG) are non-psychoactive cannabinoids that exert diverse biological activities in both normal and cancerous epithelial cells. Although autophagy plays a pivotal role in maintaining cellular homeostasis, the effects of combined CBD-CBG treatment on autophagic regulation across epithelial cell types remain largely unexplored. In this study, GFP-LC3-RFP reporter assays and ATG9-deficient cell models were employed to examine the influence of CBD and CBG on autophagy in Ca9-22 and HaCaT cells. Certain concentrations of either compound alone failed to induce autophagy and, in some cases, appeared to suppress autophagic activity. In contrast, their combined administration markedly enhanced autophagic flux in both cell lines. Low-dose CBG or high-dose CBD promoted differential greater cell survival in HaCaT-WT cells compared to their ATG9-KO counterparts. Collectively, these findings provide novel insights into the cooperative regulation of autophagy by CBD and CBG, underscoring their combined effects on cellular autophagic responses in cancer or normal epithelial cells. HighlightsO_LIIn both Ca9-22 and HaCaT cells, certain doses of CBD alone failed to induce autophagy, whereas CBG at some concentrations showed a trend toward autophagy suppression. C_LIO_LISub-effective doses of CBD and CBG in combination enhance autophagic flux in Ca9-22 and HaCaT cells, with some combinations exceeding the flux induced by higher doses of either compound alone. C_LIO_LICBD and CBG exhibit distinct dose-dependent effects on the survival of HaCaT ATG9-deficient cells compared with HaCaT-WT cells, indicating differential ATG9-dependence. C_LI

Extensive research around mRNA vaccines and their proposed utility during the current COVID-19 pandemic resulted in many publications concerning the SARS-Cov-2 spike protein and angiotensin converting enzyme-2 receptor-binding domain of the virus, but none describe the characteristics of the full-length protein obtained from the modified/synthetic mRNA that is part of the Moderna and Pfizer-BioNTech vaccines. In this paper, we provide the first data characterizing the actual proteins produced by mouse and human cells in culture that had been incubated up to 30 minutes with the commercial vaccine produced by Moderna (i.e., Spikevax). The mRNA vaccine continues to produce proteins up to 12-14 days after introduction to the cells. The molecular weight of the SARS-CoV-2 encoded protein ranges from 135-200 kilodaltons depending on the extent of glycosylation.

Cannabis Sativa a medical plant rich in phytochemicals have a range of terpenoids and cannabinoids with a wide range of therapeutic uses. The possible interaction of terpenoids with cannabinoid receptors implicated in analgesic pathways has not received enough attention. This work used in silico methods to target Cannabinoid Receptors Type I (CNR1) and II (CNR2) in order to find novel terpenoid compounds from Cannabis sativa that may have pain-relieving properties. QSAR modelling based on known cannabinoid receptor inhibitors was used to build and screen a curated library of 119 terpenoids. The terpenoid library was screened using pharmacophore models that were created. Molecular docking was performed on the top candidates using CNR1 (PDB: 5U09) and CNR2 (PDB: 5ZTY). To evaluate the stability of receptor-ligand complexes over 100 ns, molecular dynamics simulations were run. SwissADME was used for ADMET profiling in order to assess drug-likeness and pharmacokinetic characteristics. Both receptors QSAR models showed strong predictive power (CNR1: r2 = 0.854; CNR2: r2 = 0.798). {gamma}-Eudesmol and Bisabolol were the top hits for CNR1 and CNR2, respectively, according to pharmacophore screening. Strong binding affinities were demonstrated by molecular docking ({gamma}-Eudesmol: -7.9 kcal/mol; Bisabolol: -8.5 kcal/mol), and simulations verified the stable connections. Both compounds were drug-like, according to ADMET analysis, while {gamma}-Eudesmol had better synthetic accessibility and fewer structural alarms. According to the results, bisabolol and {gamma}-Eudesmol show promise as cannabinoid receptor-targeted analgesics. The finding encourages more biological validation and emphasises the potential of terpenoids obtained from Cannabis sativa in medicinal medication discovery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/674146v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@3e2544org.highwire.dtl.DTLVardef@cefborg.highwire.dtl.DTLVardef@114cf19org.highwire.dtl.DTLVardef@128b069_HPS_FORMAT_FIGEXP M_FIG C_FIG

Turmeric extract (TE) with curcumin as its main active ingredient has been studied as a potential COVID-19 therapeutic. Curcumin has been studied in silico and in vitro against a naive SARS-CoV-2 virus, yet little is known about TEs impact on SARS-CoV-2 infection. Moreover, no study reveals the potential of both curcumin and TE on the inhibition of SARS-CoV-2 cell-to-cell transmission. Here, we investigated the effects of both curcumin and TE on inhibiting SARS-CoV-2 entry and cell-to-cell transmission using pseudovirus (PSV) and syncytia models. We performed a PSV entry assay in 293T or 293 cells expressing hACE2. The cells were pretreated with curcumin or TE and then treated with PSV with or without the test samples. Next, we carried out syncytia assay by co-transfecting 293T cells with plasmids encoding spike, hACE2, and TMPRSS2 to be treated with the test samples. The results showed that in PSV entry assay on 293T/hACE/TMPRSS2 cells, both curcumin and TE inhibited PSV entry at concentrations of 1 {micro}M and 10 {micro}M for curcumin and 1 {micro}g/ml and 10 {micro}g/ml for TE. Moreover, both curcumin and TE reduced syncytia formation compared to control cells. Our study shows that TE and curcumin are potential inhibitors of SARS-CoV-2 infection at entry points, either by direct or indirect infection models. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/560070v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@18f3faforg.highwire.dtl.DTLVardef@19e2818org.highwire.dtl.DTLVardef@5a6670org.highwire.dtl.DTLVardef@fb82d8_HPS_FORMAT_FIGEXP M_FIG C_FIG

The jasmonates are a class of oxylipin phytohormones known to exhibit anti-inflammatory, antioxidant, and anti-cancer effects in mammalian cells. We investigated the ability of three jasmonate compounds (jasmonic acid, methyl jasmonate, and 12-OPDA) and two structurally distinct jasmonate precursors (alpha-linolenic acid and palmitic acid) to attenuate inflammation in an in vitro model of neurodegenerative disease, for which the mechanisms of action have not been well identified. The study modeled chronic neuroinflammation in SH-SY5Y neuroblastoma cells using exogenous prostaglandin E2 (PGE2) treatment. Prostaglandin E2 caused concentration-dependent levels of inflammation and SH-SY5Y cell death, which were attenuated by the jasmonates and their precursors. To this end, structural similarities between the jasmonates and PGE2 were correlated with increased potency of their anti-inflammatory effects. Downstream biomarkers of signaling through the pro-inflammatory E prostanoid receptor subtype 2 (EP2) were then quantified using enzyme-linked immunosorbent assay methods. Of the compounds tested, only jasmonic acid and methyl jasmonate attenuated inflammation in the SH-SY5Y cells via crosstalk with the PGE2/EP2 signaling axis. Additionally, structural models and molecular binding simulations serve as evidence for our hypothesis that JA and MeJA achieve this crosstalk through competitive inhibition of the receptor EP2. This novel finding has implications in the study of neurodegenerative diseases for which the disease pathology is related to chronic neuroinflammation, including Alzheimers Disease (AD), Parkinsons Disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In addition, these findings add to the understanding of the relationship between pro-inflammatory prostaglandin E2 signaling and disease severity.

The use of Psychedelics by patients with cancer to relieve anxiety and depression has increased in the past few years. Since Psychedelics have immunomodulatory effects, their consumption among cancer patients should be carefully considered due to their potential negative effects on the tumor immune stroma, especially in view of the increase in the utilization of therapeutic approaches that are based on immune activation such as treatment with immune checkpoint inhibitors (ICIs). Preclinical data provided in this report indicate a potentially negative impact on tumor growth as a result of Psychedelics consumption during treatment with ICIs. Furthermore, our research suggests that the use of psychedelic agents (Lysergic acid diethylamide [LSD] or Psylocibin) might diminish the beneficial therapeutic benefits of ICIs. It might be necessary to expend this line of research in order to validate these findings, in view of the increase use of cannabinoids and psychedelics among cancer patients, some of them being treated with immune-based modalities.

Excess fat accumulation contributes to metabolic disorders such as insulin resistance, type 2 diabetes, cardiovascular disease and increases risk of dementia. Promoting lipolysis and inhibiting adipogenesis through natural compounds offers a promising therapeutic approach to obesity. This study investigates the lipolytic and anti-adipogenic effects of capsaicin, camphor, and caffeic acid in human Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte model. First, we determined appropriate treatment concentrations using MTT assays, which demonstrated a dose dependent reduction in cell viability for all three compounds. Selected doses were applied to differentiating SGBS cells until day 14. Lipid droplet accumulation and free fatty acid release were assessed using Oil Red O (ORO) staining and a lipolysis assay kit, respectively. Gene expression of adipogenic and lipolytic markers was analysed by RT-PCR and TRPV1 receptor involvement was examined by immunofluorescence. A network pharmacology approach incorporating GeneCards, STITCH, and other databases revealed downregulation of PPARG, CEBPA, and FABP4, and upregulation of HSL, ATGL, and PLIN1. TRPV1 activation was prominent in capsaicin treated cells. Network analysis identified shared regulatory hubs such as PPARG, STAT3, and MTOR. All treatments significantly reduced lipid accumulation and increased lipolysis, with capsaicin showing the strongest effects. Combination treatments, especially capsaicin with caffeic acid, exhibited synergistic effects. While the previous studies showed interference of these compounds in the molecular pathways involved in fat cell metabolism, our work establishes for the first time potential thermogenic capacity of camphor individually and of combinatory effects of three compounds to inhibit adipogenesis and promote lipolysis in human adipocytes, potentially through TRPV1 signalling and modulation of metabolic gene networks. These findings highlight their therapeutic potential for metabolic disorders.

Allicin, a natural sulfur-rich compound, is formed when garlic is crushed or chopped. It has been used for centuries as a natural defence against bacteria and fungi. However, we do not fully understand how well it works against viruses, such as SARS-CoV-2. In this study, we investigated the effect of allicin on the expression of the SARS-CoV-2 receptor-binding domain of the spike protein in human primary splenic fibroblasts. These cells were transfected with a plasmid encoding RBD-S protein fused to a superfolder green fluorescent protein (sfGFP), a bright, stable marker. When cells were treated with 50{square}{micro}M allicin, either 30 min before or 6 h after transfection, a pronounced drop in fluorescence was observed, indicating reduced spike protein expression. Interestingly, the cell morphology, growth, and behavior remained normal, indicating that allicin could minimize spike protein levels without being toxic to the cells. These results open the door to the use of allicin as a gentle, natural antiviral agent and raise critical questions regarding the regulation of protein expression after transcription. Further research is required to understand these effects better.

Peptide-based drugs are widely used as therapeutic products that exhibit strong binding affinities with high specificity and low toxicity. To develop novel therapeutics against severe involuntary muscle movement and trembling disorder (Dyskinesia), the study explored the design of peptides that could target the nicotine acetylcholine receptor (nAChR) as antagonistic leads. The work aimed to suggest that the pharmacological interaction of snake venom toxins and its associated peptides with nAChRs could be exploited as plausible solutions for PD. Molecular docking and Molecular dynamics exercises were carried out using long chain neurotoxins (-BTx, 1NTN) to analyze the efficacies of their binding to nAChRs, with both the entire toxin and short peptide moieties. The study demonstrated that the novel-peptide (F8J2D7) system appears to possess better affinity with the nAChR than the entire toxin, which is a first step towards designing peptide-based drugs from snake venom proteins that could facilitate further research in the peptide-engineering and drug designing prospects for various neurodegenerative diseases.