J Ginseng Res. 2022 Feb 25. doi: 10.1016/j.jgr.2022.02.006. Online ahead of print.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is currently a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 are directly associated with hyper-activation of innate immune response that excessively produce pro-inflammatory cytokines and induce cytokine storm, leading to multi-organ-failure and significant morbidity/mortality. Currently, several antiviral drugs such as Paxlovid (nirmatrelvir and ritonavir) and molnupiravir are authorized to treat mild to moderate COVID-19, however, there are still no drugs that can specifically fight against challenges of SARS-CoV-2 variants. Panax ginseng, a medicinal plant widely used for treating various conditions, might be appropriate for this need due to its anti-inflammatory/cytokine/viral activities, fewer side effects, and cost efficiency. To review Panax ginseng and its pharmacologically active-ingredients as potential phytopharmaceuticals for treating cytokine storm of COVID-19, articles that reporting its positive effects on the cytokine production were searched from academic databases. Experimental/clinical evidences for the effectiveness of Panax ginseng and its active-ingredients in preventing or mitigating cytokine storm, especially for the cascade of cytokine storm, suggest that they might be beneficial as an adjunct treatment for cytokine storm of COVID-19. This review may provide a new approach to discover specific medications using Panax ginseng to control cytokine storm of COVID-19.

PMID:35233163 | PMC:PMC8876050 | DOI:10.1016/j.jgr.2022.02.006

Nihon Yakurigaku Zasshi. 2022;157(2):111-114. doi: 10.1254/fpj.21085.

ABSTRACT

The expansion of COVID-19 in the world has not ended yet, and the situation in Japan is still unpredictable. Under these circumstances, the development of SARS-CoV-2 treatments such as vaccines and medicines is still underway. We have been conducting research on the drug screening for SARS-CoV-2 using the supercomputer "Fugaku". Specifically, we searched for and identified therapeutic drug candidates that showed high affinity to the target protein (main protease) related to the multiplication of SARS-CoV-2 from among about 2,000 existing drugs by performing molecular dynamics calculations using Fugaku. This is the first attempt in the world to screen drugs on a scale of several thousand using molecular dynamics calculations, and it is a case where we were able to take on the challenge because Fugaku is ranked No. 1 in the world. In this chapter, we will show the impact of the supercomputer "Fugaku" on drug discovery using our search for therapeutic agents for SARS-CoV-2 as an example.

PMID:35228441 | DOI:10.1254/fpj.21085

Adv Exp Med Biol. 2022;1361:269-282. doi: 10.1007/978-3-030-91836-1_15.

ABSTRACT

Single-cell sequencing technologies are revolutionizing cancer research and are poised to become the standard for translational cancer studies. Rapidly decreasing costs and increasing throughput and resolution are paving the way for the adoption of single-cell technologies in clinical settings for personalized medicine applications. In this chapter, we review the state of the art of single-cell DNA and RNA sequencing technologies, the computational tools to analyze the data, and their potential application to precision oncology. We also discuss the advantages of single-cell over bulk sequencing for the dissection of intra-tumor heterogeneity and the characterization of subclonal cell populations, the implementation of targeted drug repurposing approaches, and describe advanced methodologies for multi-omics data integration and to assess cell signaling at single-cell resolution.

PMID:35230694 | DOI:10.1007/978-3-030-91836-1_15

Adv Exp Med Biol. 2022;1361:119-141. doi: 10.1007/978-3-030-91836-1_7.

ABSTRACT

The wealth of knowledge and multi-omics data available in drug research has allowed the rise of several computational methods in the drug discovery field, resulting in a novel and exciting strategy called drug repurposing. Drug repurposing consists in finding new applications for existing drugs. Numerous computational methods perform a high-level integration of different knowledge sources to facilitate the discovery of unknown mechanisms. In this chapter, we present a survey of data resources and computational tools available for drug repositioning.

PMID:35230686 | DOI:10.1007/978-3-030-91836-1_7

mBio. 2022 Mar 1:e0370521. doi: 10.1128/mbio.03705-21. Online ahead of print.

ABSTRACT

Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the in vitro antiviral activity of remdesivir in a cobicistat-like manner. When administered in vivo to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19. IMPORTANCE The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.

PMID:35229634 | DOI:10.1128/mbio.03705-21

Nihon Yakurigaku Zasshi. 2022;157(2):124-127. doi: 10.1254/fpj.21078.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which results in a rapid increase in the number of patients and deaths. In addition, various mutant strains have emerged and to be considered to accelerate the number of infected persons. To overcome this situation, effective strategies against COVID-19 include the development of vaccines to prevent SARS-CoV-2 infection and therapeutic agents that suppress the severity after infection. The drug repositioning approach, which search existing drugs that are effective against COVID-19, are expected to develop anti-COVID-19 drugs. In addition, various methods using human iPSC-derived differentiated cells has been developed to evaluate the efficacy and safety of drugs, and are also used for searching for therapeutic drugs for COVID-19. Here, we would like to describe the recent research and future perspectives for COVID-19 therapeutic drugs from the viewpoint of human iPS cell technology.

PMID:35228444 | DOI:10.1254/fpj.21078

Drug Discov Today. 2022 Feb 25:S1359-6446(22)00080-0. doi: 10.1016/j.drudis.2022.02.022. Online ahead of print.

ABSTRACT

Given the continual increase in the number of patients and the lack of curative treatment, the development of new therapies to treat Alzheimer's disease (AD) is becoming ever more urgent. In this review, we summarize the most promising preclinical studies in, and the significant benefits offered by, nanocarriers to realize the full potential of marketed drugs and identify repurposed drugs. No clinical trials have yet been conducted on nanocarriers for drug repurposing in AD. However, recent preclinical results suggest that nanocarriers could overcome the bioavailability and/or selectivity issues of repurposed drugs, improving their therapeutic efficacy.

PMID:35227886 | DOI:10.1016/j.drudis.2022.02.022

Neurotherapeutics. 2022 Feb 28. doi: 10.1007/s13311-022-01203-0. Online ahead of print.

ABSTRACT

Ischemic stroke is a primary cause of morbidity and mortality worldwide. Beyond the approved thrombolytic therapies, there is no effective treatment to mitigate its progression. Drug repositioning combinational therapies are becoming promising approaches to identify new uses of existing drugs to synergically target multiple disease-response mechanisms underlying complex pathologies. Here, we used a systems biology-based approach based on artificial intelligence and pattern recognition tools to generate in silico mathematical models mimicking the ischemic stroke pathology. Combinational treatments were acquired by screening these models with more than 5 million two-by-two combinations of drugs. A drug combination (CA) formed by ceruletide and alpha-1 antitrypsin showing a predicted value of neuroprotection of 92% was evaluated for their synergic neuroprotective effects in a mouse pre-clinical stroke model. The administration of both drugs in combination was safe and effective in reducing by 39.42% the infarct volume 24 h after cerebral ischemia. This neuroprotection was not observed when drugs were given individually. Importantly, potential incompatibilities of the drug combination with tPA thrombolysis were discarded in vitro and in vivo by using a mouse thromboembolic stroke model with t-PA-induced reperfusion, revealing an improvement in the forepaw strength 72 h after stroke in CA-treated mice. Finally, we identified the predicted mechanisms of action of ceruletide and alpha-1 antitrypsin and we demonstrated that CA modulates EGFR and ANGPT-1 levels in circulation within the acute phase after stroke. In conclusion, we have identified a promising combinational treatment with neuroprotective effects for the treatment of ischemic stroke.

PMID:35226340 | DOI:10.1007/s13311-022-01203-0

Med Sci (Basel). 2022 Feb 18;10(1):15. doi: 10.3390/medsci10010015.

ABSTRACT

Prostate cancer (PCa) is the second most common cancer in men. Common treatments include active surveillance, surgery, or radiation. Androgen deprivation therapy and chemotherapy are usually reserved for advanced disease or biochemical recurrence, such as castration-resistant prostate cancer (CRPC), but they are not considered curative because PCa cells eventually develop drug resistance. The latter is achieved through various cellular mechanisms that ultimately circumvent the pharmaceutical's mode of action. The need for novel therapeutic approaches is necessary under these circumstances. An alternative way to treat PCa is by repurposing of existing drugs that were initially intended for other conditions. By extrapolating the effects of previously approved drugs to the intracellular processes of PCa, treatment options will expand. In addition, drug repurposing is cost-effective and efficient because it utilizes drugs that have already demonstrated safety and efficacy. This review catalogues the drugs that can be repurposed for PCa in preclinical studies as well as clinical trials.

PMID:35225948 | DOI:10.3390/medsci10010015

3 Biotech. 2022 Mar;12(3):71. doi: 10.1007/s13205-022-03130-5. Epub 2022 Feb 15.

ABSTRACT

The increasing prevalence of ischemic stroke combined with limited therapeutic options highlights the compelling need for continued research into the development of future neuro-therapeutics. Death-Associated Protein Kinase 1 (DAPK1) and p53 protein-protein interaction serve as a signaling point for the convergence of apoptosis and necrosis in cerebral ischemia. In this study, we used an integrated chemo-informatics and in vitro experimental drug repurposing strategy to screen potential small-molecule inhibitors of DAPK1-p53 interaction from the United States of America Food and Drug Administration (FDA) approved drug database exhibiting post-ischemic neuroprotective and neuro-regenerative efficacy and mechanisms. The computational docking and molecular dynamics simulation of FDA-approved drugs followed by an in vitro experimental validation identified acarbose, an anti-diabetic medication and caloric restriction mimetic as a potential inhibitor of DAPK1-p53 interaction. The evaluation of post-ischemic neuroprotective and regenerative efficacy and mechanisms of action for acarbose was carried out using a set of experimental methods, including cell viability, proliferation and differentiation assays, fluorescence staining, and gene expression analysis. Post-ischemic administration of acarbose conferred significant neuroprotection against ischemia-reperfusion injury in vitro. The reduced fluorescence emission in cells stained with pS20 supported the potential of acarbose in inhibiting the DAPK1-p53 interaction. Acarbose prevented mitochondrial and lysosomal dysfunction, and favorably modulated gene expression related to cell survival, inflammation, and regeneration. BrdU staining and neurite outgrowth assay showed a significant increase in cell proliferation and differentiation in acarbose-treated group. This is the first study known to provide mechanistic insight into the post-ischemic neuroprotective and neuro-regenerative potential of acarbose. Our results provide a strong basis for preclinical studies to evaluate the safety and neuroprotective efficacy of acarbose against ischemic stroke.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03130-5.

PMID:35223357 | PMC:PMC8847516 | DOI:10.1007/s13205-022-03130-5

Front Microbiol. 2022 Feb 10;13:828984. doi: 10.3389/fmicb.2022.828984. eCollection 2022.

ABSTRACT

The COVID-19 pandemic has had an unprecedented impact on the global economy and public health. Its etiologic agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible, pathogenic and has a rapid global spread. Currently, the increase in the number of new confirmed cases has been slowed down due to the increase of vaccination in some regions of the world. Still, the rise of new variants has influenced the detection of additional waves of rising cases that some countries have experienced. Since the virus replication cycle is composed of many distinct stages, some viral proteins related to them, as the main-protease (Mpro) and RNA dependent RNA polymerase (RdRp), constitute individual potential antiviral targets. In this study, we challenged the mentioned enzymes against compounds pre-approved by health regulatory agencies in a virtual screening and later in Molecular Mechanics/Poisson-Bolzmann Surface Area (MM/PBSA) analysis. Our results showed that, among the identified potential drugs with anti-SARS-CoV-2 properties, Hypericin, an important component of the Hypericum perforatum that presents antiviral and antitumoral properties, binds with high affinity to viral Mpro and RdRp. Furthermore, we evaluated the activity of Hypericin anti-SARS-CoV-2 replication in an in vitro model of Vero-E6 infected cells. Therefore, we show that Hypericin inhibited viral replication in a dose dependent manner. Moreover, the cytotoxicity of the compound, in cultured cells, was evaluated, but no significant activity was found. Thus, the results observed in this study indicate that Hypericin is an excellent candidate for repurposing for the treatment of COVID-19, with possible inhibition of two important phases of virus maturation.

PMID:35222340 | PMC:PMC8866965 | DOI:10.3389/fmicb.2022.828984

Front Neurosci. 2022 Feb 9;16:814445. doi: 10.3389/fnins.2022.814445. eCollection 2022.

ABSTRACT

Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. As a consequence, neurons progressively die and patients progressively lose their ability to coordinate movement and perform daily activities. Therapeutic strategies aim at restoring sufficient frataxin levels or at correcting some of the downstream consequences of frataxin deficiency. However, the classical pathways of drug discovery are challenging, require a significant amount of resources and time to reach the final approval, and present a high failure rate. Drug repositioning represents a viable alternative to boost the identification of a therapy, particularly for rare diseases where resources are often limited. In this review we will describe recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning, and discuss the limitation of such strategies.

PMID:35221903 | PMC:PMC8863941 | DOI:10.3389/fnins.2022.814445

J Dairy Sci. 2022 Feb 24:S0022-0302(22)00115-1. doi: 10.3168/jds.2021-21247. Online ahead of print.

ABSTRACT

Bovine lactoferrin (bLF), a naturally occurring glycoprotein found in milk, has bioactive characteristics against many microbes, viruses, and other pathogens. Bovine lactoferrin strongly inhibits SARS-CoV-2 infection in vitro through direct entry inhibition and immunomodulatory mechanisms. This study reports on the anti-SARS-CoV-2 efficacy of commercially available bLF and common dairy ingredients in the human lung cell line H1437 using a custom high-content imaging and analysis pipeline. We also show for the first time that bLF has potent efficacy across different viral strains including the South African B.1.351, UK B.1.1.7, Brazilian P.1, and Indian Delta variants. Interestingly, we show that bLF is most potent against the B.1.1.7 variant [half-maximal inhibitory concentration (IC50) = 3.7 µg/mL], suggesting that this strain relies on entry mechanisms that are strongly inhibited by bLF. We also show that one of the major proteolysis products of bLF, lactoferricin B 17-41, has a modest anti-SARS-CoV-2 activity that could add to the clinical significance of this protein for SARS-CoV-2 treatment as lactoferricin is released by pepsin during digestion. Finally, we show that custom chewable lactoferrin tablets formulated in dextrose or sorbitol have equivalent potency to unformulated samples and provide an option for future human clinical trials. Lactoferrin's broad inhibition of SARS-CoV-2 variants in conjunction with the low cost and ease of production make this an exciting clinical candidate for treatment or prevention of SARS-CoV-2 in the future.

PMID:35221061 | DOI:10.3168/jds.2021-21247

Methods. 2022 Feb 24:S1046-2023(22)00037-8. doi: 10.1016/j.ymeth.2022.02.007. Online ahead of print.

ABSTRACT

Predicting drug-target interactions (DTIs) is essential for both drug discovery and drug repositioning. Recently, deep learning methods have achieved relatively significant performance in predicting DTIs. Generally, it needs a large amount of approved data of DTIs to train the model, which is actually tedious to obtain. In this work, we propose DeepFusion, a deep learning based multi-scale feature fusion method for predicting DTIs. To be specific, we generate global structural similarity feature based on similarity theory, convolutional neural network and generate local chemical sub-structure semantic feature using transformer network respectively for both drug and protein. Data experiments are conducted on four sub-datasets of BIOSNAP, which are 100%, 70%, 50% and 30% of BIOSNAP dataset. Particularly, using 70% sub-dataset, DeepFusion achieves ROC-AUC and PR-AUC by 0.877 and 0.888, which is close to the performance of some baseline methods trained by the whole dataset. In case study, DeepFusion achieves promising prediction results on predicting potential DTIs in case study.

PMID:35219861 | DOI:10.1016/j.ymeth.2022.02.007

Genomics. 2022 Feb 24:110322. doi: 10.1016/j.ygeno.2022.110322. Online ahead of print.

ABSTRACT

Non-cardiomyocytes (non-CMs) play an important role in the process of cardiac remodeling of chronic heart failure. The mechanism of non-CMs transit and interact with each other remains largely unknown. Here, we try to characterize the cellular landscape of non-CMs in mice with chronic heart failure by using single-cell RNA sequencing (scRNA-seq) and provide potential therapeutic hunts. Cellular and molecular analysis revealed that the most affected cellular types are mainly fibroblasts and endothelial cells. Specially, Fib_0 cluster, the most abundant cluster in fibroblasts, was the only increased one, enriched for collagen synthesis genes such as Adamts4 and Crem, which might be responsible for the fibrosis in cardiac remodeling. End_0 cluster in endothelial cells was also the most abundant and only increased one, which has an effect of blood vessel morphogenesis. Cell communication further confirmed that fibroblasts and endothelial cells are the driving hubs in chronic heart failure. Furthermore, using fibroblasts and endothelial cells as the entry point of CMap technology, histone deacetylation (HDAC) inhibitors and HSP inhibitors were identified as potential anti-heart failure new drugs, which should be evaluated in the future. The combined application of scRNA-seq and CMap might be an effective way to achieve drug repositioning.

PMID:35219850 | DOI:10.1016/j.ygeno.2022.110322

Biochem Pharmacol. 2022 Feb 24:114979. doi: 10.1016/j.bcp.2022.114979. Online ahead of print.

ABSTRACT

Tauopathies are neurodegenerative diseases characterized by the deposition of abnormal tau in the brain. To date, there are no disease-modifying therapies approved by the U.S. Food and Drug Administration (US FDA) for the treatment of tauopathies. In the past decades, extensive efforts have been provided to develop disease-modifying therapies to treat tauopathies. Specifically, exploring existing drugs with the intent of repurposing for the treatment of tauopathies affords a reasonable alternative to discover potent drugs for treating these formidable diseases. Drug repurposing will not only reduce formulation and development stage effort and cost but will also take a key advantage of the established toxicological studies, which is one of the main causes of clinical trial failure of new molecules. In this review, we provide an overview of the current treatment strategies for tauopathies and the recent progress in drug repurposing as an alternative approach to treat tauopathies.

PMID:35219701 | DOI:10.1016/j.bcp.2022.114979

J Ethnopharmacol. 2022 Feb 22:115129. doi: 10.1016/j.jep.2022.115129. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houttuyn is a medicinal ingredient in more than 300 prescriptions in traditional Korean medicine. It is especially important for women's health and blood-related diseases. Recent research revealed that Leonurus japonicus Houttuyn extracts have antioxidative, anticancer, analgesic, anti-inflammatory, and neuroprotective properties.

AIM OF THE STUDY: However, its underlying anti-cancerous mechanisms remain unclear. This study elucidated the anticancer mechanism of Leonurus japonicus Houttuyn in U937 and THP-1 cancer cells.

MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) was used for detecting main compound of Leonurus japonicus Houttuyn, rutin. EZ-Cytox cell viability assay, Western blot analysis, live and dead cell assay, 2', 7' dichlorofluorescin diacetate (DCFDA) assay, quantitative real-time PCR (qRT-PCR) analysis, and microRNA (miR) mimic transfection assay were applied to further investigate anti-cancer efficacies and underlying mechanism in U937 and THP-1 cells.

RESULTS: The main compound of Leonurus japonicus Houttuyn, rutin was detected using HPLC. The cytotoxic effect of Leonurus japonicus Houttuyn was exerted in U937 and THP-1 cancer cells but not in MDBK and IEC-6 normal cells. Leonurus japonicus Houttuyn decreased mitochondria membrane potential (ΔΨm). Consistently, Leonurus japonicus Houttuyn reduced the expression of survivin and cleaved caspase-9, caspase-3, and poly (ADP-ribose) polymerase (PARP). Cell death was increased in Leonurus japonicus Houttuyn treated groups. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and CCAAT-enhancer-binding protein homologous protein (CHOP) was increased and phosphatidylinositol-3-kinase (PI3K) and Protein kinase B (AKT) were decreased by Leonurus japonicus Houttuyn. Reactive oxygen speices generation was elevated by Leonurus japonicus Houttuyn and its cytotoxicity was reversed by N-acetyl-l-cysteine (NAC) pretreatment. Moreover, onco-microRNA (miR), miR-19a-3p was suppressed by Leonurus japonicus Houttuyn and transfection of miR-19a-3p mimic reversed the regulated PTEN, p-AKT, CHOP expression, attenuating Leonurus japonicus Houttuyn induced apoptosis.

CONCLUSIONS: These findings indicated that Leonurus japonicus Houttuyn has anti-cancer effects by regulation of PTEN/PI3K/AKT signal pathway and ROS-related ER stress-induced apoptosis via regulation of miR-19a-3p. Leonurus japonicus Houttuyn may be an effective candidate for triggering PTEN-dependent apoptosis of cancer cells related to acute myeloid leukemia.

PMID:35217209 | DOI:10.1016/j.jep.2022.115129

Pharmaceuticals (Basel). 2022 Feb 18;15(2):247. doi: 10.3390/ph15020247.

ABSTRACT

PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin's antiseizure action.

PMID:35215359 | DOI:10.3390/ph15020247

Pharmaceuticals (Basel). 2022 Feb 10;15(2):212. doi: 10.3390/ph15020212.

ABSTRACT

Because of their epidemic and pandemic potential, emerging viruses are a major threat to global healthcare systems. While vaccination is in general a straightforward approach to prevent viral infections, immunization can also cause escape mutants that hide from immune cell and antibody detection. Thus, other approaches than immunization are critical for the management and control of viral infections. Viruses are prone to mutations leading to the rapid emergence of resistant strains upon treatment with direct antivirals. In contrast to the direct interference with pathogen components, host-directed therapies aim to target host factors that are essential for the pathogenic replication cycle or to improve the host defense mechanisms, thus circumventing resistance. These relatively new approaches are often based on the repurposing of drugs which are already licensed for the treatment of other unrelated diseases. Here, we summarize what is known about the mechanisms and modes of action for a potential use of antifungals as repurposed host-directed anti-infectives for the therapeutic intervention to control viral infections.

PMID:35215323 | DOI:10.3390/ph15020212

Pharmaceuticals (Basel). 2022 Feb 9;15(2):208. doi: 10.3390/ph15020208.

ABSTRACT

Cisplatin is a well-known chemotherapeutic agent used to treat various types of cancers; however, it can also induce anorexia, which results in reduced food intake, loss of body weight, and lower quality of life. Although drugs such as megestrol acetate and cyproheptadine are used to decrease this severe feeding disorder, they can also induce side effects, such as diarrhea and somnolence, which limit their widespread use. Various types of herbal medicines have long been used to prevent and treat numerous gastrointestinal tract diseases; however, to date, no study has been conducted to analyze and summarize their effects on cisplatin-induced anorexia. In this paper, we analyze 12 animal studies that used either a single herbal medicine extract or mixtures thereof to decrease cisplatin-induced anorexia. Among the herbal medicines, Ginseng Radix was the most used, as it was included in seven studies, whereas both Glycyrrhizae Radix et Rhizoma and Angelicae Gigantis Radix were used in four studies. As for the mechanisms of action, the roles of serotonin and its receptors, cytokines, white blood cells, ghrelin, and leptin were investigated. Based on these results, we suggest that herbal medicines could be considered a useful treatment method for cisplatin-induced anorexia.

PMID:35215322 | DOI:10.3390/ph15020208