AMIA Jt Summits Transl Sci Proc. 2023 Jun 16;2023:378-387. eCollection 2023.

ABSTRACT

Alzheimer's Disease (AD) is a multifactorial disease that shares common etiologies with its multiple comorbidities, especially vascular diseases. To predict repurposable drugs for AD utilizing the relatively well-investigated comorbidities' knowledge, we proposed a multi-task graph neural network (GNN)-based pipeline that incorporates the corresponding biomedical interactome of these diseases with their genetic markers and effective therapeutics. Our pipeline can accurately capture the interactions and disease classification in the network. Next, we predicted drugs that might interact with the AD module by the node embedding similarity. Our candidates are mostly BBB permeable, and literature evidence showed their potential for treating AD pathologies, accompanying symptoms, or cotreating AD pathology and its common comorbidities. Our pipeline demonstrated a workable strategy that predicts drug candidates with current knowledge of biological interplays between AD and several vascular diseases.

PMID:37350918 | PMC:PMC10283123

Probiotics Antimicrob Proteins. 2023 Jun 22. doi: 10.1007/s12602-023-10105-2. Online ahead of print.

ABSTRACT

Heart failure (HF) is a global pandemic with increasing prevalence and mortality rates annually. Its main cause is myocardial infarction (MI), followed by rapid cardiac remodeling. Several clinical studies have shown that probiotics can improve the quality of life and reduce cardiovascular risk factors. This systematic review and meta-analysis aimed to investigate the effectiveness of probiotics in preventing HF caused by a MI according to a prospectively registered protocol (PROSPERO: CRD42023388870). Four independent evaluators independently extracted the data using predefined extraction forms and evaluated the eligibility and accuracy of the studies. A total of six studies consisting of 366 participants were included in the systematic review. Probiotics are not significant in intervening left ventricular ejection fraction (LVEF) and high-sensitivity C-reactive protein (hs-CRP) when compared between the intervention group and the control group due to inadequate studies supporting its efficacy. Among sarcopenia indexes, hand grip strength (HGS) showed robust correlations with the Wnt biomarkers (p < 0.05), improved short physical performance battery (SPPB) scores were also strongly correlated with Dickkopf-related protein (Dkk)-3, followed by Dkk-1, and sterol regulatory element-binding protein 1 (SREBP-1) (p < 0.05). The probiotic group showed improvement in total cholesterol (p = 0.01) and uric acid (p = 0.014) compared to the baseline. Finally, probiotic supplements may be an anti-inflammatory, antioxidant, metabolic, and intestinal microbiota modulator in cardiac remodeling conditions. Probiotics have great potential to attenuate cardiac remodeling in HF or post-MI patients while also enhancing the Wnt signaling pathway which can improve sarcopenia under such conditions.

PMID:37349622 | DOI:10.1007/s12602-023-10105-2

Comput Biol Chem. 2023 Jun 16;105:107902. doi: 10.1016/j.compbiolchem.2023.107902. Online ahead of print.

ABSTRACT

Breast cancer is characterized as being a heterogeneous pathology with a broad phenotype variability. Breast cancer subtypes have been developed in order to capture some of this heterogeneity. Each of these breast cancer subtypes, in turns retains varied characteristic features impacting diagnostic, prognostic and therapeutics. Basal breast tumors, in particular have been challenging in these regards. Basal breast cancer is often more aggressive, of rapid evolution and no tailor-made targeted therapies are available yet to treat it. Arguably, epigenetic variability is behind some of these intricacies. It is possible to further classify basal breast tumor in groups based on their non-coding transcriptome and methylome profiles. It is expected that these groups will have differences in survival as well as in sensitivity to certain classes of drugs. With this in mind, we implemented a computational learning approach to infer different subpopulations of basal breast cancer (from TCGA multi-omic data) based on their epigenetic signatures. Such epigenomic signatures were associated with different survival profiles; we then identified their associated gene co-expression network structure, extracted a signature based on modules within these networks, and use these signatures to find and prioritize drugs (in the LINCS dataset) that may be used to target these types of cancer. In this way we are introducing the analytical workflow for an epigenomic signature-based drug repurposing structure.

PMID:37348299 | DOI:10.1016/j.compbiolchem.2023.107902

World J Gastroenterol. 2023 May 28;29(20):3103-3118. doi: 10.3748/wjg.v29.i20.3103.

ABSTRACT

BACKGROUND: The transforming growth factor β (TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type II receptor (TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.

AIM: To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.

METHODS: Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.

RESULTS: We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson's trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.

CONCLUSION: DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

PMID:37346154 | PMC:PMC10280794 | DOI:10.3748/wjg.v29.i20.3103

Protein Cell. 2023 Jun 22:pwad038. doi: 10.1093/procel/pwad038. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.

PMID:37345888 | DOI:10.1093/procel/pwad038

J Transl Med. 2023 Jun 21;21(1):403. doi: 10.1186/s12967-023-04263-8.

ABSTRACT

Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.

PMID:37344841 | PMC:PMC10286395 | DOI:10.1186/s12967-023-04263-8

Sci Transl Med. 2023 Jun 21;15(701):eabq7839. doi: 10.1126/scitranslmed.abq7839. Epub 2023 Jun 21.

ABSTRACT

Ca2+/calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and tractability for high-throughput screening. Using this tool, we carried out a drug repurposing screen (4475 compounds in clinical use) in human cells expressing constitutively active CaMKII. This yielded five previously unrecognized CaMKII inhibitors with clinically relevant potency: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. We found that ruxolitinib, an orally bioavailable and U.S. Food and Drug Administration-approved medication, inhibited CaMKII in cultured cardiomyocytes and in mice. Ruxolitinib abolished arrhythmogenesis in mouse and patient-derived models of CaMKII-driven arrhythmias. A 10-min pretreatment in vivo was sufficient to prevent catecholaminergic polymorphic ventricular tachycardia, a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. At cardioprotective doses, ruxolitinib-treated mice did not show any adverse effects in established cognitive assays. Our results support further clinical investigation of ruxolitinib as a potential treatment for cardiac indications.

PMID:37343080 | DOI:10.1126/scitranslmed.abq7839

Eur J Pharm Sci. 2023 Jun 18:106501. doi: 10.1016/j.ejps.2023.106501. Online ahead of print.

ABSTRACT

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1-3 h. Here, we show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells' metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.

PMID:37339708 | DOI:10.1016/j.ejps.2023.106501

BMC Med. 2023 Jun 21;21(1):209. doi: 10.1186/s12916-023-02877-9.

ABSTRACT

BACKGROUND: Currently, the main pharmaceutical intervention for COVID-19 is vaccination. While antidepressant (AD) drugs have shown some efficacy in treatment of symptomatic COVID-19, their preventative potential remains largely unexplored. Analysis of association between prescription of ADs and COVID-19 incidence in the population would be beneficial for assessing the utility of ADs in COVID-19 prevention.

METHODS: Retrospective study of association between AD prescription and COVID-19 diagnosis was performed in a cohort of community-dwelling adult mental health outpatients during the 1st wave of COVID-19 pandemic in the UK. Clinical record interactive search (CRIS) was performed for mentions of ADs within 3 months preceding admission to inpatient care of the South London and Maudsley (SLaM) NHS Foundation Trust. Incidence of positive COVID-19 tests upon admission and during inpatient treatment was the primary outcome measure.

RESULTS: AD mention was associated with approximately 40% lower incidence of positive COVID-19 test results when adjusted for socioeconomic parameters and physical health. This association was also observed for prescription of ADs of the selective serotonin reuptake inhibitor (SSRI) class.

CONCLUSIONS: This preliminary study suggests that ADs, and SSRIs in particular, may be of benefit for preventing COVID-19 infection spread in the community. The key limitations of the study are its retrospective nature and the focus on a mental health patient cohort. A more definitive assessment of AD and SSRI preventative potential warrants prospective studies in the wider demographic.

PMID:37340474 | DOI:10.1186/s12916-023-02877-9

Sci Rep. 2023 Jun 20;13(1):10032. doi: 10.1038/s41598-023-37120-1.

ABSTRACT

Diabetic foot ulcers (DFUs) are a common complication of diabetes and can lead to severe disability and even amputation. Despite advances in treatment, there is currently no cure for DFUs and available drugs for treatment are limited. This study aimed to identify new candidate drugs and repurpose existing drugs to treat DFUs based on transcriptomics analysis. A total of 31 differentially expressed genes (DEGs) were identified and used to prioritize the biological risk genes for DFUs. Further investigation using the database DGIdb revealed 12 druggable target genes among 50 biological DFU risk genes, corresponding to 31 drugs. Interestingly, we highlighted that two drugs (urokinase and lidocaine) are under clinical investigation for DFU and 29 drugs are potential candidates to be repurposed for DFU therapy. The top 5 potential biomarkers for DFU from our findings are IL6ST, CXCL9, IL1R1, CXCR2, and IL10. This study highlights IL1R1 as a highly promising biomarker for DFU due to its high systemic score in functional annotations, that can be targeted with an existing drug, Anakinra. Our study proposed that the integration of transcriptomic and bioinformatic-based approaches has the potential to drive drug repurposing for DFUs. Further research will further examine the mechanisms by which targeting IL1R1 can be used to treat DFU.

PMID:37340026 | DOI:10.1038/s41598-023-37120-1

Sci Rep. 2023 Jun 19;13(1):9952. doi: 10.1038/s41598-023-36872-0.

ABSTRACT

Modifications in the epigenetic landscape have been considered a hallmark of cancer. Histone deacetylation is one of the crucial epigenetic modulations associated with the aggressive progression of various cancer subtypes. Herein, we have repurposed the neprilysin inhibitor sacubitrilat as a potent anticancer agent using in-silico protein-ligand interaction profiler (PLIP) analysis, molecular docking, and in vitro studies. The screening of PLIP profiles between vorinostat/panobinostat and HDACs/LTA4H followed by molecular docking resulted in five (Sacubitrilat, B65, BDS, BIR, and NPV) FDA-approved, experimental and investigational drugs. Sacubitrilat has demonstrated promising anticancer activity against colorectal cancer (SW-480) and triple-negative breast cancer (MDA-MB-231) cells, with IC50 values of 14.07 μg/mL and 23.02 μg/mL, respectively. FACS analysis revealed that sacubitrilat arrests the cell cycle at the G0/G1 phase and induces apoptotic-mediated cell death in SW-480 cells. In addition, sacubitrilat inhibited HDAC isoforms at the transcriptomic level by 0.7-0.9 fold and at the proteomic level by 0.5-0.6 fold as compared to the control. Sacubitrilat increased the protein expression of tumor-suppressor (p53) and pro-apoptotic makers (Bax and Bid) by 0.2-2.5 fold while decreasing the expression of anti-apoptotic Bcl2 and Nrf2 proteins by 0.2-0.5 fold with respect to control. The observed cleaved PARP product indicates that sacubitrilat induces apoptotic-mediated cell death. This study may pave the way to identify the anticancer potential of sacubitrilat and can be explored in human clinical trials.

PMID:37336927 | PMC:PMC10279647 | DOI:10.1038/s41598-023-36872-0

Genes Dis. 2023 Jul;10(4):1402-1428. doi: 10.1016/j.gendis.2022.12.019. Epub 2023 Apr 7.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.

PMID:37334160 | PMC:PMC10079314 | DOI:10.1016/j.gendis.2022.12.019

Front Aging Neurosci. 2023 Jun 2;15:1161405. doi: 10.3389/fnagi.2023.1161405. eCollection 2023.

ABSTRACT

BACKGROUND: Neuroinflammation is one of the key factors leading to neuron death and synapse dysfunction in Alzheimer's disease (AD). Amyloid-β (Aβ) is thought to have an association with microglia activation and trigger neuroinflammation in AD. However, inflammation response in brain disorders is heterogenous, and thus, it is necessary to unveil the specific gene module of neuroinflammation caused by Aβ in AD, which might provide novel biomarkers for AD diagnosis and help understand the mechanism of the disease.

METHODS: Transcriptomic datasets of brain region tissues from AD patients and the corresponding normal tissues were first used to identify gene modules through the weighted gene co-expression network analysis (WGCNA) method. Then, key modules highly associated with Aβ accumulation and neuroinflammatory response were pinpointed by combining module expression score and functional information. Meanwhile, the relationship of the Aβ-associated module to the neuron and microglia was explored based on snRNA-seq data. Afterward, transcription factor (TF) enrichment and the SCENIC analysis were performed on the Aβ-associated module to discover the related upstream regulators, and then a PPI network proximity method was employed to repurpose the potential approved drugs for AD.

RESULTS: A total of 16 co-expression modules were primarily obtained by the WGCNA method. Among them, the green module was significantly correlated with Aβ accumulation, and its function was mainly involved in neuroinflammation response and neuron death. Thus, the module was termed the amyloid-β induced neuroinflammation module (AIM). Moreover, the module was negatively correlated with neuron percentage and showed a close association with inflammatory microglia. Finally, based on the module, several important TFs were recognized as potential diagnostic biomarkers for AD, and then 20 possible drugs including ibrutinib and ponatinib were picked out for the disease.

CONCLUSION: In this study, a specific gene module, termed AIM, was identified as a key sub-network of Aβ accumulation and neuroinflammation in AD. Moreover, the module was verified as having an association with neuron degeneration and inflammatory microglia transformation. Moreover, some promising TFs and potential repurposing drugs were presented for AD based on the module. The findings of the study shed new light on the mechanistic investigation of AD and might make benefits the treatment of the disease.

PMID:37333458 | PMC:PMC10272561 | DOI:10.3389/fnagi.2023.1161405

ArXiv. 2023 May 24:arXiv:2305.15453v1. Preprint.

ABSTRACT

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

PMID:37332567 | PMC:PMC10274948

FEMS Microbes. 2022 Apr 26;3:xtac014. doi: 10.1093/femsmc/xtac014. eCollection 2022.

ABSTRACT

A total of 1253 compounds approved as therapeutic drugs in Japan (Pharmaceuticals and Medical Devices Agency (PMDA)-approved compounds) were screened for their therapeutic effects against Staphylococcus aureus infection using the silkworm infection model. In the first stage of screening with an index of prolonged survival, 80 compounds were identified as hits. Of these, 64 compounds were clinically used as antimicrobial agents, and the remaining 16 compounds were not. The 16 compounds were examined for their dose-dependent therapeutic effects on the silkworm model as a second screening step, and we obtained five compounds as a result. One of the compounds (capecitabine) had no documented in vitro minimum inhibitory concentration (MIC) value against S. aureus. The MIC value of capecitabine against S. aureus strains ranged from 125 to 250 µg/ml, and capecitabine was therapeutically effective at a dose of 200 mg/kg in a murine model of S. aureus infection. These results suggest that silkworm-based drug repositioning studies are of potential value. Furthermore, the therapeutic effects of capecitabine demonstrated in this study provide an important scientific rationale for clinical observational studies examining the association between staphylococcal infection events and capecitabine administration in cancer chemotherapy patients.

PMID:37332511 | PMC:PMC10117882 | DOI:10.1093/femsmc/xtac014

Int J Antimicrob Agents. 2023 Jun 14:106888. doi: 10.1016/j.ijantimicag.2023.106888. Online ahead of print.

ABSTRACT

The rapid emergence and spread of multidrug- or pan-drug-resistant bacterial pathogens, such as ESKAPE, pose a serious threat to global health. However, the development of novel antibiotics is hindered by difficulties in identifying new antibiotic targets and the rapid development of drug resistance. Drug repurposing is an effective alternative strategy for combating antibiotic resistance that both saves resources and extends the life of existing antibiotics in combination treatment regimens. Screening of a chemical compound library identified BMS-833923 (BMS), a smoothened antagonist, that directly kills Gram-positive bacteria and potentiates colistin to destroy various Gram-negative bacteria. BMS did not induce detectable antibiotic resistance in vitro and showed effective activity against drug-resistant bacteria in vivo. Mechanistic studies revealed that BMS caused membrane disruption by targeting membrane phospholipid phosphatidylglycerol (PG) and cardiolipin (CL), promoting membrane dysfunction, metabolic disturbance, leakage of cellular components, and ultimately cell death. The current study describes a potential strategy to enhance colistin efficacy and combat multidrug-resistant ESKAPE pathogens.

PMID:37328075 | DOI:10.1016/j.ijantimicag.2023.106888

J Pathol. 2023 Jun 16. doi: 10.1002/path.6142. Online ahead of print.

ABSTRACT

Lactic acid export from highly glycolytic cancer cells is critical to maintain cellular homeostasis. The identification of syrosingopine as an inhibitor of the lactate transporters monocarboxylate transporter (MCT) 1 and the tumor-induced isoform MCT4 suggests a potential therapeutic intervention. In a recent issue of this journal, Van der Vreken, Oudaert I and colleagues showed that syrosingopine, together with another drug metformin, had a synergistic effect in killing cultured multiple myeloma (MM) cell lines, primary MM blasts from patients, and in a mouse MM model. The antidiabetic drug metformin is currently also being investigated for anticancer efficacy. The synthetic lethality of these two drugs, which have good safety records and are approved for noncancer indications, raises the possibility of their combination for clinical anticancer therapy. © 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:37325933 | DOI:10.1002/path.6142

Heliyon. 2023 Jun;9(6):e17174. doi: 10.1016/j.heliyon.2023.e17174. Epub 2023 Jun 12.

ABSTRACT

We have developed a mechanistic model of SARS-CoV-2 and SARS-CoV infection, exploring the relationship between the viral diffusion in the mucosa and viral affinity for the angiotensin converting enzyme 2 (ACE2) target. Utilising the structural similarity of SARS-CoV and SARS-CoV-2 and a shared viral target receptor (ACE2), but a dramatic difference in upper or lower respiratory tract infectivity, we were able to generate insights into the linkage of mucosal diffusion and target receptor affinity in determining the pathophysiological pathways of these two viruses. Our analysis reveals that for SARS-CoV-2 the higher affinity of ACE2 binding, the faster and more complete the mucosal diffusion in its transport from the upper airway to the region of the ACE2 target on the epithelium. This diffusional process is essential for the presentation of this virus to the furin catalysed highly efficient entry and infection process in the upper respiratory tract epithelial cells. A failure of SARS-CoV to follow this path is associated with lower respiratory tract infection and decreased infectivity. Thus, our analysis supports the view that through tropism SARS-CoV-2 has evolved a highly efficient membrane entry process that can act in concert with a high binding affinity of this virus and its variants for its ACE2 which in turn promotes enhanced movement of the virus from airway to epithelium. In this way ongoing mutations yielding higher affinities of SARS-CoV-2 for the ACE2 target becomes the basis for higher upper respiratory tract infectivity and greater viral spread. It is concluded that SARS-CoV-2 is constrained in the extent of its activities by the fundamental laws of physics and thermodynamics. Laws that describe diffusion and molecular binding. Moreover it can be speculated that the very earliest contact of this virus with the human mucosa defines the pathogenesis of this infection.

PMID:37325453 | PMC:PMC10259165 | DOI:10.1016/j.heliyon.2023.e17174

Case Rep Oncol Med. 2023 Jun 7;2023:2079654. doi: 10.1155/2023/2079654. eCollection 2023.

ABSTRACT

BACKGROUND: Recurrent platinum-resistant clear-cell ovarian cancer has a low overall survival duration of 7-8 months, making it a fatal disease. Currently, chemotherapy is the major kind of treatment, but it offers little advantage. Repurposed conventional drugs have recently been found to offer the ability to control cancer with few side effects and at a reasonable cost to healthcare organizations. Case Presentation. In this case report, we present the case of a 41-year-old Thai female patient diagnosed with recurrent platinum-resistant clear-cell ovarian cancer (PRCCC) in the year 2020. After undergoing chemotherapy for two courses and failing to respond to treatment, she began alternative medicine with repurposing drugs in November 2020. Simvastatin, metformin, niclosamide, mebendazole, itraconazole, loratadine, and chloroquine were also administered. Two months after therapy, a computerized tomography (CT) scan revealed a conflict between a decline in tumor marker levels (CA 125, CA 19-9) and an increase in the number of lymph nodes. However, after continuing all medications for 4 months, the CA 125 level decreased from 303.6 to 54 U/ml, and the CA 19-9 level decreased from 1210.3 to 386.10 U/ml. The patient's EQ-5D-5L score increased from 0.631 to 0.829 (abdominal pain and depression), indicating improved quality of life. Overall survival was 8.5 months, and progression-free survival was 2 months.

CONCLUSION: The response to drug repurposing is demonstrated by a four-month-long improvement in symptoms. This work introduces a novel strategy for the management of recurrent platinum-resistant clear-cell ovarian cancer that needs further evaluation in large-scale studies.

PMID:37323625 | PMC:PMC10266906 | DOI:10.1155/2023/2079654

Biochem Pharmacol. 2023 Jun 13:115644. doi: 10.1016/j.bcp.2023.115644. Online ahead of print.

ABSTRACT

Fibrosis is a pathological repair process common among organs, that responds to damage by replacement of tissue with non-functional connective tissue. Despite the widespread prevalence of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may enable a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy.

PMID:37321414 | DOI:10.1016/j.bcp.2023.115644