DRD4 promotes chemo-resistance and cancer stem cell-like phenotypes by mediating the activation of the Akt/ß-catenin signaling axis in liver cancer.

BACKGROUND: Liver cancer stem cells (LCSCs) significantly impact chemo-resistance and recurrence in liver cancer. Dopamine receptor D4 (DRD4) is known to enhance the cancer stem cell (CSC) phenotype in glioblastoma and correlates with poor prognosis in some non-central nervous system tumors; however, its influence on LCSCs remains uncertain. METHODS: To investigate the gene and protein expression profiles of DRD4 in LCSCs and non-LCSCs, we utilized transcriptome sequencing and Western blotting analysis. Bioinformatics analysis and immunohistochemistry were employed to assess the correlation between DRD4 expression levels and the pathological characteristics of liver cancer patients. The impact of DRD4 on LCSC phenotypes and signaling pathways were explored using pharmacological or gene-editing techniques. Additionally, the effect of DRD4 on the protein expression and intracellular localization of ß-catenin were examined using Western blotting and immunofluorescence. RESULTS: DRD4 expression is significantly elevated in LCSCs and correlates with short survival in liver cancer. The expression and activity of DRD4 are positive to resistance, self renewal and tumorigenicity in HCC. Mechanistically, DRD4 stabilizes ß-catenin and promotes its entry into the nucleus via activating the PI3K/Akt/GSK-3ß pathway, thereby enhancing LCSC phenotypes. CONCLUSIONS: Inhibiting DRD4 expression and activation offers a promising targeted therapy for eradicating LCSCs and relieve chemo-resistance.

Role of hydrogen sulfide in health and disease.

In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H2S can act as an endogenous regulatory transmitter. In mammals, H2S-catalyzing enzymes, such as cystathionine-ß-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues, by producing H2S. Various preclinical studies have shown that H2S affects physiological and pathological processes in the body. However, a detailed systematic summary of these roles in health and disease is lacking. Therefore, this review provides a thorough overview of the physiological roles of H2S in different systems and the diseases associated with disorders of H2S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H2S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options.

Role of hydrogen sulfide in dermatological diseases.

Hydrogen sulfide (H2S), together with carbon monoxide (CO) and nitric oxide (NO), is recognized as a vital gasotransmitter. H2S is biosynthesized by enzymatic pathways in the skin and exerts significant physiological effects on a variety of biological processes, such as apoptosis, modulation of inflammation, cellular proliferation, and regulation of vasodilation. As a major health problem, dermatological diseases affect a large proportion of the population every day. It is urgent to design and develop effective drugs to deal with dermatological diseases. Dermatological diseases can arise from a multitude of etiologies, including neoplastic growth, infectious agents, and inflammatory processes. The abnormal metabolism of H2S is associated with many dermatological diseases, such as melanoma, fibrotic diseases, and psoriasis, suggesting its therapeutic potential in the treatment of these diseases. In addition, therapies based on H2S donors are being developed to treat some of these conditions. In the review, we discuss recent advances in the function of H2S in normal skin, the role of altering H2S metabolism in dermatological diseases, and the therapeutic potential of diverse H2S donors for the treatment of dermatological diseases.

Circulating tumor DNA and its role in detection, prognosis and therapeutics of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is considered the fifth most prevalent cancer among all types of cancers and has the third most morbidity value. It has the most frequent duplication time and a high recurrence rate. Recently, the most unique technique used is liquid biopsies, which carry many markers; the most prominent is circulating tumor DNA (ctDNA). Varied methods are used to investigate ctDNA, including various forms of polymerase chain reaction (PCR) [emulsion PCR (ePCR), digital PCR (dPCR), and bead, emulsion, amplification, magnetic (BEAMing) PCR]. Hence ctDNA is being recognized as a potential biomarker that permits early cancer detection, treatment monitoring, and predictive data on tumor burden are subjective to therapy or surgery. Numerous ctDNA biomarkers have been investigated based on their alterations such as 1) single nucleotide variations (either insertion or deletion of a nucleotide) markers including TP53, KRAS, and CCND1; 2) copy number variations which include markers such as CDK6, EFGR, MYC and BRAF; 3) DNA methylation (RASSF1A, SEPT9, KMT2C and CCNA2); 4) homozygous mutation includes ctDNA markers as CDKN2A, AXIN1; and 5) gain or loss of function of the genes, particularly for HCC. Various researchers have conducted many studies and gotten fruitful results. Still, there are some drawbacks to ctDNA namely low quantity, fragment heterogeneity, less stability, limited mutant copies and standards, and differential sensitivity. However, plenty of investigations demonstrate ctDNA's significance as a polyvalent biomarker for cancer and can be viewed as a future diagnostic, prognostic and therapeutic agent. This article overviews many conditions in genetic changes linked to the onset and development of HCC, such as dysregulated signaling pathways, somatic mutations, single-nucleotide polymorphisms, and genomic instability. Additionally, efforts are also made to develop treatments for HCC that are molecularly targeted and to unravel some of the genetic pathways that facilitate its early identification.

Identification of the myxobacterial secondary metabolites Aurachin A and Soraphinol A as promising inhibitors of thymidylate kinase of the Monkeypox virus.

Thymidylate kinase (TMPK) of monkeypox virus (MPXV) has emerged as a promising target for potential therapeutics due to its significant role in pyrimidine metabolism. While smallpox drugs are advised for treating monkeypox, the European Medicine Agency has sanctioned Tecovirimat due to its potent nanomolar activity. Nonetheless, there is a need for monkeypox-specific therapeutic options. In this work, we employed docking-based virtual screening and molecular dynamics (MD) simulations to identify myxobacterial secondary metabolites as promising anti-viral natural compounds capable of inhibiting thymidylate kinase. The computational pharmacokinetics and manual curation of top-scoring compounds identified six lead compounds that were compared in terms of protein-ligand contacts and protein-essential dynamics. The study shows that among the six candidates, Aurachin A and the Soraphinol analogues such as Soraphinol A and Soraphinol C remain very stable compared to other compounds, enabling the active site integrity via a stable dynamics pattern. We also show that other compounds such as Phenoxan, Phenylnannolone C, and 8E-Aurafuron B remain unstable and have a negative impact on the active site integrity and may not be suitable binders for TMPK protein. Analyzing the Aurachin A and Soraphinol A binding, the established hydrogen bonds with Arg93 and the conserved hydrophobic interaction with Tyr101 are consistent with previous experimental interactions. Additionally, a deeper insight into the indole and the aromatic ring interaction through π-π stacking and π-cation interactions, as well as the background of Aurachin A and Soraphinol A as a bioactive compound, has significant implications not only for its potential as a promising drug but also for directing future drug discovery efforts targeting the TMPK protein.

Monkeypox Entry and Emergence Preparation in Pakistan.

Monkeypox (Mpox) is a virus that first emerged in Africa in 1970 [...].

Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis.

BACKGROUND: Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2. AIM: To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment. METHODS: Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo. RESULTS: The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy. CONCLUSION: Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.

Vaccinomics-based next-generation multi-epitope chimeric vaccine models prediction against Leishmania tropica - a hierarchical subtractive proteomics and immunoinformatics approach.

Leishmania tropica is a vector-borne parasitic protozoa that is the leading cause of leishmaniasis throughout the global tropics and subtropics. L. tropica is a multidrug-resistant parasite with a diverse set of serological, biochemical, and genomic features. There are currently no particular vaccines available to combat leishmaniasis. The present study prioritized potential vaccine candidate proteins of L. tropica using subtractive proteomics and vaccinomics approaches. These vaccine candidate proteins were downstream analyzed to predict B- and T-cell epitopes based on high antigenicity, non-allergenic, and non-toxic characteristics. The top-ranked overlapping MHC-I, MHC-II, and linear B-cell epitopes were prioritized for model vaccine designing. The lead epitopes were linked together by suitable linker sequences to design multi-epitope constructs. Immunogenic adjuvant sequences were incorporated at the N-terminus of the model vaccine constructs to enhance their immunological potential. Among different combinations of constructs, four vaccine designs were selected based on their physicochemical and immunological features. The tertiary structure models of the designed vaccine constructs were predicted and verified. The molecular docking and molecular dynamic (MD) simulation analyses indicated that the vaccine design V1 demonstrated robust and stable molecular interactions with toll-like receptor 4 (TLR4). The top-ranked vaccine construct model-IV demonstrated significant expressive capability in the E. coli expression system during in-silico restriction cloning analysis. The results of the present study are intriguing; nevertheless, experimental bioassays are required to validate the efficacy of the predicted model chimeric vaccine.

Thermal compensation design of achromatic and apochromatic optical systems using a 3D glass chart.

It is important to determine the ideal combination of housing materials, groups of refractive materials, and their optical powers for athermalizing achromatic and apochromatic optical systems. This study proposes a combined design approach that utilizes three or more glass types to resolve thermal aberrations and defocus achromatic and apochromatic optical systems. It selects a suitable glass type using a 3D glass chart and calculates the optical power analytically. Furthermore, a temperature-insensitive optical system with a 450-750 nm band based on refractive materials (CDGM Glass Co., Ltd.) is designed, with the modular transfer function value of the center field of view decreasing by less than 0.024 in the temperature range of -40∘ C to +80∘ C and the secondary spectrum aberration decreasing by over three times and being maintained within 0.08 mm.

Comprehensive analysis of the lncRNAs-related immune gene signatures and their correlation with immunotherapy in lung adenocarcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs)-related immune genes (lrRIGs) play a crucial role in the development and progression of lung adenocarcinoma (LUAD). However, reliable prognostic signatures based on lrRIGs have not yet been identified. METHODS: We screened lrRIGs associated with the prognosis of LUAD using The Cancer Genome Atlas (TCGA) database and then established a novel prognostic nine-gene signature composed of CD79A, INHA, SHC3, LIFR, TNFRSF11A, GPI, F2RL1, SEMA7A and WFDC2 through bioinformatic approaches. A risk score derived from this gene signature was used to divide LUAD patients into the low- and high-risk groups. The latter was confirmed to have markedly worse overall survival (O.S.). A nomogram was developed using the risk score and other independent prognostic elements, demonstrating excellent performance in predicting the O.S. rate of LUAD patients. RESULTS: We observed that the infiltration of diverse immune cell subtypes and response to immunotherapy and chemotherapy significantly differed between the low- and high-risk groups. CONCLUSIONS: Overall, stratification based on this gene signature could be used to guide better therapeutic management and improve outcomes for LUAD patients.

Fragment-Based Approaches Identified Tecovirimat-Competitive Novel Drug Candidate for Targeting the F13 Protein of the Monkeypox Virus.

Monkeypox is a serious public health issue in tropical and subtropical areas. Antivirals that target monkeypox proteins might lead to more effective and efficient therapy. The F13 protein is essential for the growth and maturation of the monkeypox virus. F13 inhibition might be a viable therapeutic target for monkeypox. The in silico fragment-based drug discovery method for developing antivirals may provide novel therapeutic options. In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox. These compounds were evaluated to identify the most promising fragments based on binding affinity and pharmacological characteristics. The top hits from the chemical screening were docked into the active site of the F13 protein. Molecular dynamics simulations were performed on the top two probable new candidates from molecular docking. The ligand-enzyme interaction analysis revealed that the C2 ligand had lower binding free energy than the standard ligand tecovirimat. Water bridges, among other interactions, were shown to stabilize the C2 molecule. Conformational transitions and secondary structure changes in F13 protein upon C2 binding show more native three-dimensional folding of the protein. Prediction of pharmacological properties revealed that compound C2 may be promising as a drug candidate for monkeypox fever. However, additional in vitro and in vivo testing is required for validation.

Clinical Manifestation, Transmission, Pathogenesis, and Diagnosis of Monkeypox Virus: A Comprehensive Review.

Monkeypox virus is a double-stranded DNA virus species that causes disease in humans and mammals. It is a zoonotic virus belongs the genus Orthopoxviral, the family of Poxviridae, associated with the smallpox virus in many aspects. The first human case of monkeypox was reported throughout the Democratic Republic of Congo in 1970. In April 2022, several cases were recorded in widespread regions of Africa, the Northern and western hemispheres. The current review spotlights taxonomic classification, clinical presentations during infection, and the pathogenicity of the monkeypox virus in humans. Furthermore, the current review also highlights different diagnostics used for virus detection.

Crosstalk between heat shock factor 1 and signal transducer and activator of transcription 3 mediated by interleukin-8 autocrine signaling maintains the cancer stem cell phenotype in liver cancer.

BACKGROUND AND AIM: Liver cancer stem cells (LCSCs) cause therapeutic refractoriness and relapse in hepatocellular carcinoma. Heat shock factor 1 (HSF1) plays versatile roles in multiple cancers. However, the role of HSF1 in LCSCs is not well understood. This study investigated the function and signal mechanisms of HSF1 in maintaining LCSC phenotypes. METHODS: We established two LCSC lines, HepG2-R and HuH-7-R. Constitutive activation of HSF1 was observed in these LCSCs. Specific short hairpin RNAs (shRNAs) and chemical inhibitors were used to identify the relationship between HSF1 expression and LCSCs phenotypes. RESULTS: We revealed a concomitant activation modality involving HSF1 and STAT3 in LCSCs and liver cancer tissues. We also found that liver cancer patients whose HSF1 and STAT3 mRNA expression levels were high presented with unfavorable clinicopathological characteristics. Moreover, the secretion of interleukin-8 (IL-8) was elevated in the LCSC medium and was directly regulated by HSF1 at the transcriptional level. In turn, IL-8 activated HSF1 and STAT3 signaling, and a neutralizing IL-8 antibody inhibited HSF1 and STAT3 activity, reduced cancer stem cell marker expression, and decreased LCSC microsphere formation. Simultaneous intervention with HSF1 and STAT3 led to synergistically suppressed stemness acquisition and growth suppression in the LCSCs in vivo and in vitro. CONCLUSIONS: Our study indicates that IL-8 mediates the crosstalk between the HSF1 and Stat3 signaling pathways in LCSCs and that the combined targeting of HSF1 and STAT3 is a promising treatment strategy for patients with advanced liver cancer.

Knowledge, Attitude, and Perception of Cancer Patients towards COVID-19 in Pakistan: A Cross-Sectional Study.

Background: Cancer patients, being immunocompromised, are at higher risk of coronavirus disease (COVID-19). The current study determines cancer patients' knowledge, attitude, perception, and impact of the COVID-19 pandemic. Method: A cross-sectional online survey was conducted in Pakistan from 1 April 2020 to 1 May 2020. The study respondents were cancer patients with ages equal to or greater than 18 years. Following a request for participation, the URL for the survey was distributed on numerous channels. Other social media platforms, including WeChat, WhatsApp, Facebook, Twitter, Instagram, Messenger, and LinkedIn, were used to increase cancer patient interaction. The questionnaire comprised five different sections such as: (1) sociodemographic information, (2) knowledge, (3) attitude, (4) perception, and (5) impact of COVID-19 on cancer patients. Descriptive medical statistics such as frequency, percentage, mean, and standard deviation were used to illustrate the demographic characteristics of the study participants. To compare mean knowledge scores with selected demographic variables, independent sample t-tests and one-way analysis of variance (ANOVA) were used, which are also practical methods in epidemiological, public health and medical research. The cut-off point for statistical significance was set at a p-value of 0.05. Results: More than 300 cancer patients were invited, of which 208 agreed to take part. The response rate was 69.33% (208/300). Gender, marital status, and employment status had a significant association with knowledge scores. Of the total recruited participants, 96% (n = 200) (p < 0.01) knew about COVID-19, and 90% were aware of general symptoms of COVID-19 disease, such as route of transmission and preventive measurements. In total, 94.5% (n = 197) (p < 0.01) were willing to accept isolation if they were infected with COVID-19, and 98% (n = 204) (p < 0.01) had reduced their use of public transportation. More than 90% (n = 188) (p < 0.01) of cancer patients were found to be practicing preventative measures such as using a face mask, keeping social distance, and avoiding handshaking and hugging. Around 94.4% (n = 196) (p < 0.01) of cancer patients had been impacted by, stopped or had changed cancer treatment during this pandemic, resulting in COVID-related anxiety and depression. Conclusion: The included cancer patients exhibited a good level of COVID-19 knowledge, awareness, positive attitude, and perception. Large-scale studies and efforts are needed to raise COVID-19 awareness among less educated and high-risk populations. The present survey indicates that mass-level effective health education initiatives are required for developing countries to improve and reduce the gap between KAP and COVID-19.

Characteristics of Chimeric West Nile Virus Based on the Japanese Encephalitis Virus SA14-14-2 Backbone.

West Nile virus disease (WND) is an arthropod-borne zoonosis responsible for nonspecific fever or severe encephalitis. The pathogen is West Nile virus belonging to the genus Flavivirus, family Flaviviridae. Every year, thousands of cases were reported, which poses significant public health risk. Here, we constructed a West Nile virus chimera, ChiVax-WN01, by replacing the prMΔE gene of JEV SA14-14-2 with that of the West Nile virus NY99. The ChiVax-WN01 chimera showed clear, different characters compared with that of JEV SA14-14-2 and WNV NY99 strain. An animal study indicated that the ChiVax-WN01 chimera presented moderate safety and immunogenicity for 4-week female BALB/c mice.

Advances and challenges in the prevention and treatment of COVID-19.

Since the end of 2019, a new type of coronavirus pneumonia (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been spreading rapidly throughout the world. Previously, there were two outbreaks of severe coronavirus caused by different coronaviruses worldwide, namely Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). This article introduced the origin, virological characteristics and epidemiological overview of SARS-CoV-2, reviewed the currently known drugs that may prevent and treat coronavirus, explained the characteristics of the new coronavirus and provided novel information for the prevention and treatment of COVID-19.

Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.

Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown. Here, we report that blocking TRAIL with a soluble DR5 immunoglobulin fusion protein diminished MI by preventing cardiac cell death and inflammation in rats, pigs, and monkeys. Mechanistically, TRAIL induced the death of cardiomyocytes and recruited and activated leukocytes, directly and indirectly causing cardiac injury. Transcriptome profiling revealed increased expression of inflammatory cytokines in infarcted heart tissue, which was markedly reduced by TRAIL blockade. Together, our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy for treating MI.

Progress in Research on SARS-CoV-2 Infection Causing Neurological Diseases and Its Infection Mechanism.

COVID-19 has spread rapidly worldwide since its outbreak and has now become a major public health problem. More and more evidence indicates that SARS-CoV-2 may not only affect the respiratory system but also cause great harm to the central nervous system. Therefore, it is extremely important to explore in-depth the impact of SARS-CoV-2 infection on the nervous system. In this paper, the possible mechanisms of SARS-CoV-2 invading the central nervous system during COVID-19, and the neurological complications caused by SARS-CoV-2 infection were reviewed.

Two mutations in viral protein enhance the adaptation of waterfowl-origin H3N2 virus in murine model.

After serial passage of a waterfowl-origin H3N2 subtype avian influenza virus in BALB/c mice, we obtained H3N2 mouse-adapted variants and identified eight amino acid substitutions in five viral proteins in our previous study. Here, we analyze the key mutations determining viral pathogenicity in mammals. We found that both PB2-D701N mutation and M1-M192V mutation were implicated in the viral pathogenic phenotypic variation of H3N2 avian influenza virus in mice. Furthermore, we found that PB2-D701N could enhance viral replication in vitro and in vivo and expanded viral tissue tropism. Our data suggest that PB2-D701N and M1-M192V are the virulence markers of H3N2 avian influenza virus, and these markers can be used in the trans-species transmission surveillance for the H3N2 avian influenza virus.

PB2 and hemagglutinin mutations confer a virulent phenotype on an H1N2 avian influenza virus in mice.

We previously obtained mouse-adapted variants of H1N2 avian influenza virus that contained PB2-L134H, PB2-I647L, PB2-D701N, HA-G228S, and M1-D231N mutations. Here, we analyzed the effects of these mutations on viral pathogenicity in a mammalian model. By evaluating the virulence of mouse-adapted H1N2 variants at different generations, we found that the PB2-D701N and HA-G228S mutations both contribute to the virulence of this virus in mammals. Furthermore, we found that the PB2-D701N and HA-G228S mutations both enhance the ability of the virus to replicate in vivo and in vitro and that the PB2-D701N substitution results in an expansion of viral tissue tropism. These results suggest that the PB2-D701N mutation and the HA-G228S mutation are the major mammalian determinants of H1N2 virus. These results help us to understand more about the mechanisms by which influenza viruses adapt to mammals, and monitoring of these mutations can be used in continuous influenza surveillance to assess the pandemic potential of avian influenza virus variants.