The double-edged sword role of hydrogen sulfide in hepatocellular carcinoma.

With an increasing worldwide prevalence, hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver in the world. It is also the primary reason for cancer-related death in the world. The pathogenesis of HCC is complex, such as DNA methylation changes, immune regulatory disorders, cell cycle disorders, chromosomal instability, and so on. Although many studies have been conducted on HCC, the molecular mechanisms of HCC are not completely understood. At present, there is no effective treatment for HCC. Hydrogen sulfide (H2S) has long been regarded as a toxic gas with the smell of rotten eggs, but recent studies have shown that it is an important gasotransmitter along with carbon monoxide (CO) and nitric oxide (NO). Increasing evidence indicates that H2S has multiple biological functions, such as anti-inflammation, anti-apoptosis, anti-oxidative stress, and so on. Recently, a lot of evidence has shown that H2S has a "double-edged sword" effect in HCC, but the mechanism is not fully understood. Here, we reviewed the progress on the role and mechanism of H2S in HCC in recent years, hoping to provide a theoretical reference for future related research.

A pH-responsive bi-MIL-88B MOF coated with folic acid-conjugated chitosan as a promising nanocarrier for targeted drug delivery of 5-Fluorouracil.

Cancer has remained one of the leading causes of death worldwide, with a lack of effective treatment. The intrinsic shortcomings of conventional therapeutics regarding tumor specificity and non-specific toxicity prompt us to look for alternative therapeutics to mitigate these limitations. In this regard, we developed multifunctional bimetallic (FeCo) bi-MIL-88B-FC MOFs modified with folic acid-conjugated chitosan (FC) as drug delivery systems (DDS) for targeted delivery of 5-Fluorouracil (5-FU). The bi-MIL-88B nanocarriers were characterized through various techniques, including powder X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray, thermogravimetric analysis, and Fourier transform infrared spectroscopy. Interestingly, 5-FU@bi-MIL-88B-FC showed slower release of 5-FU due to a gated effect phenomenon endowed by FC surface coating compared to un-modified 5-FU@bi-MIL-88B. The pH-responsive drug release was observed, with 58% of the loaded 5-FU released in cancer cells mimicking pH (5.2) compared to only 24.9% released under physiological pH (5.4). The in vitro cytotoxicity and cellular internalization experiments revealed the superiority of 5-FU@bi-MIL-88B-FC as a highly potent targeted DDS against folate receptor (FR) positive SW480 cancer cells. Moreover, due to the presence of Fe and Co in the structure, bi-MIL-88B exhibited peroxidase-like activity for chemodynamic therapy. Based on the results, 5-FU@bi-MIL-88B-FC could serve as promising candidate for smart DDS by sustained drug release and selective targeting.

Nanotechnology prospects in brain therapeutics concerning gene-targeting and nose-to-brain administration.

Neurological diseases are one of the most pressing issues in modern times worldwide. It thus possesses explicit attention from researchers and medical health providers to guard public health against such an expanding threat. Various treatment modalities have been developed in a remarkably short time but, unfortunately, have yet to lead to the wished-for efficacy or the sought-after clinical improvement. The main hurdle in delivering therapeutics to the brain has always been the blood-brain barrier which still represents an elusive area with lots of mysteries yet to be solved. Meanwhile, nanotechnology has emerged as an optimistic platform that is potentially holding the answer to many of our questions on how to deliver drugs and treat CNS disorders using novel technologies rather than the unsatisfying conventional old methods. Nanocarriers can be engineered in a way that is capable of delivering a certain therapeutic cargo to a specific target tissue. Adding to this mind-blowing nanotechnology, the revolutionizing gene-altering biologics can have the best of both worlds, and pave the way for the long-awaited cure to many diseases, among those diseases thus far are Alzheimer's disease (AD), brain tumors (glioma and glioblastoma), Down syndrome, stroke, and even cases with HIV. The review herein collects the studies that tested the mixture of both sciences, nanotechnology, and epigenetics, in the context of brain therapeutics using three main categories of gene-altering molecules (siRNA, miRNA, and CRISPR) with a special focus on the advancements regarding the new favorite, intranasal route of administration.

Feedback Modulation between Human INO80 Chromatin Remodeling Complex and miR-372 in HCT116 Cells.

Human INO80 chromatin remodeling complex (INO80 complex) as a transcription cofactor is widely involved in gene transcription regulation and is frequently highly expressed in tumor cells. However, few reports exist on the mutual regulatory mechanism between INO80 complex and non-coding microRNAs. Herein, we showed evidence that the INO80 complex transcriptionally controls microRNA-372 (miR-372) expression through RNA-Seq analysis and a series of biological experiments. Knocking down multiple subunits in the INO80 complex, including the INO80 catalytic subunit, YY1, Ies2, and Arp8, can significantly increase the expression level of miR-372. Interestingly, mimicking miR-372 expression in HCT116 cells, in turn, post-transcriptionally suppressed INO80 and Arp8 expression at both mRNA and protein levels, indicating the existence of a mutual regulatory mechanism between the INO80 complex and miR-372. The target relationship between miR-372 and INO80 complex was verified using luciferase assays in HCT116 colon cancer cells. As expected, miR-372 mimics significantly suppressed the luciferase activity of pMIR-luc/INO80 and pMIR-luc/Arp8 3'-UTR in cells. In contrast, the miR-372 target sites in the 3'-UTRs linked to the luciferase reporter were mutagenized, and both mutant sites lost their response to miR-372. Furthermore, the mutual modulation between the INO80 complex and miR-372 was involved in cell proliferation and the p53/p21 signaling pathway, suggesting the synergistic anti-tumor role of the INO80 complex and miR372. Our results will provide a solid theoretical basis for exploring miR-372 as a biological marker of tumorigenesis.

Role of Nanomedicine-Based Therapeutics in the Treatment of CNS Disorders.

Central nervous system disorders, especially neurodegenerative diseases, are a public health priority and demand a strong scientific response. Various therapy procedures have been used in the past, but their therapeutic value has been insufficient. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier is two of the barriers that protect the central nervous system (CNS), but are the main barriers to medicine delivery into the CNS for treating CNS disorders, such as brain tumors, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Nanotechnology-based medicinal approaches deliver valuable cargos targeting molecular and cellular processes with greater safety, efficacy, and specificity than traditional approaches. CNS diseases include a wide range of brain ailments connected to short- and long-term disability. They affect millions of people worldwide and are anticipated to become more common in the coming years. Nanotechnology-based brain therapy could solve the BBB problem. This review analyzes nanomedicine's role in medication delivery; immunotherapy, chemotherapy, and gene therapy are combined with nanomedicines to treat CNS disorders. We also evaluated nanotechnology-based approaches for CNS disease amelioration, with the intention of stimulating the immune system by delivering medications across the BBB.

Hydrogen sulfide and its donors: Novel antitumor and antimetastatic agents for liver cancer.

Hepatocellular carcinoma (HCC) is the sixth most frequent human cancer and the world's third most significant cause of cancer mortality. HCC treatment has recently improved, but its mortality continues to increase worldwide due to its extremely complicated and heterogeneous genetic abnormalities. After nitric oxide (NO) and carbon monoxide (CO), the third gas signaling molecule discovered is hydrogen sulfide (H2S), which has long been thought to be a toxic gas. However, numerous studies have proven that H2S plays many pathophysiological roles in mammals. Endogenous or exogenous H2S can decrease cell proliferation, promote apoptosis, block cell cycle, invasion and migration through various cellular signaling pathways. This review analyzes and discusses the recent literature on the function and molecular mechanism of H2S and H2S donors in HCC, so as to provide convenience for the scientific research and clinical application of H2S in the treatment of liver cancer.

Cystathionine γ-lyase mediates cell proliferation, migration, and invasion of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelia-derived malignancy with a distinctive geographic distribution. Cystathionine γ-lyase (CSE) is involved in cancer development and progression. Nevertheless, the role of CSE in the growth of NPC is unknown. In this study, we found that CSE levels in human NPC cells were higher than those in normal nasopharyngeal cells. CSE overexpression enhanced the proliferative, migrative, and invasive abilities of NPC cells and CSE downregulation exerted reverse effects. Overexpression of CSE decreased the expressions of cytochrome C, cleaved caspase (cas)-3, cleaved cas-9, and cleaved poly-ADP-ribose polymerase, whereas CSE knockdown exhibited reverse effects. CSE overexpression decreased reactive oxygen species (ROS) levels and the expressions of phospho (p)-extracellular signal-regulated protein kinase 1/2, p-c-Jun N-terminal kinase, and p-p38, but promoted the expressions of p-phosphatidylinositol 3-kinase (PI3K), p-AKT, and p-mammalian target of rapamycin (mTOR), whereas CSE knockdown showed oppose effects. In addition, CSE overexpression promoted NPC xenograft tumor growth and CSE knockdown decreased tumor growth by modulating proliferation, angiogenesis, cell cycle, and apoptosis. Furthermore, DL-propargylglycine (an inhibitor of CSE) dose-dependently inhibited NPC cell growth via ROS-mediated mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR pathways without significant toxicity. In conclusion, CSE could regulate the growth of NPC cells through ROS-mediated MAPK and PI3K/AKT/mTOR cascades. CSE might be a novel tumor marker for the diagnosis and prognosis of NPC. Novel donors/drugs that inhibit the expression/activity of CSE can be developed in the treatment of NPC.

Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.

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.

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression.

Hydrogen sulfide (H2S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H2S production or exposure of H2S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H2S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H2S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells' viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H2S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H2S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H2S-based anti-tumor drugs to cure BC.

Hydrogen Sulfide Biology and Its Role in Cancer.

Hydrogen sulfide (H2S) is an endogenous biologically active gas produced in mammalian tissues. It plays a very critical role in many pathophysiological processes in the body. It can be endogenously produced through many enzymes analogous to the cysteine family, while the exogenous source may involve inorganic sulfide salts. H2S has recently been well investigated with regard to the onset of various carcinogenic diseases such as lung, breast, ovaries, colon cancer, and neurodegenerative disorders. H2S is considered an oncogenic gas, and a potential therapeutic target for treating and diagnosing cancers, due to its role in mediating the development of tumorigenesis. Here in this review, an in-detail up-to-date explanation of the potential role of H2S in different malignancies has been reported. The study summarizes the synthesis of H2S, its roles, signaling routes, expressions, and H2S release in various malignancies. Considering the critical importance of this active biological molecule, we believe this review in this esteemed journal will highlight the oncogenic role of H2S in the scientific community.

Role of Hydrogen Sulfide in Oral Disease.

Oral diseases are among the most common human diseases yet less studied. These diseases affect both the physical, mental, and social health of the patients resulting in poor quality of life. They affect all ages, although severe stages are mostly observed in older individuals. Poor oral hygiene, genetics, and environmental factors contribute enormously to the development and progression of these diseases. Although there are available treatment options for these diseases, the recurrence of the diseases hinders their efficiency. Oral volatile sulfur compounds (VSCs) are highly produced in oral cavity as a result of bacteria activities. Together with bacteria components such as lipopolysaccharides, VSCs participate in the progression of oral diseases by regulating cellular activities and interfering with the immune response. Hydrogen sulfide (H2S) is a gaseous neurotransmitter primarily produced endogenously and is involved in the regulation of cellular activities. The gas is also among the VSCs produced by oral bacteria. In numerous diseases, H2S have been reported to have dual effects depending on the cell, concentration, and donor used. In oral diseases, high production and subsequent utilization of this gas have been reported. Also, this high production is associated with the progression of oral diseases. In this review, we will discuss the production of H2S in oral cavity, its interaction with cellular activities, and most importantly its role in oral diseases.

Potential Biomarkers of miR-371-373 Gene Cluster in Tumorigenesis.

microRNAs (miRNAs) are small non-coding RNA transcripts (20-24 nucleotides) that bind to their complementary sequences in the 3'-untranslated regions (3'-UTR) of targeted genes to negatively or positively regulate their expression. miRNAs affect the expression of genes in cells, thereby contributing to several important biological processes, including tumorigenesis. Identifying the miRNA cluster as a human embryonic stem cell (hESC)-specific miRNAs initially led to the identification of miR-371, miR-372, miR-373, and miR-373*, which can ultimately be translated into mature miRNAs. Recent evidence suggests that miR-371-373 genes are abnormally expressed in various cancers and act either as oncogenes or tumor suppressors, indicating they may be suitable as molecular biomarkers for cancer diagnosis and prevention. In this article, we summarize recent studies linking miR-371-373 functions to tumorigenesis and speculate on the potential applications of miR-371-373 as biomarkers for cancer diagnosis and treatment.

Impact of the factors shaping gut microbiota on obesity.

Obesity is considered as a risk factor for chronic health diseases such as heart diseases, cancer and diabetes 2. Reduced physical activities, lifestyle, poor nutritional diet and genetics are among the risk factors associated with the development of obesity. In recent years, several studies have explored the link between the gut microbiome and the progression of diseases including obesity, with the shift in microbiome abundance and composition being the main focus. The alteration of gut microbiome composition affects both nutrients metabolism and specific gene expressions, thereby disturbing body physiology. Specifically, the abundance of fibre-metabolizing microbes is associated with weight loss and that of protein and fat-metabolizing bacteria with weight gain. Various internal and external factors such as genetics, maternal obesity, mode of delivery, breastfeeding, nutrition, antibiotic use and the chemical compounds present in the environment are known to interfere with the richness of the gut microbiota (GM), thus influencing weight gain/loss and ultimately the development of obesity. However, the effectiveness of each factor in potentiating the shift in microbes' abundance to result in significant changes that can lead to obesity is not yet clear. In this review, we will highlight the factors involved in shaping GM, their influence on obesity and possible interventions. Understanding the influence of these factors on the diversity of the GM and how to improve their effectiveness on disease conditions could be keys in the treatment of metabolic diseases.

Role of hydrogen sulfide donors in cancer development and progression.

In recent years, a vast number of potential cancer therapeutic targets have emerged. However, developing efficient and effective drugs for the targets is of major concern. Hydrogen sulfide (H2S), one of the three known gasotransmitters, is involved in the regulation of various cellular activities such as autophagy, apoptosis, migration, and proliferation. Low production of H2S has been identified in numerous cancer types. Treating cancer cells with H2S donors is the common experimental technique used to improve H2S levels; however, the outcome depends on the concentration/dose, time, cell type, and sometimes the drug used. Both natural and synthesized donors are available for this purpose, although their effects vary independently ranging from strong cancer suppressors to promoters. Nonetheless, numerous signaling pathways have been reported to be altered following the treatments with H2S donors which suggest their potential in cancer treatment. This review will analyze the potential of H2S donors in cancer therapy by summarizing key cellular processes and mechanisms involved.

Multifaceted behavior of PEST sequence enriched nuclear proteins in cancer biology and role in gene therapy.

The amino acid sequence enriched with proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) is a signal-transducing agent providing unique features to its substrate nuclear proteins (PEST-NPs). The PEST motif is responsible for particular posttranslational modifications (PTMs). These PTMs impart distinct properties to PEST-NPs that are responsible for their activation/inhibition, intracellular localization, and stability/degradation. PEST-NPs participate in cancer metabolism, immunity, and protein transcription as oncogenes or as tumor suppressors. Gene-based therapeutics are getting the attention of researchers because of their cell specificity. PEST-NPs are good targets to explore as cancer therapeutics. Insights into PTMs of PEST-NPs demonstrate that these proteins not only interact with each other but also recruit other proteins to/from their active site to promote/inhibit tumors. Thus, the role of PEST-NPs in cancer biology is multivariate. It is hard to obtain therapeutic objectives with single gene therapy. An especially designed combination gene therapy might be a promising strategy in cancer treatment. This review highlights the multifaceted behavior of PEST-NPs in cancer biology. We have summarized a number of studies to address the influence of structure and PEST-mediated PTMs on activation, localization, stability, and protein-protein interactions of PEST-NPs. We also recommend researchers to adopt a pragmatic approach in gene-based cancer therapy.