Therapeutic targeting of TRAIL death receptors.

The discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) along with its potent and selective antitumor effects initiated a decades-long search for therapeutic strategies to target the TRAIL pathway. First-generation approaches were focused on the development of TRAIL receptor agonists (TRAs), including recombinant human TRAIL (rhTRAIL) and TRAIL receptor-targeted agonistic antibodies. While such TRAIL pathway-targeted therapies showed promise in preclinical data and clinical trials have been conducted, none have advanced to FDA approval. Subsequent second-generation approaches focused on improving upon the specific limitations of first-generation approaches by ameliorating the pharmacokinetic profiles and agonistic abilities of TRAs as well as through combinatorial approaches to circumvent resistance. In this review, we summarize the successes and shortcomings of first- and second-generation TRAIL pathway-based therapies, concluding with an overview of the discovery and clinical introduction of ONC201, a compound with a unique mechanism of action that represents a new generation of TRAIL pathway-based approaches. We discuss preclinical and clinical findings in different tumor types and provide a unique perspective on translational directions of the field.

Long-term side effects and lingering symptoms post COVID-19 recovery.

Since the Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), our understanding regarding the pathophysiology and clinical manifestations of this disease have been improving. However, we still have limited data on long-term effects and lingering symptoms of post COVID-19 recovery. Despite predilection of COVID-19 for lungs, multiple extra-pulmonary manifestations appear in multiple organs and biological systems and with continued infection and recovery worldwide. It is necessary that clinicians provide patients with previous SARS-CoV-2 infection with expectations of long-term effects during or after recovery from COVID-19. Herein, we review the long-term impact of COVID-19 on different organ systems reported from different clinical studies. Understanding risk factors and signs and symptoms of long-term consequences after recovery from COVID-19 will allow for proper follow-up and management of the disease post recovery.

Aquaporin 4 and brain-related disorders: Insights into its apoptosis roles.

Brain-related disorders are leading global health problems. Various internal and external factors are involved in the progression of brain-related disorders. Inflammatory pathways, oxidative stresses, apoptosis, and deregulations of various channels are critical players in brain-related disorder pathogenesis. Among these players, aquaporins (AQP) have critical roles in various physiological and pathological conditions. AQPs are water channel molecules that permit water to cross the hydrophobic lipid bilayers of cellular membranes. AQP4 is one of the important members of AQP family. AQPs are involved in controlling apoptosis pathways in brain-related disorders. In this regard, several reports have evaluated the pathological effects of AQP4 by targeting the apoptosis-related processes in brain-related disorders. Here, for the first time, we highlight the impact of AQP4 on apoptosis-related processes in brain-related disorders.

Cell death pathways and viruses: Role of microRNAs.

Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.

Use of Salmonella Bacteria in Cancer Therapy: Direct, Drug Delivery and Combination Approaches.

Over the years, conventional cancer treatments, such as chemotherapy with only a limited specificity for tumors, have undergone significant improvement. Moreover, newer therapies such as immunotherapy have undergone a revolution to stimulate the innate as well as adaptive immune responses against the tumor. However, it has been found that tumors can be selectively colonized by certain bacteria, where they can proliferate, and exert direct oncolytic effects as well as stimulating the immune system. Bacterial-mediated cancer therapy (BMCT) is now one example of a hot topic in the antitumor field. Salmonella typhimurium is a Gram-negative species that generally causes self-limiting gastroenteritis in humans. This species has been designed and engineered in order to be used in cancer-targeted therapeutics. S. typhimurium can be used in combination with other treatments such as chemotherapy or radiotherapy for synergistic modification of the tumor microenvironment. Considerable benefits have been shown by using engineered attenuated strains for the diagnosis and treatment of tumors. Some of these treatment approaches have received FDA approval for early-phase clinical trials. This review summarizes the use of Salmonella bacteria for cancer therapy, which could pave the way towards routine clinical application. The benefits of this therapy include an automatic self-targeting ability, and the possibility of genetic manipulation to produce newly engineered attenuated strains. Nevertheless, Salmonella-mediated anticancer therapy has not yet been clinically established, and requires more research before its use in cancer treatment.

Exosomal microRNAs and exosomal long non-coding RNAs in gynecologic cancers.

Gynecologic cancer is a group of any malignancies affecting reproductive tissues and organs of women, including ovaries, uterine, cervix, vagina, vulva, and endometrium. Several types of molecular mechanisms are associated with the progression of gynecologic cancers. Among it can be referred to the most widely studied non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long ncRNAs (lncRNAs). As yet, lncRNAs are known to serve key biological roles via various mechanisms, such as splicing regulation, chromatin rearrangement, translation regulation, cell-cycle control, genetic imprinting and mRNA decay. Besides, miRNAs govern gene expression by modulation of mRNAs and lncRNAs degradation, suggestive of needing more research in this field. Generally, driving gynecological cancers pathways by miRNAs and lncRNAs lead to the current improvement in cancer-related technologies. Exosomes are extracellular microvesicles which can carry cargo molecules among cells. In recent years, more studies have been focused on exosomal non-coding RNAs (exo-ncRNAs) and exosomal microRNAs (exo-miRs) because of being natural carriers of lnc RNAs and microRNAs via programmed process. In this review we summarized recent reports concerning the function of exosomal microRNAs and exosomal long non-coding RNAs in gynecological cancers.

An Update on the Effects of Probiotics on Gastrointestinal Cancers.

Because of their increasing prevalence, gastrointestinal (GI) cancers are regarded as an important global health challenge. Microorganisms residing in the human GI tract, termed gut microbiota, encompass a large number of living organisms. The role of the gut in the regulation of the gut-mediated immune responses, metabolism, absorption of micro- and macro-nutrients and essential vitamins, and short-chain fatty acid production, and resistance to pathogens has been extensively investigated. In the past few decades, it has been shown that microbiota imbalance is associated with the susceptibility to various chronic disorders, such as obesity, irritable bowel syndrome, inflammatory bowel disease, asthma, rheumatoid arthritis, psychiatric disorders, and various types of cancer. Emerging evidence has shown that oral administration of various strains of probiotics can protect against cancer development. Furthermore, clinical investigations suggest that probiotic administration in cancer patients decreases the incidence of postoperative inflammation. The present review addresses the efficacy and underlying mechanisms of action of probiotics against GI cancers. The safety of the most commercial probiotic strains has been confirmed, and therefore these strains can be used as adjuvant or neo-adjuvant treatments for cancer prevention and improving the efficacy of therapeutic strategies. Nevertheless, well-designed clinical studies are still needed for a better understanding of the properties and mechanisms of action of probiotic strains in mitigating GI cancer development.

Gynecologic cancers and non-coding RNAs: Epigenetic regulators with emerging roles.

Gynecologic cancers involve the female genital organs, such as the vulva, vagina, cervix, endometrium, ovaries, and fallopian tubes. The occurrence and frequency of gynecologic cancer depends on personal lifestyle, history of exposure to viruses or carcinogens, genetics, body shape, and geographical habitat. For a long time, research into the molecular biology of cancer was broadly restricted to protein-coding genes. Recently it has been realized that non-coding RNAs (ncRNA), including long noncoding RNAs (LncRNAs), microRNAs, circular RNAs and piRNAs (PIWI-interacting RNAs), can all play a role in the regulation of cellular function within gynecological cancer. It is now known that ncRNAs are able to play dual roles, i.e. can exert both oncogenic or tumor suppressive functions in gynecological cancer. Moreover, several clinical trials are underway looking at the biomarker and therapeutic roles of ncRNAs. These efforts may provide a new horizon for the diagnosis and treatment of gynecological cancer. Herein, we summarize some of the ncRNAs that have been shown to be important in gynecological cancers.