Immunotherapeutics in lung cancers: from mechanistic insight to clinical implications and synergistic perspectives.

BACKGROUND: Lung cancer is one of the highly lethal forms of cancer whose incidence has worldwide rapidly increased over the past few decades. About 80-85% of all lung cancer cases constitute non-small cell lung cancer (NSCLC), with adenocarcinoma, squamous cell carcinoma and large cell carcinoma as the main subtypes. Immune checkpoint inhibitors have led to significant advances in the treatment of a variety of solid tumors, significantly improving cancer patient survival rates. METHODS AND RESULTS: The cytotoxic drugs in combination with anti-PD-(L)1 antibodies is a new method that aims to reduce the activation of immunosuppressive and cancer cell prosurvival responses while also improving direct cancer cell death. The most commonly utilized immune checkpoint inhibitors for patients with non-small cell lung cancer are monoclonal antibodies (Atezolizumab, Cemiplimab, Ipilimumab, Pembrolizumab etc.) against PD-1, PD-L1, and CTLA-4. Among them, Atezolizumab (TECENTRIQ) and Cemiplimab (Libtayo) are engineered monoclonal anti programmed death ligand 1 (PD-L1) antibodies that inhibit binding of PD-L1 to PD-1 and B7.1. As a result, T-cell proliferation and cytokine synthesis are inhibited leading to restoring the immune homeostasis to fight cancer cells. CONCLUSIONS: In this review article, the path leading to the introduction of immunotherapeutic options in lung cancer treatment is described, with analyzing the benefits and shortages of the current immunotherapeutic drugs. In addition, possibilities to co-administer immunotherapeutic agents with standard cancer treatment modalities are also considered.

Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis.

ROS include hydroxyl radicals (HO.), superoxide (O2..), and hydrogen peroxide (H2O2). ROS are typically produced under physiological conditions and play crucial roles in living organisms. It is known that ROS, which are created spontaneously by cells through aerobic metabolism in mitochondria, can have either a beneficial or detrimental influence on biological systems. Moderate levels of ROS can cause oxidative damage to proteins, DNA and lipids, which can aid in the pathogenesis of many disorders, including cancer. However, excessive concentrations of ROS can initiate programmed cell death in cancer. Presently, a variety of chemotherapeutic drugs and herbal agents are being investigated to induce ROS-mediated cell death in cancer. Therefore, preserving ROS homeostasis is essential for ensuring normal cell development and survival. On account of a significant association of ROS levels at various concentrations with carcinogenesis in a number of malignancies, further studies are needed to determine the underlying molecular mechanisms and develop the possibilities for intervening in these processes.

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions.

Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.

Effect of in utero exposure to antiepileptic drugs on cognitive function in children.

Epilepsy, being one of the most common neurological disorders, has raised concerns in developed and developing countries. Due to its heterogeneous pathophysiology and different cellular, molecular and genetic mechanisms, it is becoming a threat worldwide. Despite wide availability of antiepileptic drugs (AEDs), epilepsy still remains a major cause of morbidity and mortality among the pediatric and geriatric populations. Commonly available AED therapies include sodium and calcium channel blockers, GABA agonists, and potassium channel activists. Along with beneficial effects, AEDs have been known to cause teratogenic responses, learning disabilities, malfunctions of different organs, and drug-induced syndrome. Nowadays, AED-related cognitive impairment is emerging as a serious condition, affecting children born to epileptic women.

The Emergence of Mpox: Epidemiology and Current Therapeutic Options.

The world recently witnessed the emergence of new epidemic outbreaks like COVID-19 and mpox. The 2022 outbreak of mpox amid COVID-19 presents an intricate situation and requires strategies to combat the status quo. Some of the challenges to controlling an epidemic include present knowledge of the disease, available treatment options, appropriate health infrastructures facilities, current scientific methods, operations concepts, availability of technical staff, financial funds, and lastly international policies to control an epidemic state. These insufficiencies often hinder the control of disease spread and jeopardize the health of countless people. Also, disease outbreaks often put a huge burden on the developing economies. These countries are the worst affected and are immensely dependent on assistance provided from the larger economies to control such outbreaks. The first case of mpox was reported in the 1970s and several outbreaks were detected thereafter in the endemic areas eventually leading to the recent outbreak. Approximately, more than 80,000 individuals were infected, and 110 countries were affected by this outbreak. Yet, no definite vaccines and drugs are available to date. The lack of human clinical trials affected thousands of individuals in availing definite disease management. This paper focuses on the epidemiology of mpox, scientific concepts, and treatment options including future treatment modalities for mpox.

Chemopreventive mechanisms of amentoflavone: recent trends and advancements.

In parallel to the continuous rise of new cancer cases all over the world, the interest of scientific community in natural anticancer agents has steadily been increased. In the past decades, numerous phytochemicals have been shown to possess a strong anticancer potential in preclinical conditions. One of such interesting compounds, derived from different plants such as ginkgo, hinoki, and St. John`s wort, is amentoflavone. In this review article, a wide range of anticancer properties of this natural biflavone are described, revealing its ability to suppress the malignant growth and lead tumor cells to apoptotic death, besides impeding also angiogenic and metastatic processes. Therefore, amentoflavone can be considered a potential lead compound for the development of novel anticancer drug candidates, definitely deserving further in vivo studies and also initiation of clinical trials. It is expected that this plant biflavone might be important, either alone or in combination with the current standard chemotherapeutics, in providing some alleviation for the continuous rise of global cancer burden.

Autophagy Induction by Scutellaria Flavones in Cancer: Recent Advances.

In parallel with a steady rise in cancer incidence worldwide, the scientific community is increasingly focused on finding novel, safer and more efficient modalities for managing this disease. Over the past decades, natural products have been described as a significant source of new structural leads for novel drug candidates. Scutellaria root is one of the most studied natural products because of its anticancer potential. Besides just describing the cytotoxic properties of plant constituents, their molecular mechanisms of action in different cancer types are equally important. Therefore, this review article focuses on the role of the Scutellaria flavones wogonin, baicalein, baicalin, scutellarein and scutellarin in regulating the autophagic machinery in diverse cancer models, highlighting these molecules as potential lead compounds for the fight against malignant neoplasms. The knowledge that autophagy can function as a dual-edged sword, acting in both a pro- and antitumorigenic manner, further complicates the issue, revealing an amazing property of flavonoids that behave either as anti- or proautophagic agents.

Pathological involvement of apoptotic and inflammatory molecules in cardiovascular remodeling in rats on high fructose diet-induced metabolic syndrome.

Fructose consumption has been linked to manifestation of metabolic syndrome (MS); an emerging epidemic. The current study attempts to demonstrate fructose overconsumption-mediated cardiovascular disease (CVD) remodeling in Wistar rats. Rats were randomly segregated into control (CON) and high fructose diet (FFR) groups and received customized diets for 20 weeks. Levels of diabetic, lipid, antioxidant, markers, mRNA levels of inflammatory, apoptotic markers, and histopathological changes were assessed in excised hearts of both groups. Significant increase in uric acid, pro-oxidants diabetic, lipid, inflammatory markers, cytosolic cytochrome C, nuclear NF-кB-p65, and decrease in antioxidants was observed in FFR group. Abnormal myocardial architecture was observed in the FFR group along with elevated mRNA levels of inflammatory, apoptotic markers, and MMP-9, -2. The outcomes of the study are suggestive of role of aforementioned molecules in high fructose intake-mediated pathological deterioration of heart and development of MS-associated CVD progression. PRACTICAL APPLICATIONS: Excessive fructose consumption in the form of high fructose corn syrup, sugary drinks, and commonly available fast foods has been shown to be linked with many diseases such as liver malfunction, metabolic syndrome diabetes, and cardiovascular diseases. However, delineated pathways and clear mechanisms and their role in cardiovascular remodeling due to excessive fructose consumption are yet to be established. The present study establishes the deleterious effects of foods with high sugar content on progression toward metabolic syndrome and cardiovascular remodeling. It further investigates the role of different pathways involved in the development of high fructose-induced diet-induced metabolic syndrome, and thereby leading to harmful effects on the hearts of rats consuming high fructose diet leading to cardiovascular in Wistar rats. The study suggests the role of immunomodulation and oxidative stress in the remodeling of cardiac muscles and in turn progression toward metabolic syndrome and cardiovascular remodeling. The study, therefore, throws light on the deleterious effects of consumption of foods and easily available fast foods on progression toward numerous non-communicable diseases.

Gut Microbiota-Assisted Synthesis, Cellular Interactions and Synergistic Perspectives of Equol as a Potent Anticancer Isoflavone.

It is well known that, historically, plants have been an important resource of anticancer agents, providing several clinically approved drugs. Numerous preclinical studies have shown a strong anticancer potential of structurally different phytochemicals, including polyphenolic constituents of plants, flavonoids. In this review article, suppressing effects of equol in different carcinogenesis models are unraveled, highlighting the mechanisms involved in these anticancer activities. Among flavonoids, daidzein is a well-known isoflavone occurring in soybeans and soy products. In a certain part of population, this soy isoflavone is decomposed to equol under the action of gut microflora. Somewhat surprisingly, this degradation product has been shown to be more bioactive than its precursor daidzein, revealing a strong and multifaceted anticancer potential. In this way, it is important to bear in mind that the metabolic conversion of plant flavonoids might lead to products that are even more efficient than the parent compounds themselves, definitely deserving further studies.

Luteolin, a Potent Anticancer Compound: From Chemistry to Cellular Interactions and Synergetic Perspectives.

Increasing rates of cancer incidence and the toxicity concerns of existing chemotherapeutic agents have intensified the research to explore more alternative routes to combat tumor. Luteolin, a flavone found in numerous fruits, vegetables, and herbs, has exhibited a number of biological activities, such as anticancer and anti-inflammatory. Luteolin inhibits tumor growth by targeting cellular processes such as apoptosis, cell-cycle progression, angiogenesis and migration. Mechanistically, luteolin causes cell death by downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, Bcl-2, and Bcl-xL, while upregulating BAX, caspase-3, and p21. It has also been reported to inhibit STAT3 signaling by the suppression of STAT3 activation and enhanced STAT3 protein degradation in various cancer cells. Therefore, extensive studies on the anticancer properties of luteolin reveal its promising role in chemoprevention. The present review describes all the possible cellular interactions of luteolin in cancer, along with its synergistic mode of action and nanodelivery insight.