CDK inhibitors from past to present: A new wave of cancer therapy.

Deregulation of the cell cycle machinery, which has been linked to dysregulation of cyclin-dependent kinases (CDKs), is a defining characteristic of cancer, eventually promoting abnormal proliferation that feeds tumorigenesis and disease development. In this regard, several CDK inhibitors (CDKIs) have been developed during the last few decades (1st, 2nd, and 3rd generation CDKIs) to inhibit cancer cell proliferation. 1st and 2nd generation CDKIs have not received much clinical attention for the treatment of cancer patients because of their limited specificity and high toxicity. However, the recent development of combination strategies allowed us to reduce the toxicity and side effects of these CDKIs, paving the way for their potential application in clinical settings. The 3rd generation CDKIs have yielded the most promising results at the preclinical and clinical levels, propelling them into the advanced stages of clinical trials against multiple malignancies, especially breast cancer, and revolutionizing traditional treatment strategies. In this review, we discuss the most-investigated candidates from the 1st, 2nd, and 3rd generations of CDKIs, their basic mechanisms of action, the reasons for their failure in the past, and their current clinical development for the treatment of different malignancies. Additionally, we briefly highlighted the most recent clinical trial results and advances in the development of 3rd generation FDA-approved selective CDK4/6 inhibitors that combat the most prevalent cancer. Overall, this review will provide a thorough knowledge of CDKIs from the past to the present, allowing researchers to rethink and develop innovative cancer therapeutic regimens.

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

Multidimensional role of bacteria in cancer: Mechanisms insight, diagnostic, preventive and therapeutic potential.

The active role of bacteria in oncogenesis has long been a topic of debate. Although, it was speculated to be a transmissible cause of cancer as early as the 16th-century, yet the idea about the direct involvement of bacteria in cancer development has only been explored in recent decades. More recently, several studies have uncovered the mechanisms behind the carcinogenic potential of bacteria which are inflammation, immune evasion, pro-carcinogenic metabolite production, DNA damage and genomic instability. On the other side, the recent development on the understanding of tumor microenvironment and technological advancements has turned this enemy into an ally. Studies using bacteria for cancer treatment and detection have shown noticeable effects. Therapeutic abilities of bioengineered live bacteria such as high specificity, selective cytotoxicity to cancer cells, responsiveness to external signals and control after ingestion have helped to overcome the challenges faced by conventional cancer therapies and highlighted the bacterial based therapy as an ideal approach for cancer treatment. In this review, we have made an effort to compile substantial evidence to support the multidimensional role of bacteria in cancer. We have discussed the multifaceted role of bacteria in cancer by highlighting the wide impact of bacteria on different cancer types, their mechanisms of actions in inducing carcinogenicity, followed by the diagnostic and therapeutic potential of bacteria in cancers. Moreover, we have also highlighted the existing gaps in the knowledge of the association between bacteria and cancer as well as the limitation and advantage of bacteria-based therapies in cancer. A better understanding of these multidimensional roles of bacteria in cancer can open up the new doorways to develop early detection strategies, prevent cancer, and develop therapeutic tactics to cure this devastating disease.

DNA replication licensing proteins: Saints and sinners in cancer.

DNA replication is all-or-none process in the cell, meaning, once the DNA replication begins it proceeds to completion. Hence, to achieve maximum control of DNA replication, eukaryotic cells employ a multi-subunit initiator protein complex known as "pre-replication complex or DNA replication licensing complex (DNA replication LC). This complex involves multiple proteins which are origin-recognition complex family proteins, cell division cycle-6, chromatin licensing and DNA replication factor 1, and minichromosome maintenance family proteins. Higher-expression of DNA replication LC proteins appears to be an early event during development of cancer since it has been a common hallmark observed in a wide variety of cancers such as oesophageal, laryngeal, pulmonary, mammary, colorectal, renal, urothelial etc. However, the exact mechanisms leading to the abnormally high expression of DNA replication LC have not been clearly deciphered. Increased expression of DNA replication LC leads to licensing and/or firing of multiple origins thereby inducing replication stress and genomic instability. Therapeutic approaches where the reduction in the activity of DNA replication LC was achieved either by siRNA or shRNA techniques, have shown increased sensitivity of cancer cell lines towards the anti-cancer drugs such as cisplatin, 5-Fluorouracil, hydroxyurea etc. Thus, the expression level of DNA replication LC within the cell determines a cell's fate thereby creating a paradox where DNA replication LC acts as both "Saint" and "Sinner". With a potential to increase sensitivity to chemotherapy drugs, DNA replication LC proteins have prospective clinical importance in fighting cancer. Hence, in this review, we will shed light on importance of DNA replication LC with an aim to use DNA replication LC in diagnosis and prognosis of cancer in patients as well as possible therapeutic targets for cancer therapy.

O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.

In vitro model of predicting metastatic ability using tumor derived extracellular vesicles; beyond seed soil hypothesis.

Lung cancer progression is often driven by metastasis, which has resulted in a considerable increase in lung cancer-related deaths. Cell-derived extracellular vesicles (EVs), particularly exosomes, serve key roles in cellular signal transmission via microenvironment, however, their biological relevance in cancer development and metastasis still needs to be clear. Here, we demonstrate that extracellular vesicles (EVs) derived from lung cancer bone metastatic patients exhibited a great capacity to promote the progression of lung cancer cells. We carried out a comprehensive meta-analysis to identify the gene expression profile of bone metastases using publicly available microarray datasets. Furthermore, mRNA expression of six identified genes was quantified by real time PCR in lung cancer with and without bone metastasis and healthy individual derived EVs. In addition, we utilized a very novel approach by to study how lung cancer cells uptake EVs by co-culturing EVs with lung cells. We observed that EVs obtained from bone metastases patients were efficiently ingested by lung cancer cells. Morevore, integration and uptake of these EVs lead to increased lung cancer cell proliferation, migration, invasion, and sphere formation. We discovered that EV uptake increase the expression of SPP1, CD44, and POSTN genes in lung cancer cells. The data obtained from this study, support to the possibility that circulating EVs play a significant role in the formation of the pre-metastatic niche, eventually leading to metastasis.

Role of Managerial Ability in Environmental, Social, and Economics Sustainability: An Empirical Evidence from China.

The current study analyzed whether the enhancement in managerial ability accelerates the environmental, social, and economic sustainability practices or not. Using panel data methodology on Chinese listed firms data from 2010 to 2019, we report that CEOs' managerial ability impacts the overall (environmental, social, and economic) sustainability practices of the firms positively. Moreover, we find that social sustainability and economic sustainability also increase with the increase of the CEO's managerial ability in the firm. The results remain robust after several alternative empirical tests. The findings justify the relationship between management skills and sustainability and demonstrate how each one of the sustainability pillars is affected individually. The support for sustainability practices that can be achieved through the communication of management skills is an essential conclusion for practitioners. Findings establish the link between CEO's managerial ability and environmental, social, and economic sustainability performance by taking insights from upper echelon theory.

Over-Activation of Minichromosome Maintenance Protein 10 Promotes Genomic Instability in Early Stages of Breast Cancer.

Genomic instability is considered as one of the key hallmark during cancer development and progression. Cellular mechanisms, such as DNA replication initiation, DNA damage and repair response, apoptosis etc are observed to block progression of genomic instability and thereby induce protective effects against cancer. DNA replication initiation protein MCM10 has been previously observed to have an increased expression in different cancer subtypes. However, MCM10 association with genomic instability, cancer development and its relevant mechanisms remain unknown. Here, using a breast cancer model, we observe a significant association of MCM10 with the degree of clinical aggressiveness in breast cancer patients. By overexpression of MCM10, we observed that MCM10 promotes tumorigenic properties in immortal non-tumorigenic mammary cells by increasing proliferation, shortening the cell cycle, and promoting tumorigenic characters in in-vivo mimicking conditions. Furthermore, overexpression of MCM10 is found to induce accumulation of ssDNA followed by overexpression of ssDNA binding protein RPA2. Mesenchymal markers such as up-regulation of Vimentin, transcription factor Snail and Twist2, and the down-regulation of E-cadherin were observed in MCM10 overexpression cells. Overall, the findings of this study revealed a novel mechanism by which MCM10 promotes genomic instability and breast cancer progression, and effectively differentiates the active degree of breast cancer aggressiveness. Thus, MCM10 has the potential to be a clinically useful biomarker as well as a therapeutic target for future breast cancer treatment.

An In Vivo Fluorescence Resonance Energy Transfer-Based Imaging Platform for Targeted Drug Discovery and Cancer Therapy.

In the present study, an efficient in vivo drug screening platform is established based on FRET technique. We transfected cancer cells with FRET-based caspase-3 (C3) sensor and validated the cell lines by detecting the change in FRET signal caused by the in vitro drug-induced cell apoptosis. Furthermore, the C3 expressing cancer cells were then injected into zebrafish embryos and nude mice to establish the corresponding in vivo xenograft models. We found that cancer cell lines expressing C3 were effective in detecting cell death following drug treatment, including the detection of the tipping point of apoptosis. The drug-induced cell apoptosis was also observed in both zebrafish embryos and nude mice xenograft models. Overall, the FRET-based platform, through in vivo imaging, is potentially useful to improve drug screening efficiency.

Corrigendum: An in vivo fluorescence resonance energy transfer-based imaging platform for targeted drug discovery and cancer therapy.

[This corrects the article DOI: 10.3389/fbioe.2022.839078.].

Flavonoid-rich foods (FRF): A promising nutraceutical approach against lifespan-shortening diseases.

It is well documented that life expectancy in developed countries at birth is going to surpass the 20th century. However, regrettably, a potential decline in life expectancy has been proposed for these nations in the 21st century due to a rapid upsurge in the prevalence of fatal degenerative diseases like cardiovascular diseases (CVD), cancer and diabetes. Collectively, these three diseases accounted for 65% of all deaths in urbanized societies and were considered as a dynamic issue for shortening the genetically determined lifespan through increased mortalities, morbidities, disabilities, immense sufferings, and premature aging. These fatal degenerative diseases and premature aging are closely associated with oxidative stress produced by the free radicals in the body. In epidemiologic studies, flavonoid-rich foods (FRF) like fruits, vegetables, and beverages have been associated as protective agents against these diseases. These also have been observed for their geroprotective effects and help in preventing premature aging and deterioration of brain function, which is related to Alzheimer's disease and dementia. In this review, we presented a comprehensive overview of the FRF for their potential role against lifespan-shortening complications, i.e., CVD, cancer, and diabetes. We also have drawn the future perspective and dietary guidelines to reduce the fatal disease burden in urban populations.

The Protective Role of Selenium Against AFB1-Induced Liver Apoptosis by Death Receptor Pathway in Broilers.

Aflatoxin B1 (AFB1) is the most toxic among the mycotoxins and causes detrimental health effects on the liver of human and animals. Selenium (Se) plays an important role in protection of various animal species against numerous notorious toxic agents. The present study is designed to explore the protective effects of Se against AFB1-induced liver pathogenesis by the methods of histopathology, flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR), and biochemical analysis. A total of 312, 1-day-old healthy Cobb-500 broilers were randomly divided into four groups and fed with basal diet (control group), 0.6 mg/kg AFB1 (AFB1 group), 0.4 mg/kg Se (+ Se group), and 0.6 mg/kg AFB1 + 0.4 mg/kg Se (AFB1 + Se group) for 21 days, respectively. Our results showed that 0.4 mg/kg Se supplement in broiler's diets could alleviate the AFB1-induced histological lesions in the liver. The apoptosis analysis by flow cytometry showed that 0.4 mg/kg Se ameliorated the AFB1-induced apoptosis in the liver. Moreover, the mRNA expression levels of Fas, TNF-α, FAS-associated death domain, TNF receptor-associated death domain, TNF receptor-associated factor 2, caspase 10, caspase 8, B cell lymphoma 2, IκB kinase, X-linked inhibitor of apoptosis protein, caspase 9, and caspase 3 analyzed by qRT-PCR demonstrated that 0.4 mg/kg Se could relieve the impact caused by AFB1 to these parameters. The biochemical analyses of activities of CAT, GSH-Px and SOD, hydroxyl ion scavenging and contents of MDA and GSH in liver cells also indicated that 0.4 mg/kg Se has positive effect on AFB1-induced oxidative stress in the liver. In conclusion, Se could relieve AFB1-induced apoptosis by the molecular regulation of death receptors pathway in the liver of broilers. The outcomes from the present study may lead to a better understanding of the nature of selenium's essentiality and its protective roles against AFB1.

Aflatoxin B1 invokes apoptosis via death receptor pathway in hepatocytes.

The fungal metabolites produced by Aspergillus flavus and Aspergillus parasiticus cause detrimental health effects on humans and animals. Particularly aflatoxin B1 (AFB1) is the most studied and a well-known global carcinogen, producing hepatotoxic, genotoxic and immunotoxic effects in multiple species. AFB1 is shown to provoke liver dysfunctioning by causing hepatocytes apoptosis and disturbing cellular enzymatic activities. In liver, AFB1 causes apoptosis via extrinsic mechanism because of high expression of death receptor pathway. The detailed mechanism of AFB1 induced hepatocytes apoptosis, via death receptor pathway still remains elusive. So the present study was conducted to explore apoptotic mechanism initiated by death receptors and associated genes in aflatoxin B1 induced liver apoptosis in chickens fed with AFB1 for 3 weeks. Results from the present study displayed histopathological and ultrastructural changes in liver such as hydropic degeneration, fatty vacuolar degeneration and proliferation of bile duct in hepatocytes in AFB1 group, along with imbalance between reactive oxygen species (ROS) and antioxidant defense system upon AFB1 ingestion. Moreover, AFB1 intoxicated chickens showed upregulation of death receptors FAS, TNFR1 and associated genes and downregulation of inhibitory apoptotic proteins XIAP and BCL-2. The results obtained from this novel and comprehensive study including histopathological, ultrastructural, flow cytometrical and death receptor pathway gene expression profiles, will facilitate better understanding of mechanisms and involvement of death receptor pathway in hepatocytes apoptosis induced by AFB1 and ultimately may be helpful in bringing down the toxigenic potential of AFB1.

Aflatoxin B1 Induced Systemic Toxicity in Poultry and Rescue Effects of Selenium and Zinc.

Among many challenges, exposure to aflatoxins, particularly aflatoxin B1 (AFB1), is one of the major concerns in poultry industry. AFB1 intoxication results in decreased meat/egg production, hepatotoxicity, nephrotoxicity, disturbance in gastrointestinal tract (GIT) and reproduction, immune suppression, and increased disease susceptibility. Selenium (Se) and zinc (Zn), in dietary supplementation, offer easy, cost-effective, and efficient ways to neutralize the toxic effect of AFB1. In the current review, we discussed the impact of AFB1 on poultry industry, its biotransformation, and organ-specific noxious effects, along with the action mechanism of AFB1-induced toxicity. Moreover, we explained the biological and detoxifying roles of Se and Zn in avian species as well as the protection mechanism of these two trace elements. Ultimately, we discussed the use of Se and Zn supplementation against AFB1-induced toxicity in poultry birds.