The dynamic role of immune checkpoint molecules in diagnosis, prognosis, and treatment of head and neck cancers.

Head and neck cancer (HNC) is the sixth most common cancer type, accounting for approximately 277,597 deaths worldwide. Recently, the Food and Drug Administration (FDA) has approved immune checkpoint blockade (ICB) agents targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) as a treatment regimen for head and neck squamous cell carcinomas (HNSCC). Studies have reported the role of immune checkpoint inhibitors as targeted therapeutic regimens that unleash the immune response against HNSCC tumors. However, the overall response rates to immunotherapy vary between 14-32% in recurrent or metastatic HNSCC, with clinical response and treatment success being unpredictable. Keeping this perspective in mind, it is imperative to understand the role of T cells, natural killer cells, and antigen-presenting cells in modulating the immune response to immunotherapy. In lieu of this, these immune molecules could serve as prognostic and predictive biomarkers to facilitate longitudinal monitoring and understanding of treatment dynamics. These immune biomarkers could pave the path for personalized monitoring and management of HNSCC. In this review, we aim to provide updated immunological insight on the mechanism of action, expression, and the clinical application of immune cells' stimulatory and inhibitory molecules as prognostic and predictive biomarkers in HNC. The review is focused mainly on CD27 and CD137 (members of the TNF-receptor superfamily), natural killer group 2 member D (NKG2D), tumor necrosis factor receptor superfamily member 4 (TNFRSF4 or OX40), S100 proteins, PD-1, PD-L1, PD-L2, T cell immunoglobulin and mucin domain 3 (TIM-3), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), indoleamine-pyrrole 2,3-dioxygenase (IDO), B and T lymphocyte attenuator (BTLA). It also highlights the importance of T, natural killer, and antigen-presenting cells as robust biomarker tools for understanding immune checkpoint inhibitor-based treatment dynamics. Though a comprehensive review, all aspects of the immune molecules could not be covered as they were beyond the scope of the review; Further review articles can cover other aspects to bridge the knowledge gap.

Chronic inflammation and cancer; the two sides of a coin.

The correlation between chronic inflammation and cancer was initially identified in the 19th century. Biomolecules like interleukins, chemokines, tumor necrosis factors, growth factors, and adhesion molecules, which regulate inflammation, are recognized contributors to neoplastic transformation through various mechanisms, including oncogenic mutations, resistance to apoptosis, and adaptive responses like angiogenesis. This review aims to establish connections between the intricate and complex mechanisms of chronic inflammation and cancer. We illuminate implicit signaling mechanisms that drive the association between chronic inflammation and the initiation/progression of cancer, exploring potential impacts on other diseases. Additionally, we discuss the modalities of currently available therapeutic options for chronic inflammation and cancer, emphasizing the dual nature of such therapies. A thorough understanding of the molecular basis of chronic inflammation is crucial for developing novel approaches in the prevention and treatment of cancer.

Role of HMGB1 and its associated signaling pathways in human malignancies.

The High-Mobility Group Box-1 (HMGB1), a non-histone chromatin-associated protein, plays a crucial role in cancer growth and response to therapy as it retains a pivotal role in promoting both cell death and survival. HMGB1 has been reported to regulate several signaling pathways engaged in inflammation, genome stability, immune function, cell proliferation, cell autophagy, metabolism, and apoptosis. However, the association between HMGB1 and cancer is complex and its mechanism in tumorigenesis needs to be further elucidated. This review aims to understand the role of HMGB1 in human malignancies and discuss the signaling pathways linked to this process to provide a comprehensive understanding on the association of HMGB1 with carcinogenesis. Further, we will review the role of HMGB1 as a target/biomarker for cancer therapy, the therapeutic strategies used to target this protein, and its potential role in preventing or treating cancers. In light of the recent growing evidence linking HMGB1 to cancer progression, we think that it may be suggested as a novel and emergent therapeutic target for cancer therapy. Hence, HMGB1 warrants paramount investigation to comprehensively map its role in tumorigenesis.

Shrinking the battlefield in cancer therapy: Nanotechnology against cancer stem cells.

Cancer remains one of the leading causes of mortality worldwide, presenting a significant healthcare challenge owing to the limited efficacy of current treatments. The application of nanotechnology in cancer treatment leverages the unique optical, magnetic, and electrical attributes of nanomaterials to engineer innovative, targeted therapies. Specifically, manipulating nanomaterials allows for enhanced drug loading efficiency, improved bioavailability, and targeted delivery systems, reducing the non-specific cytotoxic effects characteristic of conventional chemotherapies. Furthermore, recent advances in nanotechnology have demonstrated encouraging results in specifically targeting CSCs, a key development considering the role of these cells in disease recurrence and resistance to treatment. Despite these breakthroughs, the clinical approval rates of nano-drugs have not kept pace with research advances, pointing to existing obstacles that must be addressed. In conclusion, nanotechnology presents a novel, powerful tool in the fight against cancer, particularly in targeting the elusive and treatment-resistant CSCs. This comprehensive review delves into the intricacies of nanotherapy, explicitly targeting cancer stem cells, their markers, and associated signaling pathways.

Studies on anti-colon cancer potential of nanoformulations of curcumin and succinylated curcumin in mannosylated chitosan.

Colon cancer (CRC) is the second leading cause of death and the third most diagnosed cancer worldwide. Although curcumin (CUR) has demonstrated a potent anticancer activity, it is characterized by its poor solubility, low bioavailability, and instability. This study is a projection from a previous investigation where CUR and succinylated CUR (CUR.SA) were separately encapsulated in mannosylated-chitosan nanoparticles (CM-NPs) to form CUR-NPs and CUR.SA-NPs, respectively. Here, we aim to assess the anti-CRC activity of these two nanoformulations. Cytotoxicity studies using CCK-8 assay indicated that both CUR-NPs and CUR.SA-NPs have a dose and time-dependent toxicity towards CRC human cell-lines (HCT116 and SW480), and more cytotoxic compared to free CUR or CUR-SA in a time-dependent manner. A significant induction of early and late apoptosis in the CUR-NPs and CUR.SA-NPs treated CRC cell lines compared to untreated cells was observed. Western blotting analyses confirmed the induction of apoptosis through activation of Caspase signaling compared to untreated cells. Based on the physicochemical properties of CUR-NPs and CUR.SA-NPs along with the data from the in vitro studies, we may conclude these nanoparticle formulations hold very promising attributes, worthy of further investigations for its role in the management of CRC.

The molecular mechanisms of apoptosis accompanied with the epigenetic regulation of the NY-ESO-1 antigen in non-small lung cancer cells treated with decitabine (5-aza-CdR).

Dysregulated epigenetic modifications are common in lung cancer but have been reversed using demethylating agent like 5-Aza-CdR. 5-Aza-CdR induces/upregulates the NY-ESO-1 antigen in lung cancer. Therefore, we investigated the molecular mechanisms accompanied with the epigenetic regulation of NY-ESO-1 in 5-Aza-CdR-treated NCI-H1975 cell line. We showed significant induction of the NY-ESO-1 protein (**p < 0.0097) using Cellular ELISA. Bisulfite-sequencing demonstrated 45.6% demethylation efficiency at the NY-ESO-1 gene promoter region and RT-qPCR analysis confirmed the significant induction of NY-ESO-1 at mRNA level (128-fold increase, *p < 0.050). We then investigated the mechanism by which 5-Aza-CdR inhibits cell proliferation in the NCI-H1975 cell line. Upregulation of the death receptors TRAIL (2.04-fold *p < 0.011) and FAS (2.1-fold *p < 0.011) indicate activation of the extrinsic apoptotic pathway. The upregulation of Voltage-dependent anion-selective channel protein 1 (1.9-fold), Major vault protein (1.8-fold), Bax (1.16-fold), and Cytochrome C (1.39-fold) indicate the activation of the intrinsic pathway. We also observed the differential expression of protein Complement C3 (3.3-fold), Destrin (-5.1-fold), Vimentin (-1.7-fold), Peroxiredoxin 4 (-1.6-fold), Fascin (-1.8-fold), Heme oxygenase-2 (-0.67-fold**p < 0.0055), Hsp27 (-0.57-fold**p < 0.004), and Hsp70 (-0.39-fold **p < 0.001), indicating reduced cell growth, cell migration, and metastasis. The upregulation of 40S ribosomal protein S9 (3-fold), 40S ribosomal protein S15 (4.2-fold), 40S ribosomal protein S18 (2.5-fold), and 60S ribosomal protein L22 (4.4-fold) implied the induction of translation machinery. These results reiterate the decisive role of 5-Aza-CdR in lung cancer treatment since it induces the epigenetic regulation of NY-ESO-1 antigen, inhibits cell proliferation, increases apoptosis, and decreases invasiveness.

Applications of polydopaminic nanomaterials in mucosal drug delivery.

Polydopamine (PDA) is a biopolymer with unique physicochemical properties, including free-radical scavenging, high photothermal conversion efficiency, biocompatibility, biodegradability, excellent fluorescent and theranostic capacity due to their abundant surface chemistry. Thus, PDA is used for a myriad of applications including drug delivery, biosensing, imaging and cancer therapy. Recent reports present a new functionality of PDA as a coating nanomaterial, with major implications in mucosal drug delivery applications, particularly muco-adhesion and muco-penetration. However, this application has received minimal traction in the literature. In this review, we present the physicochemical and functional properties of PDA and highlight its key biomedical applications, especially in cancer therapy. A detailed presentation of the role of PDA as a promising coating material for nanoparticulate carriers intended for mucosal delivery forms the core aspect of the review. Finally, a reflection on key considerations and challenges in the utilizing PDA for mucosal drug delivery, along with the possibilities of translation to clinical studies is expounded.

Nano-vitamin C: A promising candidate for therapeutic applications.

Vitamin C is an important nutrient implicated in different physiological functions in humans. Despite its important biological functions, therapeutic applications of vitamin C are rare and its use is further impacted by low chemical stability. Several nano-encapsulation techniques have been described in the literature and yet, there are only a handful of clinical investigations dedicated to unlocking the therapeutic applications of nano-encapsulated vitamin C. Clearly, further investigations are warranted in order to affirm the promising clinical potential of nano-encapsulated vitamin C. In this review, we describe the mechanisms of vitamin C activity as a modulator of crucial therapeutic uses in biological systems. We look at key factors affecting the chemical stability of vitamin C alone and in nano-encapsulated and explore pre-clinical and clinical evidence on current vitamin C nano-formulations along with their therapeutic applications. Finally, we critically appraise the gaps and opportunities prevailing in nano-vitamin C research and its potential translation towards relevant clinical outcomes.

A novel approach of encapsulating curcumin and succinylated derivative in mannosylated-chitosan nanoparticles.

Curcumin (CUR) manifests anti-colon cancer activity but suffers from low solubility, bioavailability, and instability, rendering it not as effective as its chemotherapeutic cousins. Here, we conjugate CUR to succinic anhydride (SA), (CUR.SA conjugate), subsequently formulated in mannose-conjugated chitosan nanoparticles (CUR-NPs and CUR.SA-NPs). Instrumental analyses confirmed formation of CUR.SA and mannosylated chitosan (CM) conjugates, with CUR.SA being less crystalline thus, more soluble. Average particle size of CUR-NPs and CUR.SA-NPs were 268 ± 6 nm and 342 ± 4.6 nm, with drug entrapment of 93.34 ± 0.40 % and 98.46 ± 0.06 % respectively. In vitro releases of CUR and CUR.SA from nanoparticles in pH 1.2 and 6.8 media were slow and sustained over 2 h and 72 h, respectively. The physical characteristics of the nanoparticles were unchanged over 3 weeks of storage. Thus, a successful CUR.SA conjugate has been developed, couriered in CM nanoparticles, with favorable attributes that warrant further anti-colon cancer studies, which is ongoing.

Curcumin and Derivatives in Nanoformulations with Therapeutic Potential on Colorectal Cancer.

There is growing concern in the rise of colorectal cancer (CRC) cases globally, and with this rise is the presentation of drug resistance. Like other cancers, current treatment options are either invasive or manifest severe side effects. Thus, there is a move towards implementing safer treatment options. Curcumin (CUR), extracted from Curcuma longa, has received significant attention by scientists as possible alternative to chemotherapeutic agents. It is safe and effective against CRC and nontoxic in moderate concentrations. Crucially, it specifically modulates apoptotic effects on CRC. However, the use of CUR is limited by its low solubility and poor bioavailability in aqueous media. These limitations are surmountable through novel approaches, such as nanoencapsulation of CUR, which masks the physicochemical properties of CUR, thus potentiating its anti-CRC effects. Furthermore, chemical derivatization of CUR is another approach that can be used to address the above constraints. This review spans published work in the last two decades, with key findings employing either of the two approaches, in addition to a combined approach in managing CRC. The combined approach affords the possibility of better treatment outcomes but not widely investigated nor yet clinically implemented.

Dynamic liquid biopsy components as predictive and prognostic biomarkers in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide. The diagnosis, prognosis and therapeutic monitoring of CRC depends largely on tissue biopsy. However, due to tumor heterogeneity and limitations such as invasiveness, high cost and limited applicability in longitudinal monitoring, liquid biopsy has gathered immense attention in CRC. Liquid biopsy has several advantages over tissue biopsy including ease of sampling, effective monitoring, and longitudinal assessment of treatment dynamics. Furthermore, the importance of liquid biopsy is signified by approval of several liquid biopsy assays by regulatory bodies indicating the powerful approach of liquid biopsy for comprehensive CRC screening, diagnostic and prognostics. Several liquid biopsy biomarkers such as novel components of the microbiome, non-coding RNAs, extracellular vesicles and circulating tumor DNA are extensively being researched for their role in CRC management. Majority of these components have shown promising results on their clinical application in CRC including early detection, observe tumor heterogeneity for treatment and response, prediction of metastases and relapse and detection of minimal residual disease. Therefore, in this review, we aim to provide updated information on various novel liquid biopsy markers such as a) oral microbiota related bacterial network b) gut microbiome-associated serum metabolites c) PIWI-interacting RNAs (piRNAs), microRNA(miRNAs), Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and d) circulating tumor DNAs (ctDNA) and circulating tumor cells (CTC) for their role in disease diagnosis, prognosis, treatment monitoring and their applicability for personalized management of CRC.

Emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis, therapeutics and vaccines.

The emergence of novel and evolving variants of SARS-CoV-2 has fostered the need for change in the form of newer and more adaptive diagnostic methods for the detection of SARS-CoV-2 infections. On the other hand, developing rapid and sensitive diagnostic technologies is now more challenging due to emerging variants and varying symptoms exhibited among the infected individuals. In addition to this, vaccines remain the major mainstay of prevention and protection against infection. Novel vaccines and drugs are constantly being developed to unleash an immune response for the robust targeting of SARS-CoV-2 and its associated variants. In this review, we provide an updated perspective on the current challenges posed by the emergence of novel SARS-CoV-2 mutants/variants and the evolution of diagnostic techniques to enable their detection. In addition, we also discuss the development, formulation, working mechanisms, advantages, and drawbacks of some of the most used vaccines/therapeutic drugs and their subsequent immunological impact.Key messageThe emergence of novel variants of the SARS-CoV-2 in the past couple of months, highlights one of the primary challenges in the diagnostics, treatment, as well as vaccine development against the virus.Advancements in SARS-CoV-2 detection include nucleic acid based, antigen and immuno- assay-based and antibody-based detection methodologies for efficient, robust, and quick testing; while advancements in COVID-19 preventive and therapeutic strategies include novel antiviral and immunomodulatory drugs and SARS-CoV-2 targeted vaccines.The varied COVID-19 vaccine platforms and the immune responses induced by each one of them as well as their ability to battle post-vaccination infections have all been discussed in this review.

The potential role of vitamin C in empowering cancer immunotherapy.

Vitamin C also known as L-ascorbic acid is a nutrient naturally occurring in many fruits and vegetables and widely known for its potent antioxidant activity. Several studies have highlighted the importance of using high dose vitamin C as an adjuvant anti-cancer therapy. Interestingly, it has been shown that vitamin C is able to modulate the anti-cancer immune response and to help to overcome the resistance to immune checkpoints blockade (ICB) drugs such as cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors. Indeed, it was reported that vitamin C regulates several mechanisms developed by cancer cells to escape T cells immune response and resist ICB. Understanding the role of vitamin C in the anti-tumor immune response will pave the way to the development of novel combination therapies that would enhance the response of cancer patients to ICB immunotherapy. In this review, we discuss the effect of vitamin C on the immune system and its potential role in empowering cancer immunotherapy through its pro-oxidant potential, its ability to modulate epigenetic factors and its capacity to regulate the expression of different cytokines involved in the immune response.

Safety evaluation, anti-oxidative and anti-inflammatory effects of subchronically dietary supplemented high dosing grape seed powder (GSP) to healthy rat.

Grape seed powder (GSP) contains high amount of bioactive polyphenols usually used as nutritional supplement or food preservatives due to their antioxidant and scavenging properties. The purpose of the present work was to evaluate the safety of increasing dosage GSP (w/w) of 0.5%, 5%, 10% and 20% corresponding to 0.4, 4, 8 and 16 g/kg bw respectively, when administered sub-chronically to Wistar rats in a 2 month-repeated dosing oral toxicity trial. Overally GSP had no effect on food intake, decreased body weight gain without affecting brain, liver, heart or kidney relative weight. GSP did not alter haematology except an increase in platelets, slightly decreased plasma transaminases, creatinine, urea and xanthine oxidase activity, without affecting uricemia, glycemia, triglyceridemia and cholesterolemia. GSP did not affect intracellular mediators as calcium, free iron or H2O2, but exerted real anti-oxidative properties in the four selected organs as assessed by lower lipoperoxidation and carbonylation, higher non protein thiols and antioxidant enzyme activities as CAT, GPx and SOD. Besides GSP exerted anti-inflammatory properties as supported by lower plasma IL17 A and CRP and higher IL10 and adiponectin. Histopathologically GSP provoked the dilation of heart and kidney arterioles and increased the size of the hippocampal dentate gyrus reflecting higher neurogenesis as assessed by Ki-67 labeling. Under the experimental conditions of the current study, GSP appeared as highly safe even when administered at very high dosage and could find potential applications in a variety of biotic or abiotic stresses-induced multi-organ dysfunction.

Supplementation of grape seed and skin extract to orlistat therapy prevents high-fat diet-induced murine spleen lipotoxicity.

Spleen is the largest lymphoid organ and obesity is related to an elevated risk of immunity dysfunction. The mechanism whereby fat adversely affects the spleen is poorly understood. This study was designed to assess the effectiveness of grape seed and skin extract (GSSE) and orlistat (Xenical, Xe) on high-fat diet (HFD)-induced spleen lipotoxicity. Obese rats were treated either with GSSE (4 g/kg body weight) or Xe (2 mg/kg body weight) or GSSE+Xe and monitored for weight loss for 3 months. Animals were then sacrificed and their spleen used for the evaluation of lipotoxicity-induced oxidative stress and inflammation as well as the putative protection afforded by GSSE and Xe treatment. HFD induced body weight gain and glycogen accumulation into the spleen; ectopic deposition of cholesterol and triglycerides and an oxidative stress characterized by increased lipoperoxidation and carbonylation; inhibition of antioxidant enzyme activities, such as catalase, glutathione peroxidase, and superoxide dismutase; depletion of zinc and copper; and a concomitant increase in calcium. HFD also increased plasma pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17A, tumour necrosis factor alpha, and C-reactive protein, and decreased plasma IL-10 and adiponectin. Importantly, GSSE counteracted all the deleterious effects of HFD on spleen (i.e., lipotoxicity, oxidative stress, and inflammation) and the best protection was obtained when combining Xe+GSSE. Combining GSSE with Xe prevented against fat-induced spleen lipotoxicity, oxidative stress, and inflammation; this combination may be beneficial in other diseases related to the spleen.

Dietary supplementation of grape seed and skin flour mitigates brain oxidative damage induced by a high-fat diet in rat: Gender dependency.

It is unknown whether gender has an impact on brain injury in obesity, and, if so, whether treatment with grape seed and skin flour could exert a protective effect. Both male and female rats were fed a standard diet (SD) or a high fat diet (HFD) during eight weeks and treated with high dosage grape seed and skin flour (GSSF). Fat-induced oxidative stress was evaluated into the brain with a special emphasis on transition metals determination. HFD induced male-cholesterol overload (+78.12%) and an oxidative stress status characterized by increased lipoperoxidation (+68.97%), carbonylation (+40.28%), decreased antioxidant enzyme activities as glutathione peroxidase (-61.07%) and manganese-superoxide dismutase (-35.47%) but not catalase. Additionally HFD depleted the brain from manganese (-71.31%) and dropped glutamine synthetase activity (-36.16%), without affecting copper nor iron nor their associated enzymes. HFD also altered intracellular mediators as superoxide anion (+36.12%), calcium (+44.41%) and also calpain (+76.54%) a calcium dependent protease. Importantly all these alterations were detected exclusively in male brain and were efficiently corrected upon GSSF treatment. In conclusion, GSSF has the potential to alleviate the deleterious lipotoxic effect of HFD treatment that occurred in male brain and perhaps in post-menauposal female brain.

Protective effect of grape seed and skin extract against diabetes-induced oxidative stress and renal dysfunction in virgin and pregnant rat.

The present work deal with the effect of alloxan-induced diabetes on kidney oxidative stress and dysfunction of virgin and pregnant rat as well as the protection that may be afforded by high dosage GSSE (4g/kg) treatment. Diabetes affected negatively several kidney function parameters as creatinemia, uremia, uricemia and proteinuria without affecting kidney index. Diabetes also induced an oxidative stress characterized by increased lipid and protein oxidation, a drop in antioxidant enzyme defenses as catalase, superoxide-dismutase, glutathione-peroxidase, an alteration in transition metals as free iron, copper, selenium and associated enzymes and an increase in calpain and acetyl-cholinesterase activities. Tremendously, GSSE treatment protected efficiently against all the deleterious effects of diabetes-induced kidney dysfunction in both virgin and pregnant animals. High dosage GSSE is a safe and potent anti-oxidant that may be further tested in clinical trials for the long-term preservation of kidney function especially in multiple pregnancies.