The Cell Death and Signal Transduction Mechanisms in Colorectal Carcinogenesis: Recent Advances.

In underdeveloped nations, colorectal carcinogenesis (CRC) is a significant health issue. It is the third most common outcome of cancer death. Despite a variety of therapy options, new medications are needed to lessen the severity of this condition. In the colon, adenomatous polyps are the most common cause of CRC, occurring in 45 percent of cases, particularly in patients over 60 years old. Inflammatory polyps are acquiring popularity in CRC, as well as inflammation appears to exert a function in the disease, according to mounting research. The azoxymethane, dimethyl hydrazine, APCmin/+ mouse model, and a combination of sulfated polysaccharides composed of dextran and sulfated and dimethylhydrazine are among the experimental models used to study CRC in animals. Numerous signal transduction pathways are engaged as CRC progresses. The p53, TGF-ß, Delta-Notch, Salvador-Warts-Hippo (SWH), and Kelch-like ECH associated protein 1 pathways are among the key signal transduction pathways. To decide cell destiny, several signalling pathways work in tandem with the death of cell modalities, such as autophagy, necroptosis, and apoptosis. In our lab, we have spent a lot of time looking into the cell signalling and mechanisms of cell death in CRC. The pathogenesis of CRC, as well as the associated cell death and cell signalling pathways, are summarised in this study.

Therapeutic approaches for the treatment of head and neck squamous cell carcinoma-An update on clinical trials.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer with a tobacco consumption and infection with high-risk human papillomavirus (HPV) being major risk factors. Despite advances in numerous therapy modalities, survival rates for HNSCC have not improved considerably; a vast number of clinical outcomes have demonstrated that a combination strategy (the most well-known docetaxel, cisplatin, and 5-fluorouracil) is the most effective treatment choice. Immunotherapy that targets immunological checkpoints is being tested in a number of clinical trials, either alone or in conjunction with chemotherapeutic or targeted therapeutic drugs. Various monoclonal antibodies, such as cetuximab and bevacizumab, which target the EGFR and VEGFR, respectively, as well as other signaling pathway inhibitors, such as temsirolimus and rapamycin, are also being studied for the treatment of HNSCC. We have reviewed the primary targets in active clinical studies in this study, with a particular focus on the medications and drug targets used.

Model of Streptozotocin-nicotinamide Induced Type 2 Diabetes: a Comparative Review.

The aim of the present study was to review the streptozotocin-nicotinamide (STZ-NA) diabetes model. Type 2 diabetes is more prevalent (90-95%) in adults than type 1. Experimentally- induced diabetes models may be established by chemicals, viral agents, insulin antibodies, surgery, etc. The most advisable and prompt method to induce diabetes is using chemicals, and STZ and alloxan are widely used chemicals. STZ has proven to be a better diabetogenic agent than alloxan because alloxan has many drawbacks, as it induces only type 1 diabetes, has a high mortality rate in rats, and causes ketosis in animals. Moreover, it has lesser selectivity towards ß-cells, and the diabetes-induced is reversible. STZ can be used to induce both type 1 and type 2 diabetes. It is noted that the genotoxic behavior of STZ in animals is accomplished through a reduction of nicotinamide adenine dinucleotide (NAD+) in pancreatic ß-cells via the GLUT2 (Glucose transporter 2), which can cause cellular damage by DNA (Deoxyribonucleic acid) strand breaks that lead to cell death. NA is a biochemical precursor of NAD+, and it is a poly-ADP-ribose-polymerase-1 (PARP- 1) inhibitor. NAD+ is an important redox reaction co-enzyme for the production of adenosine triphosphate (ATP) and many other metabolic pathways. Extreme DNA damage contributes to the over-activation of PARP-1, loss of cellular resources, and necrotic cells death. Some studies have expressed that NA can protect pancreatic ß-cells against the severe cytotoxicity of STZ. The review concluded that the STZ-NA model is dependent on the competency of NA to attain partial protection against the ß-cytotoxic essence of STZ to induce type-2 diabetes.

Injectable hydrogels of newly designed brush biopolymers as sustained drug-delivery vehicle for melanoma treatment.

Novel biocompatible and brush copolymers have been developed for cancer treatment using its controlled drug-release potential. Polyurethane graft on linear dextrin has been synthesized to control the hydrophilic-hydrophobic balance for regulated drug delivery. The properties of the graft copolymers have been tuned through graft density. The prepared grafts are thermally stable and mechanically strong. An injectable hydrogel has been developed by embedding the drug-loaded brush copolymers in methyl cellulose to better control the release for a prolonged period, importantly by keeping the drug release at a constant rate. Cellular studies indicate the biocompatible nature of the brush copolymers whose controlled and slow release of drug exhibit significant cytotoxic effects on cancer cells. Endocytosis of drug tagged contrast agent indicates greater transport of biologically active material inside cell as observed through cellular uptake studies. In vivo studies on melanoma mice exhibit the real efficacy of the controlled drug release from the injectable hydrogel with significant melanoma suppression without any side effects as opposed to severe toxic effects observed in conventional chemotherapy. Special application method of drug-loaded hydrogel just beneath the tumor makes this system incredibly effective through confinement. Thus, brush copolymer injectable hydrogel is a promising vehicle for control release of drug for cancer treatment in future.

Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles.

The application of nanomedicines is increasing rapidly with the promise of targeted and efficient drug delivery. Nanomedicines address the shortcomings of conventional therapy, as evidenced by several preclinical and clinical investigations indicating site-specific drug delivery, reduced side effects, and better treatment outcome. The development of suitable and biocompatible drug delivery vehicles is a prerequisite that has been successfully achieved by using simple and functionalized liposomes, nanoparticles, hydrogels, micelles, dendrimers, and mesoporous particles. A variety of drug delivery vehicles have been established for the targeted and controlled delivery of therapeutic agents in a wide range of chronic diseases, such as diabetes, cancer, atherosclerosis, myocardial ischemia, asthma, pulmonary tuberculosis, Parkinson's disease, and Alzheimer's disease. After successful outcomes in preclinical and clinical trials, many of these drugs have been marketed for human use, such as Abraxane®, Caelyx®, Mepact®, Myocet®, Emend®, and Rapamune®. Apart from drugs/compounds, novel therapeutic agents, such as peptides, nucleic acids (DNA and RNA), and genes have also shown potential to be used as nanomedicines for the treatment of several chronic ailments. However, a large number of extensive clinical trials are still needed to ensure the short-term and long-term effects of nanomedicines in humans. This review discusses the advantages of various drug delivery vehicles for better understanding of their utility in terms of current medical needs. Furthermore, the application of a wide range of nanomedicines is also described in the context of major chronic diseases.

Health benefits of resveratrol: Evidence from clinical studies.

Resveratrol is a polyphenolic nutraceutical that exhibits pleiotropic activities in human subjects. The efficacy, safety, and pharmacokinetics of resveratrol have been documented in over 244 clinical trials, with an additional 27 clinical trials currently ongoing. Resveretrol is reported to potentially improve the therapeutic outcome in patients suffering from diabetes mellitus, obesity, colorectal cancer, breast cancer, multiple myeloma, metabolic syndrome, hypertension, Alzheimer's disease, stroke, cardiovascular diseases, kidney diseases, inflammatory diseases, and rhinopharyngitis. The polyphenol is reported to be safe at doses up to 5 g/d, when used either alone or as a combination therapy. The molecular basis for the pleiotropic activities of resveratrol are based on its ability to modulate multiple cell signaling molecules such as cytokines, caspases, matrix metalloproteinases, Wnt, nuclear factor-κB, Notch, 5'-AMP-activated protein kinase, intercellular adhesion molecule, vascular cell adhesion molecule, sirtuin type 1, peroxisome proliferator-activated receptor-γ coactivator 1α, insulin-like growth factor 1, insulin-like growth factor-binding protein 3, Ras association domain family 1α, pAkt, vascular endothelial growth factor, cyclooxygenase 2, nuclear factor erythroid 2 like 2, and Kelch-like ECH-associated protein 1. Although the clinical utility of resveratrol is well documented, the rapid metabolism and poor bioavailability have limited its therapeutic use. In this regard, the recently produced micronized resveratrol formulation called SRT501, shows promise. This review discusses the currently available clinical data on resveratrol in the prevention, management, and treatment of various diseases and disorders. Based on the current evidence, the potential utility of this molecule in the clinic is discussed.

Controlling Drug Delivery Using Nanosheet-Embedded Electrospun Fibers for Efficient Tumor Treatment.

The objective of this study is to fabricate biodegradable polymers into scaffolds to embed drugs for tumor treatment without any toxic side effects. Scaffold preparation is optimized by changing the conditions, e.g., poly(lactic acid) concentration (10% w/v), applied potential (15 kV), flow rate (1 mL/h), distance between needle and collector (20 cm), and nanosheet concentration (4 wt % nanoclay), during electrospinning. A drug-embedded nanofiber scaffold is used to regulate the drug delivery in a sustainable manner utilizing the enhanced barrier effect from dispersed nanosheet and good interaction between the components. The effect of thermal treatment improves the stability and slower release of drug through alteration in microstructure. Cell culture studies using a nanofiber scaffold indicate its biocompatibility and applicability as a biomaterial for tumor treatment. Sustained drug release from the scaffold enhances the in vitro cancer cytotoxicity up to 85% in 3 days. In vivo studies clearly suggest suppression of tumor volume using scaffold as a patch over the tumor site as compared to control, pure drug, and drug-embedded film in the mice model. Evaluation of biochemical parameters indicates no toxic side effects for the liver and kidney using a hybrid scaffold as a delivery vehicle as opposed to severe liver injury in control and pure drug-treated mice group. Histopathology of the organs confirms the side effects for the pure drug-treated mice group against normal tissue morphology observed in scaffold-treated animals. Thus, sustained release of drug from this novel delivery vehicle has every potential to be used for tumor treatment more efficiently without any considerable side effects.

Third Generation Cyclodextrin Graft with Polyurethane Embedded in Hydrogel for a Sustained Drug Release: Complete Shrinkage of Melanoma.

An injectable hydrogel-based drug delivery carrier has been developed for long-term drug release by assembling various generations of cyclodextrin (CD) followed by hydrophobic layers to control the drug release for effective cancer treatment. Three generations of CD are designed through urethane linkages using small spacers to create a large hydrophilic core, which is covered with hydrophobic layers of polyurethane through grafting to maintain the hydrophilic hydrophobic balance of the whole superstructure. Drug release becomes sustained from the intricate superstructure following the non-Fickian diffusion process, resulting in massive cancer cell killing as compared to the low killing rate from the pure drug/material arising from its burst release. The superstructure is found to be a good biomaterial, and its drug-loaded conjugate as a carrier is applied to albino mice to treat their tumors, generated through a melanoma cell line. A drug-embedded superstructure is inoculated in an injectable hydrogel and is placed subcutaneously, below the tumor site, which completely healed the melanoma. No side effect was observed, as opposed to the conventional/control system, due to a sustained drug release from the superstructure as evident from histopathological studies of sensitive body organs and biochemical parameters. Thus, a new design of the vehicle heals the melanoma tumor by enhancing the bioavailability of drug and specific interaction without having any side effects as opposed to conventional chemotherapeutic treatment.

Efficacy of polyurethane graft on cyclodextrin to control drug release for tumor treatment.

Hydrophilicity of cyclodextrin is controlled through grafting of polyurethane of varying graft density, thereby maintain the hydrophilic-hydrophobic balance, to sustain the drug delivery rate for better tumor treatment. Grafting is verified through nuclear magnetic resonance (1H NMR) and other spectroscopic techniques along with the hydrodynamic volume measurement of grafted species and the degree of substitution has been calculated from the integrated peak areas. Thermal and mechanical stability of the graft copolymers have improved significantly with respect to cyclodextrin and the formation of smaller blobs having larger in number has been obtained from small angle neutron scattering, atomic force microscopy and optical images. Sustained drug delivery has been achieved using graft copolymer as opposed to burst release in pure cyclodextrin and polyurethane and the phenomenon is understood from the specific interactions, as observed though spectroscopic and thermal measurement, between graft copolymer and drug followed by this novel architecture of the graft copolymers. Biocompatibility of graft copolymers has been checked using cellular studies through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell adhesion. Importantly, the cell killing efficiency has been demonstrated by embedding anti-cancer drug in polymer matrices causing mortality rate of 80% using graft copolymer against meagre 20% using pure drug or drug embedded in cyclodextrin and the result is realised from the sustained release of drug from the graft copolymer vis-à-vis burst release in other systems. Cellular studies have been translated into an animal model showing the efficacy of newly developed patch, made of drug embedded in copolymer, towards the significant suppression of tumors in mice as compared to control. Histopathological images and biochemical parameters indicate the normal body organ/blood in copolymer treated mice against severely damaged organ especially liver/blood in the mice treated with pure drug or drug embedded in cyclodextrin arising from burst release. Thus, graft copolymer with unique architecture is found to be an effective drug delivery vehicle for melanoma cancer treatment without side effect.

Biodegradable toughened nanohybrid shape memory polymer for smart biomedical applications.

A polyurethane nanohybrid has been prepared through the in situ polymerization of an aliphatic diisocyanate, ester polyol and a chain extender in the presence of two-dimensional platelets. Polymerization within the platelet galleries helps to intercalate, generate diverse nanostructure and improve the nano to macro scale self-assembly, which leads to a significant enhancement in the toughness and thermal stability of the nanohybrid in comparison to pure polyurethane. The extensive interactions, the reason for property enhancement, between nanoplatelets and polymer chains are revealed through spectroscopic measurements and thermal studies. The nanohybrid exhibits significant improvement in the shape memory phenomena (91% recovery) at the physiological temperature, which makes it suitable for many biomedical applications. The structural alteration, studied through temperature dependent small angle neutron scattering and X-ray diffraction, along with unique crystallization behavior have extensively revealed the special shape memory behavior of this nanohybrid and facilitated the understanding of the molecular flipping in the presence of nanoplatelets. Cell line studies and subsequent imaging testify that this nanohybrid is a superior biomaterial that is suitable for use in the biomedical arena. In vivo studies on albino rats exhibit the potential of the shape memory effect of the nanohybrid as a self-tightening suture in keyhole surgery by appropriately closing the lips of the wound through the recovery of the programmed shape at physiological temperature with faster healing of the wound and without the formation of any scar. Further, the improved biodegradable nature along with the rapid self-expanding ability of the nanohybrid at 37 °C make it appropriate for many biomedical applications including a self-expanding stent for occlusion recovery due to its tough and flexible nature.

Controlled drug release through regulated biodegradation of poly(lactic acid) using inorganic salts.

Biodegradation rate of poly(lactic acid) (PLA) has been regulated, both increase and decrease with respect to the biodegradation of pure PLA, by embedding meager amount of inorganic salts in polymer matrix. Biodegradation is performed in enzyme medium on suspension and film and the extent of biodegradation is measured through spectroscopic technique which is also verified by weight loss measurement. Media pH has been controlled using trace amount of inorganic salt which eventually control the biodegradation of PLA. High performance liquid chromatography confirms the hydrolytic degradation of PLA to its monomer/oligomer. Induced pH by metal salts show maximum degradation at alkaline range (with calcium salt) while inhibition is observed in acidic medium (with iron salt). The pH of media changes the conformation of enzyme which in turn regulate the rate of biodegradation. Thermal degradation and increment of modulus indicate improvement in thermo-mechanical properties of PLA in presence of inorganic salts. Functional stability of enzyme with metal salts corresponding to acidic and alkaline pH has been established through a model to explain the conformational changes of the active sites of enzyme at varying pH influencing the rate of hydrolysis leading to regulated biodegradation of PLA. The tuned biodegradation has been applied for the controlled release of drug from the polymer matrix (both sustained and enhanced cumulative release as compared to pure polymer). The cell proliferation and adhesion are influenced by the acidic and basic nature of polymeric material tuned by two different inorganic salts showing better adhesion and proliferation in calcium based composite and, therefore, suggest biological use of these composites in biomedical applications.

Concomitant and discrete expressions of aldose reductase and sorbitol dehydrogenase in the male reproductive tract.

This study aimed at investigating the expression and localization of the polyol pathway enzymes; aldose reductase (AR) and sorbitol dehydrogenase (SDH), in the male reproductive tract of rat. Gene expression analysis showed maximum expression of AR and SDH in the coagulating glands. Western blot analysis showed a coordinated presence of the two enzymes in the coagulating glands, seminal vesicle and epididymis. Immunohistochemistry showed a concordant expression of the two enzymes in the coagulating gland, which goes well with its function of fructose production in rats. A less concordant expression of the two enzymes in the seminal vesicle was also seen. Discrete expression of AR was seen in the Sertoli cells without SDH. Germ cells including sperm in the seminiferous tubules lacked AR, but SDH was present in all stages of developing germ cells including sperm present in the seminiferous tubules. The epithelial layer of epididymis showed the presence of AR, but it was negligible in vas deferens and prostate. SDH was not seen in the epithelial layer of epididymis, vas deferens or prostate. Though sperm in the seminiferous tubules lacked AR, sperm extracted from cauda showed the presence of both AR and SDH. Immunofluorescence localization of AR and SDH on sperm showed the presence of both the enzymes all over sperm. Discrete expression of AR in the Sertoli cells may be linked to detoxification of a number of metabolism by-products. Similarly, the presence of polyol enzymes on sperm in epididymis and beyond may be to tackle toxic metabolites they may encounter during their journey along the male or female reproductive tract.

CatSper channel, sperm function and male fertility.

A number of physiological events, such as sperm hyperactivation, chemotaxis towards the egg, capacitation and acrosome reaction, are triggered by activation of sperm ion channels in response to a diverse range of chemical cues. Cation channel of sperm (CatSper), a sperm-specific ion channel, is unique in orchestrating the events for fertilization, and seems to be exclusively evolved for sperm function and male fertility. CatSper acts as a polymodal, chemosensory calcium channel and plays a vital role in the regulation of sperm hyperactivation. CatSper knockout models and application of patch clamp recordings have shown that it is indispensable for male fertility, and mutations and deletions in CatSper gene(s) may lead to infertility. In fact, mutations in CatSper1 and 2 have been identified in infertile individuals; however, CatSper3 and 4 have not been explored. Restricted localization and expression of CatSper in sperm offer an added advantage to developing gamete-based safe non-hormonal contraceptives. This review concisely covers identification, structure, function, and mechanism of action of CatSper channels. The functional importance of this complex ion channel in sperm motility and male fertility is highlighted for further research on male fertility, infertility, and contraception.

Mucuna pruriens and its major constituent L-DOPA recover spermatogenic loss by combating ROS, loss of mitochondrial membrane potential and apoptosis.

BACKGROUND: The Ayurvedic medicinal system claims Mucuna pruriens (MP) to possess pro-male fertility, aphrodisiac and adaptogenic properties. Some scientific evidence also supports its pro-male fertility properties; however, the mechanism of its action is not yet clear. The present study aimed at demonstrating spermatogenic restorative efficacy of MP and its major constituent L-DOPA (LD), and finding the possible mechanism of action thereof in a rat model. METHODOLOGY/FINDINGS: Ethinyl estradiol (EE) was administered at a rate of 3 mg/kg body weight (BW)/day for a period of 14 days to generate a rat model with compromised spermatogenesis. MP and LD were administered in two separate groups of these animals starting 15(th) day for a period of 56 days, and the results were compared with an auto-recovery (AR) group. Sperm count and motility, testis histo-architecture, level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, peripheral hormone levels and testicular germ cell populations were analysed, in all experimental groups. We observed efficient and quick recovery of spermatogenesis in MP and LD groups in comparison to the auto-recovery group. The treatment regulated ROS level, apoptosis, and mitochondrial membrane potential (MMP), recovered the hypothalamic-pituitary-gonadal axis and the number of testicular germ cells, ultimately leading to increased sperm count and motility. CONCLUSION/SIGNIFICANCE: M. pruriens efficiently recovers the spermatogenic loss induced due to EE administration. The recovery is mediated by reduction in ROS level, restoration of MMP, regulation of apoptosis and eventual increase in the number of germ cells and regulation of apoptosis. The present study simplified the complexity of mechanism involved and provided meaningful insights into MP/LD mediated correction of spermatogenic impairment caused by estrogens exposure. This is the first study demonstrating that L-DOPA largely accounts for pro-spermatogenic properties of M. pruriens. The manuscript bears CDRI communication number 8374.