Olsalazine pretreatment augments chemosensitivity of gemcitabine in hepatocellular carcinoma.

Recently, olsalazine a DNA hypomethylating agent was found to inhibit the growth of breast cancer cells. The present study was carried out to evaluate the effects of olsalazine pretreatment in the potentiation of chemosensitivity of gemcitabine for the treatment of hepatocellular carcinoma (HCC). In silico molecular docking was performed to analyze the interaction of olsalazine and gemcitabine with DNMT1 and DNA, respectively, using the AutoDock tools 1.5.6. Cytotoxicity of olsalazine, gemcitabine, and combination were measured on human HePG2 cells using MTT assay. Antiproliferative effects were assessed using animal model of N-nitrosodiethylamine and carbon tetrachloride-induced HCC. Treatment was initiated from 8th week of induction to 11th week and change in body weight, liver weight, and survival rate were measured. Following treatment, blood samples were collected for estimation serum biochemistry. Blood serum was used for the estimation of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), C-reactive protein [CRP], lactate dehydrogenase (LDH), and P53 levels. Oxidative stress markers were measured in liver tissue homogenates. Histopathology and immunohistochemistry (IHC) were performed on liver sections to detect the morphological changes and P53 expression. Docking analysis revealed the interactions between olsalazine and DNMT1 with a binding energy score of -5.34 and gemcitabine and DNA with a binding energy score of -5.93. Olsalazine pretreatment potentiated the antiproliferative effect of gemcitabine in cell line study. In the group receiving olsalazine pretreatment showed significant reductions in relative liver weight and improved survival rate of gemcitabine treatment group. Serum biochemical markers: serum glutamate pyruvate transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, and bilirubin revealed improved liver functions. Olsalazine pretreatment also reduced the levels of inflammatory markers like CRP, LDH, TNF-α, and IL-6 and oxidative stress markers dose dependently. Histopathology and IHC showed improved liver morphology with potentiated the induction of P53 upon olsalazine pretreatment in combination with gemcitabine. In conclusion, sequential combination of olsalazine and gemcitabine improved the treatment outcomes during the progression of HCC.

CRISPR-Cas based diagnostic tools: Bringing diagnosis out of labs.

Timely detection is important for the effective management of infectious diseases. Reverse Transcription Polymerase Chain Reaction (RT-PCR) stands as the prime nucleic acid based test that is employed for the detection of infectious diseases. The method ensures sensitivity and specificity. However, RT-PCR is a relatively expensive technique due to the requirement of costly equipment and reagents. Further, it requires skilled personnel and established laboratories that are usually inaccessible in underdeveloped areas. On the other hand, rapid antigen based techniques are cost effective and easily accessible, but are less effective in terms of sensitivity and specificity. CRISPR-Cas systems are advanced diagnostic tools that combine the advantages of both PCR and antigen based detection techniques, and allows the rapid detection with high sensitivity/specificity. The present review aims to discuss the applicability of CRISPR-Cas based diagnostic tools for the infectious disease detection. The review further attempts to highlight the current limitations and future research directions to improve the CRISPR based diagnostic tools for rapid and effective disease detection.

Conventional and Novel Diagnostic Tools for the Diagnosis of Emerging SARS-CoV-2 Variants.

Accurate identification at an early stage of infection is critical for effective care of any infectious disease. The "coronavirus disease 2019 (COVID-19)" outbreak, caused by the virus "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)", corresponds to the current and global pandemic, characterized by several developing variants, many of which are classified as variants of concern (VOCs) by the "World Health Organization (WHO, Geneva, Switzerland)". The primary diagnosis of infection is made using either the molecular technique of RT-PCR, which detects parts of the viral genome's RNA, or immunodiagnostic procedures, which identify viral proteins or antibodies generated by the host. As the demand for the RT-PCR test grew fast, several inexperienced producers joined the market with innovative kits, and an increasing number of laboratories joined the diagnostic field, rendering the test results increasingly prone to mistakes. It is difficult to determine how the outcomes of one unnoticed result could influence decisions about patient quarantine and social isolation, particularly when the patients themselves are health care providers. The development of point-of-care testing helps in the rapid in-field diagnosis of the disease, and such testing can also be used as a bedside monitor for mapping the progression of the disease in critical patients. In this review, we have provided the readers with available molecular diagnostic techniques and their pitfalls in detecting emerging VOCs of SARS-CoV-2, and lastly, we have discussed AI-ML- and nanotechnology-based smart diagnostic techniques for SARS-CoV-2 detection.

Replicating Viral Vector-Based Vaccines for COVID-19: Potential Avenue in Vaccination Arena.

The "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)" is the third member of human coronavirus (CoV) that is held accountable for the current "coronavirus disease 2019 (COVID-19)" pandemic. In the past two decades, the world has witnessed the emergence of two other similar CoVs, namely SARS-CoV in 2002 and MERS-CoV in 2013. The extent of spread of these earlier versions was relatively low in comparison to SARS-CoV-2. Despite having numerous reports inclined towards the zoonotic origin of the virus, one cannot simply sideline the fact that no animal originated CoV is thus far identified that is considered similar to the initial edition of SARS-CoV-2; however, under-sampling of the diverse variety of coronaviruses remains a concern. Vaccines are proved to be an effective tool for bringing the end to such a devastating pandemic. Many vaccine platforms are explored for the same but in this review paper, we will discuss the potential of replicating viral vectors as vaccine carriers for SARS-CoV-2.

PCOS and Depression: Common Links and Potential Targets.

PCOS or polycystic ovary syndrome is a common endocrine disorder that occurs during the reproductive age in females. It manifests in the form of a wide range of symptoms including (but not limited to) hirsutism, amenorrhea, oligomenorrhea, obesity, acne vulgaris, infertility, alopecia, and insulin resistance. The incidence of depression in PCOS population is increasing as compared to the general population. Increased depression in PCOS significantly alters the quality of life (QOL) of affected females. Also, self-esteem is found to be low in both depression and PCOS. The loss in self-esteem in such patients can be largely attributed to the associated factors including (but not limited to) obesity, acne, androgenic alopecia, and hirsutism. The reason behind the occurrence of depression in PCOS remains elusive to date. Literature suggests that there is an overlap of clinical symptoms between depression and PCOS. As the symptoms overlap, there is a possibility of common associations between depression, PCOS, and PCOS-associated abnormalities including insulin resistance (IR), obesity, CVD, and androgen excess. Studies demonstrate that depression is an inflammatory disorder marked with increased levels of inflammatory markers. On the other hand, PCOS is also regarded as a pro-inflammatory state that is characterized by increased levels of pro-inflammatory markers. Thus, there is a possibility of an inflammatory relationship existing between depression and PCOS. It is also possible that the inflammatory markers in PCOS can cross the blood-brain barrier (BBB) leading to the development of depression. Through the present review, we have attempted to shed light on common associations/shared links between depression and PCOS with respect to the levels of cortisol, androgen, vitamin D, neurotransmitters, monoaminoxidase (MAO), and insulin-like growth factor-1 (IGF-1). Tracking down common associations between depression and PCOS will help find potential drug therapies and improve the QOL of females with depression in PCOS.

Targeting pyruvate kinase muscle isoform 2 (PKM2) in cancer: What do we know so far?

Cancer is a leading cause of death globally. Cancer cell transformation is the result of intricate crosstalk between intracellular components and proteins. A characteristic feature of cancer cells is the ability to reprogram their metabolic pathways to ensure their infinite proliferative potential. Pyruvate kinase muscle isoform 2 (PKM2) is a glycolytic enzyme that plays crucial roles in cancer, apart from carrying out its metabolic roles. PKM2 is involved in all the major events associated with cancer growth. Modulation of PKM2 activity (dimer inhibition or tetramer activation) has been successful in controlling cancer. However, recent studies provide contrary evidences regarding the oncogenic functions of PKM2. Moreover, several studies have highlighted the cancerous roles of PKM1 isoform in certain contexts. The present review aims at providing the current updates regarding PKM2 targeting in cancer. Further, the review discusses the contradictory results that suggest that both the isoforms of PKM can lead to cancer growth. In conclusion, the review emphasizes revisiting the approaches to target cancer metabolism through PKM to find novel and effective targets for anticancer therapy.

AGE-RAGE synergy influences programmed cell death signaling to promote cancer.

Advanced glycation end products (AGEs) are formed as a result of non-enzymatic reaction between the free reducing sugars and proteins, lipids, or nucleic acids. AGEs are predominantly synthesized during chronic hyperglycemic conditions or aging. AGEs interact with their receptor RAGE and activate various sets of genes and proteins of the signal transduction pathway. Accumulation of AGEs and upregulated expression of RAGE is associated with various pathological conditions including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer. The role of AGE-RAGE signaling has been demonstrated in the progression of various types of cancer and other pathological disorders. The expression of RAGE increases manifold during cancer progression. The activation of AGE-RAGE signaling also perturbs the cellular redox balance and modulates various cell death pathways. The programmed cell death signaling often altered during the progression of malignancies. The cellular reprogramming of AGE-RAGE signaling with cell death machinery during tumorigenesis is interesting to understand the complex signaling mechanism of cancer cells. The present review focus on multiple molecular paradigms relevant to cell death particularly Apoptosis, Autophagy, and Necroptosis that are considerably influenced by the AGE-RAGE signaling in the cancer cells. Furthermore, the review also attempts to shed light on the provenience of AGE-RAGE signaling on oxidative stress and consequences of cell survival mechanism of cancer cells.

Management of Type 2 Diabetes: Current Strategies, Unfocussed Aspects, Challenges, and Alternatives.

Type 2 diabetes mellitus (T2DM) accounts for >90% of the cases of diabetes in adults. Resistance to insulin action is the major cause that leads to chronic hyperglycemia in diabetic patients. T2DM is the consequence of activation of multiple pathways and factors involved in insulin resistance and ß-cell dysfunction. Also, the etiology of T2DM involves the complex interplay between genetics and environmental factors. This interplay can be governed efficiently by lifestyle modifications to achieve better management of diabetes. The present review aims at discussing the major factors involved in the development of T2DM that remain unfocussed during the anti-diabetic therapy. The review also focuses on lifestyle modifications that are warranted for the successful management of T2DM. In addition, it attempts to explain flaws in current strategies to combat diabetes. The employability of phytoconstituents as multitargeting molecules and their potential use as effective therapeutic adjuvants to first line hypoglycemic agents to prevent side effects caused by the synthetic drugs are also discussed.

Targeting receptors of advanced glycation end products (RAGE): Preventing diabetes induced cancer and diabetic complications.

Cancer and diabetes are the two major disorders that affect a large proportion of the world's population. Results from multiple epidemiological studies have concluded that diabetes and cancer are linked, and diabetic patients live at much higher risks of developing cancer and diabetic complications at the later phase of disease. Inflammation is the central pathway that mediates both diabetic complications as well as cancer. Receptor of advanced glycation end products (RAGE) is a non-specific multi-ligand pattern recognition receptor that induces the inflammatory responses by binding with multiple ligands. RAGE and its ligands are upregulated in diabetes, inflammation and cancer. Advanced glycation end products (AGEs), high mobility group box protein-1 (HMGB1) and S100 proteins are the major RAGE ligands that contribute to these consequences and an increased release of RAGE ligands during diabetic conditions can be a possible mechanism leading to diabetic complications and cancer. Moreover, further release of RAGE ligands from cancer cells can be a possible mechanism behind the worsening of diabetic complications in diabetic cancer patients. Inhibition of RAGE signaling can prevent diabetic complications and cancer in diabetic patients and can be helpful in the management of worsening diabetic complications and cancer in diabetic cancer patients. Curcumin, Quercetin and Withaferin A are known to inhibit multiple molecular pathways that are involved in RAGE signaling. The combined effects of these molecules can be explored to achieve the complete inhibition of RAGE signaling in diabetic patients.