Deciphering the chemical constituents and antimicrobial activity of Prangos pabularia Lindl. using LC-MS/MS in combination with experimental evaluation and computational studies.

This study meticulously explores the antimicrobial potential of Prangos pabularia Lindl.'s aerial parts through a comprehensive blend of in vitro and in silico analysis. Extracts with varying polarities underwent LC-MS/MS identification of active components, followed by in vitro and in silico assessments of antimicrobial efficacy against Escherichia coli, Bacillus cereus, Candida albicans, Candida glabrata, and Candida paropsilosis. The methanolic extract exhibited significant antimicrobial activity with a MIC value of 48 µg/mL against all tested strains. Molecular docking revealed the compound 9-(3-methylbut-2-enoxy)-furo-(3,2-g)-chromen-7-one's highest binding affinity against the penicillin-binding protein (PBP) bacterial drug target molecule. Other compounds also displayed substantial interactions with key antimicrobial drug target proteins. Further, Molecular dynamics simulations affirmed the stability of protein and ligand conformations. Collectively, these results underscore Prangos pabularia Lindl.'s aerial parts as a promising botanical resource in combating diverse microbial infections. This comprehensive approach not only validates it's in vitro antimicrobial properties but also provides molecular insights into interaction mechanisms, advancing our comprehension of the plant's therapeutic potential.

A network pharmacology-based investigation of brugine reveals its multi-target molecular mechanism against Breast Cancer.

Breast cancer represents the leading cause of mortality among women worldwide. Since the complexity of breast cancer as a disease resides in its heterogeneity as it consists of several subtypes such as hormone receptor-positive subtypes: Luminal A, Luminal B, Her2- overexpressed, basal-like and hormone receptor-negative subtype: TNBC. Among all the subtypes, triple negative breast cancer (TNBC) is the most lethal and complex subtype. Moreover, the available treatment options like surgery, radiation therapy, and chemotherapy are not sufficient because of the associated side effects and drug resistance development. Therefore, discovery of new effective natural compounds with anti-tumor activity is required. In this pursuit, marine organisms provide a plentiful supply of such chemicals compounds. A marine compound Brugine found in the bark and stem of mangrove species Bruguiera sexangula is a potential anti-cancer compound. It has shown its cytotoxic activity against sarcoma 180 and lewis lung cancer. The molecular processes, however, are currently unknown. So, in order to research the molecular pathways this compound utilizes, we sought to apply a network pharmacology approach. The network pharmacology strategy we used in this investigation to identify and evaluate possible molecular pathways involved in the treatment of breast cancer with brugine was supported by simulation and molecular docking experiments. The study was conducted using various databases such as the cancer genome atlas (TCGA) for the genetic profile study of breast cancer, Swiss ADME for studying the pharmacodynamic study of brugine, Gene cards for collection of information of genes, STRING was used to study the interaction among proteins, AutoDock vina was to study the binding efficacy of brugine with the best fit protein. The results showed that the compound and breast cancer target network shared 90 common targets. According to the functional enrichment analysis brugine exhibited its effects in breast cancer via modulating certain pathways such as cAMP signaling pathway, JAK/STAT pathway, HIF-1 signaling pathway PI3K-Akt pathway, calcium signaling pathway, and Necroptosis. Molecular docking investigations demonstrated that the investigated marine compound has a high affinity for the key target, protein kinase A (PKA). A stable protein-ligand combination was created by the best hit molecule, according to molecular dynamics modeling. The purpose of this research was to examine the importance of brugine as a potentially effective treatment for breast cancer and to obtain knowledge of the molecular mechanism used by this substance in breast cancer.

Targeting tumor microenvironment using tumor-infiltrating lymphocytes as therapeutics against tumorigenesis.

The immune system plays a vital role in suppressing tumor cell progression. The tumor microenvironment augmented with significant levels of tumor-infiltrating lymphocytes has been widely investigated and it is suggested that tumor-infiltrating lymphocytes have shown a significant role in the prognosis of cancer patients. Compared to ordinary non-infiltrating lymphocytes, tumor-infiltrating lymphocytes (TILs) are a significant population of lymphocytes that infiltrate tumor tissue and have a higher level of specific immunological reactivity against tumor cells. They serve as an effective immunological defense against various malignancies. TILs are a diverse group of immune cells that are divided into immune subsets based on the pathological and physiological impact they have on the immune system. TILs mainly consist of B-cells, T-cells, or natural killer cells with diverse phenotypic and functional properties. TILs are known to be superior to other immune cells in that they can recognize a wide range of heterogeneous tumor antigens by producing many clones of T cell receptors (TCRs), outperforming treatments like TCR-T cell and CAR-T therapy. With the introduction of genetic engineering technologies, tumor-infiltrating lymphocytes (TILs) have become a ground-breaking therapeutic option for malignancies, but because of the hindrances opposed by the immune microenvironment and the mutation of antigens, the development of TILs as therapeutic has been hindered. By giving some insight into the many variables, such as the various barriers inhibiting its usage as a potential therapeutic agent, we have examined various aspects of TILs in this work.

Targeting p53 misfolding conundrum by stabilizing agents and their analogs in breast cancer therapy: a comprehensive computational analysis.

Cancer continues to be a major global public health concern and one of the foremost causes of death. Delays in the diagnosis and cure may cause an increase in advanced stage disease and mortality. The most common cancer found in women currently is breast carcinoma. Breast carcinoma has surpassed lung carcinoma and currently represents the chief type of cancer diagnosed (2.3 million new cases, which amount to 11.7% of all cancer cases). In addition, by 2040, the incidence will increase by more than 46% as per the estimates of GLOBOCAN. Triple-negative breast cancer (TNBC) represents a highly aggressive and invasive subtype of breast cancer, characterized by rapid progression, short response time to the available treatment, and poor clinical results. Thus, it is very crucial to develop novel diagnostic tools and therapeutics with good efficacy. A majority of cancers display malfunction along the p53 pathway. Moreover, p53 not only loses its function but is also prone to misfolding and aggregation, leading to formation of amyloid aggregates as well. Research is being carried out to find ways to restore the normal action and expression of p53. Here, we have explored PhiKan-083 for its possible stabilizing effect on p53 in order to address the problem with its misfolding. Thus, examining the analogs of PhiKan-083 that have a role in p53 stability will help update our understanding of cancer progression and may expedite the progress of new anticancer treatments. We anticipate that the drug molecules and their analogs targeting p53 aggregation may be used in combination with other anticancer compounds to solve the problem with p53 aggregation. In this study, by employing ADMET analysis, the compounds were screened, and we further examined the chosen compounds with the help of molecular docking. By using databases like UALCAN, TIMER, GEPIA, and PredictProtein, we investigated TP53's expression pattern and prognostic relevance in various cancer settings.

Manipulation and exploitation of host immune system by pathogenic Mycobacterium tuberculosis for its advantage.

Mycobacterium tuberculosis (Mtb) can become a long-term infection by evading the host immune response. Coevolution of Mtb with humans has resulted in its ability to hijack the host's immune systems in a variety of ways. So far, every Mtb defense strategy is essentially dependent on a subtle balance that, if shifted, can promote Mtb proliferation in the host, resulting in disease progression. In this review, the authors summarize many important and previously unknown mechanisms by which Mtb evades the host immune response. Besides recently found strategies by which Mtb manipulates the host molecular regulatory machinery of innate and adaptive immunity, including the intranuclear regulatory machinery, costimulatory molecules, the ubiquitin system and cellular intrinsic immune components will be discussed. A holistic understanding of these immune-evasion mechanisms is of foremost importance for the prevention, diagnosis and treatment of tuberculosis and will lead to new insights into tuberculosis pathogenesis and the development of more effective vaccines and treatment regimens.

Expression pattern and prognostic significance of CDKs in breast cancer: An integrated bioinformatic study.

BACKGROUND: Globally, breast cancer (BC) has become one of the most prevalent malignancies and the leading cause of tumor-related deaths among women. Dysregulation of the cell cycle is a well-known hallmark of cancer development and metastasis. CDKs are essential components of the cell-cycle regulatory system with aberrant expression in a variety of cancers, including BC. In the development of targeted cancer treatment, reestablishing the regulation of the cell cycle by modulation of CDKs has emerged as a promising approach. METHODS: Herein, we used a bioinformatic approach to assess the expression pattern, prognostic and diagnostic importance, and clinical relevance of CDKs in BC. Additionally, we conducted a functional enrichment analysis of deregulated CDKs using the STRING and KEGG databases to delineate the role of CDKs in breast tumorigenesis. RESULTS: Gene expression analysis revealed substantial deregulation of CDKs in BC, with CDK1, CDK11A, and CDK18 showing a fold change of >± 1.5. Also, metastatic tumors showed high expression of CDK1 in the single cell RNA sequencing analysis of primary and metastatic breast tumors. Additionally, it was found that dysregulated CDK expression affects overall survival (OS) and relapse-free survival (RFS) of BC patients. CONCLUSION: The study's multimodal analytical methodologies imply that modulating CDKs for BC treatment is a promising approach.

Cyclin-dependent kinases in breast cancer: expression pattern and therapeutic implications.

Presently, breast cancer (BC) is one of the most common malignancies diagnosed and the leading cause of tumor-related deaths among women worldwide. Cell cycle dysregulation is one of the hallmarks of cancer, resulting in uncontrolled cell proliferation. Cyclin-dependent kinases (CDKs) are central to the cell cycle control system, and deregulation of these kinases leads to the development of malignancies, including breast cancer. CDKs and cyclins have been reported as crucial components involved in tumor cell proliferation and metastasis. Given the aggressive nature, tumor heterogeneity, and chemoresistance, there is an urgent need to explore novel targets and therapeutics to manage breast cancer effectively. Inhibitors targeting CDKs modulate the cell cycle, thus throwing light upon their therapeutic aspect where the progression of tumor cells could be inhibited. This article gives a comprehensive account of CDKs in breast cancer progression and metastasis and recent developments in the modulation of CDKs in treating malignancies. We have also explored the expression pattern and prognostic significance of CDKs in breast cancer patients. The article will also shed light on the Implications of CDK inhibition and TGF-ß signaling in breast cancer.

Chemokines in triple-negative breast cancer heterogeneity: New challenges for clinical implications.

Tumor heterogeneity is a hallmark of cancer and one of the primary causes of resistance to therapies. Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers and is the most aggressive subtype, is very diverse, connected to metastatic potential and response to therapy. It is a very diverse disease at the molecular, pathologic, and clinical levels. TNBC is substantially more likely to recur and has a worse overall survival rate following diagnosis than other breast cancer subtypes. Chemokines, low molecular weight proteins that stimulate chemotaxis, have been shown to control the cues responsible for TNBC heterogeneity. In this review, we have focused on tumor heterogeneity and the role of chemokines in modulating tumor heterogeneity, since this is the most critical issue in treating TNBC. Additionally, we examined numerous cues mediated by chemokine networks that contribute to the heterogeneity of TNBC. Recent developments in our knowledge of the chemokine networks that regulate TNBC heterogeneity may pave the way for developing effective therapeutic modalities for effective treatment of TNBC.

Strategies Employed to Evade the Host Immune Response and the Mechanism of Drug Resistance in Mycobacterium tuberculosis: In Search of Finding New Targets.

The partial effectiveness of the host immune response to M. tuberculosis drives bacteria into a latent state, but it is difficult to eliminate the bacteria completely. Usually, this latent condition of M. tuberculosis is reversible, and reactivation of tuberculosis is the leading cause of the majority of transmission. A number of studies performed on animal models and humans have not yet provided a detailed understanding of the mechanisms or correlates of immunity of M. tuberculosis infection or why there is a significant immunity failure to remove the pathogen. Moreover, the mechanism of resistance involved in drug-resistant M. tuberculosis leads to the emergence of strains of bacteria that show significant resistance to the majority of anti-tuberculosis drugs. We have also provided the recent findings and trends regarding the development of new drug molecules to treat drug and multidrug-resistant tuberculosis and the advancements in immunotherapy in the treatment of drug-resistant tuberculosis. This article provides an in-depth and critical analysis of various strategies employed by the drug-resistant M. tuberculosis to escape the host immune response. This bacterium persists in the host for a longer period of time and leads to the development of tuberculosis infection. Furthermore, we also discussed the new targets for the effective treatment of drug-resistant tuberculosis.

The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities.

BACKGROUND: Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. The tumor microenvironment (TME), comprising cellular components, such as cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and adipocytes, and noncellular components such as extracellular matrix (ECM), has been recognized as a critical contributor to the development and progression of BC. The interplay between TME components and cancer cells promotes phenotypic heterogeneity, cell plasticity and cancer cell stemness that impart tumor dormancy, enhanced invasion and metastasis, and the development of therapeutic resistance. While most previous studies have focused on targeting cancer cells with a dismal prognosis, novel therapies targeting stromal components are currently being evaluated in preclinical and clinical studies, and are already showing improved efficacies. As such, they may offer better means to eliminate the disease effectively. CONCLUSIONS: In this review, we focus on the evolving concept of the TME as a key player regulating tumor growth, metastasis, stemness, and the development of therapeutic resistance. Despite significant advances over the last decade, several clinical trials focusing on the TME have failed to demonstrate promising effectiveness in cancer patients. To expedite clinical efficacy of TME-directed therapies, a deeper understanding of the TME is of utmost importance. Secondly, the efficacy of TME-directed therapies when used alone or in combination with chemo- or radiotherapy, and the tumor stage needs to be studied. Likewise, identifying molecular signatures and biomarkers indicating the type of TME will help in determining precise TME-directed therapies.

An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most complex, aggressive and fatal subtype of breast cancer. Owing to the lack of targeted therapy and heterogenic nature of TNBC, chemotherapy remains the sole treatment option for TNBC, with taxanes and anthracyclines representing the general chemotherapeutic regimen in TNBC therapy. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. Breast cancer stem cells (BCSCs) are one of the major causes for the development of chemoresistance in TNBC patients. After surviving the chemotherapy damage, the presence of BCSCs results in relapse and recurrence of TNBC. Several pathways are known to regulate BCSCs' survival, such as the Wnt/ß-catenin, Hedgehog, JAK/STAT and HIPPO pathways. Therefore it is imperative to target these pathways in the context of eliminating chemoresistance. In this review we will discuss the novel strategies and various preclinical and clinical studies to give an insight into overcoming TNBC chemoresistance. We present a detailed account of recent studies carried out that open an exciting perspective in relation to the mechanisms of chemoresistance.

Prognostic significance and targeting tumor-associated macrophages in cancer: new insights and future perspectives.

Macrophages are phagocytic sentinel cells of the immune system that are central to both innate and adaptive immune responses and serve as the first line of defense against pathogenic insults to tissues. In the tumor microenvironment, tumor-derived factors induce monocyte polarization towards a pro-tumor phenotype. The pro-tumor macrophages regulate key steps in tumorigenicity including tumor growth, angiogenesis, immune suppression, and metastasis. Macrophage infiltration in solid tumors correlates with poor prognosis and resistance to chemotherapy in most cancers. Here in this review, we will shed light on tumor-associated macrophages (TAMs) in regulating tumorigenicity and TAMs as a prognostic biomarker. Also, we will review the recent advances in targeting TAMs to increase the prognosis of cancer patients.

Tumor microenvironment promotes breast cancer chemoresistance.

Breast cancer is presently the most predominant tumor type and the second leading cause of tumor-related deaths among women. Although advancements in diagnosis and therapeutics have momentously improved, chemoresistance remains an important challenge. Tumors oppose chemotherapeutic agents through a variety of mechanisms, with studies revealing that the tumor microenvironment (TME) is central to this process. The components of TME including stromal cells, immune cells, and non-stromal factors on exposure to chemotherapy promote the acquisition of resistant phenotype. Consequently, limited targeting of tumor cells leads to tumor recurrence after chemotherapy. Here, in this article, we summarize how TME alters chemotherapy responses in breast cancer. Furthermore, the role of different stromal cells viz., CAFs, TAMs, MSCs, endothelial cells, and cancer stem cells (CSC) in breast cancer chemoresistance is discussed in greater detail.

Nano-Drug Delivery Systems: Possible End to the Rising Threats of Tuberculosis.

Tuberculosis (TB) is still one of the deadliest disease across the globe caused by Mycobacterium tuberculosis (Mtb). Mtb invades host macrophages and other immune cells, modifies their lysosome trafficking proteins, prevents phagolysosomes formation, and inhibits the TNF receptor-dependent apoptosis in macrophages and monocytes. Tuberculosis (TB) killed 1.4 million people worldwide in the year 2019. Despite the advancements in tuberculosis (TB) treatments, multidrugresistant tuberculosis (MDR-TB) remains a severe threat to human health. The complications are further compounded by the emergence of MDR/XDR strains and the failure of conventional drug regimens to eradicate the resistant bacterial strains. Thus, new therapeutic approaches aim to ensure cure without relapse, to prevent the occurrence of deaths and emergence of drug-resistant strains. In this context, this review article summarises the essential nanotechnology-related research outcomes in the treatment of tuberculosis (TB), including drug-susceptible and drug-resistant strains of Mtb. The novel anti-tuberculosis drug delivery systems are also being detailed. This article highlights recent advances in tuberculosis (TB) treatments, including the use of novel drug delivery technologies such as solid lipid nanoparticles, liposomes, polymeric micelles, nano-suspensions, nano-emulsion, niosomes, liposomes, polymeric nanoparticles and microparticles for the delivery of anti-TB drugs and hence eradication and control of both drug-susceptible as well as drug-resistant strains of Mtb.

Development of New Therapeutics to Meet the Current Challenge of Drug Resistant Tuberculosis.

Tuberculosis (TB) is a prominent infective disease and a major reason of mortality/ morbidity globally. Mycobacterium tuberculosis causes a long-lasting latent infection in a significant proportion of human population. The increasing burden of tuberculosis is mainly caused due to multi drug-resistance. The failure of conventional treatment has been observed in large number of cases. Drugs that are used to treat extensively drug-resistant tuberculosis are expensive, have limited efficacy, and have more side effects for a longer duration of time and are often associated with poor prognosis. To regulate the emergence of multidrug resistant tuberculosis, extensively drug-resistant tuberculosis and totally drug resistant tuberculosis, efforts are being made to understand the genetic/molecular basis of target drug delivery and mechanisms of drug resistance. Understanding the molecular approaches and pathology of Mycobacterium tuberculosis through whole genome sequencing may further help in the improvement of new therapeutics to meet the current challenge of global health. Understanding cellular mechanisms that trigger resistance to Mycobacterium tuberculosis infection may expose immune associates of protection, which could be an important way for vaccine development, diagnostics, and novel host-directed therapeutic strategies. The recent development of new drugs and combinational therapies for drug-resistant tuberculosis through major collaboration between industry, donors, and academia gives an improved hope to overcome the challenges in tuberculosis treatment. In this review article, an attempt was made to highlight the new developments of drug resistance to the conventional drugs and the recent progress in the development of new therapeutics for the treatment of drugresistant and non-resistant cases.

Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer accounting for 15-20% of cases and is defined by the lack of hormonal receptors viz., estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth receptor 2 (HER2). Treatment of TNBC is more challenging than other subtypes of breast cancer due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/ Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Despite, TNBC being more chemo-responsive than other subtypes, unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance. Using a monotherapy for the treatment of cancer, especially high-grade tumors like TNBC, is mostly worthless due to the inherent genetic instability of tumor cells to develop intrinsic and acquired resistance. Thus, a cocktail of two or more drugs with different mechanisms of action is more effective and could successfully control the disease. Furthermore, combination therapy reveals more, or at least the same, effectiveness with lower doses of every single agent and decreases the likelihood of chemoresistance. Herein, we shed light on the novel combinatorial approaches targeting PARP, EGFR, PI3K pathway, AR, and wnt signaling, HDAC, MEK pathway for efficient treatment of high-grade tumors like TNBC and decreasing the onset of resistance.

Nanobodies: The "Magic Bullets" in therapeutics, drug delivery and diagnostics.

Antibodies represent a well-established class of clinical diagnostics for medical applications as well as essential research and biotechnological tools. Although both polyclonal and monoclonal antibodies are indispensable reagents in basic research and diagnostics but both of them have their limitations. Hence, there is urgent need to develop strategies aimed at production of alternative scaffolds and recombinant antibodies of smaller dimensions that could be easily produced, selected and manipulated. Unlike conventional antibodies, members of Camelidae and sharks produce antibodies composed only of heavy chains with small size, high solubility, thermal stability, refolding capacity and good tissue penetration in vivo. The discovery of these naturally occurring antibodies having only heavy-chain in Camelidae family and their further development into small recombinant nanobodies represents an attractive alternative in drug delivery, diagnostics and imaging. Nanobody derivatives are soluble, stable, versatile, have unique refolding capacities, reduced aggregation tendencies and high-target binding capabilities. They can be genetically customized to target enzymes, transmembrane proteins or molecular interactions. Their ability to recognize recessed antigenic sites has been attributed to their smaller size and the ability of the extended CDR3 loop to quickly penetrate into such epitopes. With the advent of molecular engineering and phage display technology, they can be of potential use in molecular imaging, drug delivery and therapeutics for several major diseases. In this review we present the recent advances in nanobodies for modulating immune functions, for targeting cancers, viruses, toxins and microbes as well as their utility as diagnostic and biosensor tools.

Signaling through CD80: an approach for treating lymphomas.

BACKGROUND: One of the mechanisms by which tumors evade the immune system is by downregulating the expression of costimulatory molecules like CD80 and CD86. The role of CD80 in the activation of T cells is well established, and current studies are exploring its role in cancer. OBJECTIVE: To examine the possible role of CD80 signaling in generating an effective immune response against cancer cells. METHODS: Many reports have described the influence of CD80 on the growth of B cell and follicular lymphomas. Signaling through CD80 in B cell lymphomas can retard their proliferation by upregulating expression of pro-apoptotic molecules and downregulating antiapoptotic molecules and can therefore induce apoptosis. Recently, a Phase I/II study of treatment with CD80-specific antibody has shown it to be quite effective in relapsed and refractory follicular lymphoma patients. CONCLUSION: This study shows that anti-CD80 immunotherapy may have a potent role in treating CD80-bearing cancer cells.