Berberine and berberine nanoformulations in cancer therapy: Focusing on lung cancer.

Lung cancer is the second most prevalent cancer and ranks first in cancer-related death worldwide. Due to the resistance development to conventional cancer therapy strategies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, various natural products and their extracts have been revealed as alternatives. Berberine (BBR), which is present in the stem, root, and bark of various trees, could exert anticancer activities by regulating tumor cell proliferation, apoptosis, autophagy, metastasis, angiogenesis, and immune responses via modulating several signaling pathways within the tumor microenvironment. Due to its poor water solubility, poor pharmacokinetics/bioavailability profile, and extensive p-glycoprotein-dependent efflux, BBR application in (pre) clinical studies is restricted. To overcome these limitations, BBR can be encapsulated in nanoparticle (NP)-based drug delivery systems, as monotherapy or combinational therapy, and improve BBR therapeutic efficacy. Nanoformulations also facilitate the selective delivery of BBR into lung cancer cells. In addition to the anticancer activities of BBR, especially in lung cancer, here we reviewed the BBR nanoformulations, including polymeric NPs, metal-based NPs, carbon nanostructures, and others, in the treatment of lung cancer.

Autophagy as a self-digestion signal in human cancers: Regulation by microRNAs in affecting carcinogenesis and therapy response.

Autophagy is defined as a "self-digestion" signal, and it is a cell death mechanism its primary function is degrading toxic agents and aged organelles to ensure homeostasis in cells. The basic leve ls of autophagy are found in cells, and when its levels exceed to standard threshold, cell death induction is observed. Autophagy dysregulation in cancer has been well-documented, and regulation of this pathway by epigenetic factors, especially microRNAs (miRNAs), is interesting and noteworthy. miRNAs are considered short endogenous RNAs that do not encode functional proteins, and they are essential regulators of cell death pathways such as apoptosis, necroptosis, and autophagy. Accumulating data has revealed miRNA dysregulation (upregulation or downregulation) during tumor progression, and their therapeutic manipulation provides new insight into cancer therapy. miRNA/autophagy axis in human cancers has been investigated an exciting point is the dual function of both autophagy and miRNAs as oncogenic and onco-suppressor factors. The stimulation of pro-survival autophagy by miRNAs can increase the survival rate of tumor cells and mediates cancer metastasis via EMT inductionFurthermore, pro-death autophagy induction by miRNAs has a negative impact on the viability of tumor cells and decreases their survival rate. The miRNA/autophagy axis functions beyond regulating the growth and invasion of tumor cells, and they can also affect drug resistance and radio-resistance. These subjects are covered in the current review regarding the new updates provided by recent experiments.

Nanotechnology-empowered lung cancer therapy: From EMT role in cancer metastasis to application of nanoengineered structures for modulating growth and metastasis.

Lung cancer is one of the leading causes of death in both males and females, and it is the first causes of cancer-related deaths. Chemotherapy, surgery and radiotherapy are conventional treatment of lung cancer and recently, immunotherapy has been also appeared as another therapeutic strategy for lung tumor. However, since previous treatments have not been successful in cancer therapy and improving prognosis and survival rate of lung tumor patients, new studies have focused on gene therapy and targeting underlying molecular pathways involved in lung cancer progression. Nanoparticles have been emerged in treatment of lung cancer that can mediate targeted delivery of drugs and genes. Nanoparticles protect drugs and genes against unexpected interactions in blood circulation and improve their circulation time. Nanoparticles can induce phototherapy in lung cancer ablation and mediating cell death. Nanoparticles can induce photothermal and photodynamic therapy in lung cancer. The nanostructures can impair metastasis of lung cancer and suppress EMT in improving drug sensitivity. Metastasis is one of the drawbacks observed in lung cancer that promotes migration of tumor cells and allows them to establish new colony in secondary site. EMT can occur in lung cancer and promotes tumor invasion. EMT is not certain to lung cancer and it can be observed in other human cancers, but since lung cancer has highest incidence rate, understanding EMT function in lung cancer is beneficial in improving prognosis of patients. EMT induction in lung cancer promotes tumor invasion and it can also lead to drug resistance and radio-resistance. Moreover, non-coding RNAs and pharmacological compounds can regulate EMT in lung cancer and EMT-TFs such as Twist and Slug are important modulators of lung cancer invasion that are discussed in current review.

Harnessing function of EMT in hepatocellular carcinoma: From biological view to nanotechnological standpoint.

Management of cancer metastasis has been associated with remarkable reduction in progression of cancer cells and improving survival rate of patients. Since 90% of mortality are due to cancer metastasis, its suppression can improve ability in cancer fighting. The EMT has been an underlying cause in increasing cancer migration and it is followed by mesenchymal transformation of epithelial cells. HCC is the predominant kind of liver tumor threatening life of many people around the world with poor prognosis. Increasing patient prognosis can be obtained via inhibiting tumor metastasis. HCC metastasis modulation by EMT and HCC therapy by nanoparticles are discussed here. First of all, EMT happens during progression and advanced stages of HCC and therefore, its inhibition can reduce tumor malignancy. Moreover, anti-cancer compounds including all-trans retinoic acid and plumbaging, among others, have been considered as inhibitors of EMT. The EMT association with chemoresistance has been evaluated. Moreover, ZEB1/2, TGF-ß, Snail and Twist are EMT modulators in HCC and enhancing cancer invasion. Therefore, EMT mechanism and related molecular mechanisms in HCC are evaluated. The treatment of HCC has not been only emphasized on targeting molecular pathways with pharmacological compounds and since drugs have low bioavailability, their targeted delivery by nanoparticles promotes HCC elimination. Moreover, nanoparticle-mediated phototherapy impairs tumorigenesis in HCC by triggering cell death. Metastasis of HCC and even EMT mechanism can be suppressed by cargo-loaded nanoparticles.

Doxorubicin-loaded micelles in tumor cell-specific chemotherapy.

Nanomedicine is a field that combines biology and engineering to improve disease treatment, particularly in cancer therapy. One of the promising techniques utilized in this area is the use of micelles, which are nanoscale delivery systems that are known for their simple preparation, high biocompatibility, small particle size, and the ability to be functionalized. A commonly employed chemotherapy drug, Doxorubicin (DOX), is an effective inhibitor of topoisomerase II that prevents DNA replication in cancer cells. However, its efficacy is frequently limited by resistance resulting from various factors, including increased activity of drug efflux transporters, heightened oncogenic factors, and lack of targeted delivery. This review aims to highlight the potential of micelles as new nanocarriers for delivering DOX and to examine the challenges involved with employing chemotherapy to treat cancer. Micelles that respond to changes in pH, redox, and light are known as stimuli-responsive micelles, which can improve the targeted delivery of DOX and its cytotoxicity by facilitating its uptake in tumor cells. Additionally, micelles can be utilized to administer a combination of DOX and other drugs and genes to overcome drug resistance mechanisms and improve tumor suppression. Furthermore, micelles can be used in phototherapy, both photodynamic and photothermal, to promote cell death and increase DOX sensitivity in human cancers. Finally, the alteration of micelle surfaces with ligands can further enhance their targeted delivery for cancer suppression.

The cardioprotective effects of cerium oxide nanoparticles against the poisoning generated by aluminum phosphide pesticide: Controlling oxidative stress and mitochondrial damage.

BACKGROUND: Aluminum phosphide (AlP) is a well-known toxic compound used as an agricultural pesticide to prevent insect damage to stored crops. However, even if just a small amount was consumed, it caused lasting harm to the human body and, in acute concentrations, death. The current study employed cerium oxide nanoparticles (CeO2 NPs) to reduce oxidative stress and various harmful outcomes of AlP poisoning. METHODS: Following finding effective concentrations of CeO2 NPs via MTT assay, Human Cardiac Myocyte (HCM) cells were pre-treated with CeO2 NPs for 24 h. After that, they were exposed to 2.36 µM AlP. The activity of oxidative stress and mitochondrial biomarkers, including mitochondrial swelling, mitochondrial membrane potential, and cytochrome c release, were evaluated in HCM cells. Finally, the population of apoptotic and necrotic cells was assessed via flow cytometry. RESULTS: After 24 h, data revealed that all tested concentrations of CeO2 NPs were safe, and 25 and 50 µM of that were selected as effective concentrations. Oxidative stress markers (malondialdehyde, protein carbonyl, superoxide dismutase, and catalase) showed that CeO2 NPs could successfully decrease AlP poisoning due to their antioxidant characteristics. Mitochondrial markers were also recovered by pre-treatment of HCM cells with CeO2 NPs. Furthermore, pre-treating with CeO2 NPs could compensate for the reduction of live cells with AlP and cause a diminishing in the population of early and late apoptotic cells. CONCLUSION: As a result, it is evident that CeO2 NPs, through the recovery of oxidative stress and mitochondrial damages caused by AlP, reduce apoptosis and have therapeutic potentials on HCM cells.

Metabolomic profiling of bacterial biofilm: trends, challenges, and an emerging antibiofilm target.

Biofilm-related infections substantially contribute to bacterial illnesses, with estimates indicating that at least 80% of such diseases are linked to biofilms. Biofilms exhibit unique metabolic patterns that set them apart from their planktonic counterparts, resulting in significant metabolic reprogramming during biofilm formation. Differential glycolytic enzymes suggest that central metabolic processes are markedly different in biofilms and planktonic cells. The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is highly expressed in Staphylococcus aureus biofilm progenitors, indicating that changes in glycolysis activity play a role in biofilm development. Notably, an important consideration is a correlation between elevated cyclic di-guanylate monophosphate (c-di-GMP) activity and biofilm formation in various bacteria. C-di-GMP plays a critical role in maintaining the persistence of Pseudomonas aeruginosa biofilms by regulating alginate production, a significant biofilm matrix component. Furthermore, it has been demonstrated that S. aureus biofilm development is initiated by several tricarboxylic acid (TCA) intermediates in a FnbA-dependent manner. Finally, Glucose 6-phosphatase (G6P) boosts the phosphorylation of histidine-containing protein (HPr) by increasing the activity of HPr kinase, enhancing its interaction with CcpA, and resulting in biofilm development through polysaccharide intercellular adhesion (PIA) accumulation and icaADBC transcription. Therefore, studying the metabolic changes associated with biofilm development is crucial for understanding the complex mechanisms involved in biofilm formation and identifying potential targets for intervention. Accordingly, this review aims to provide a comprehensive overview of recent advances in metabolomic profiling of biofilms, including emerging trends, prevailing challenges, and the identification of potential targets for anti-biofilm strategies.

Socio-economic Correlates and Spatial Heterogeneity in the Prevalence of Asthma among Young Women in India.

BACKGROUND: Asthma is one of the leading causes of disease burden when measured in terms of disability adjusted life years, despite low prevalence of self-reported cases among young women. This paper deals with the meso-scale correlates and spatial heterogeneity in the prevalence of self-reported Asthma across 640 districts in India, using a nationally representative sample of 699,686 women aged 15-49 years from all 36 States/UTs under NFHS-4 (2015-16). METHODS: Analytical methods used in this paper include multivariate logistic regression to examine the adjusted effects of various independent variables on self-reported Asthma and poor-rich ratios (PRR) and concentration index (CI) to understand the economic inequalities in the prevalence of Asthma. For the spatial analysis in the prevalence of Asthma, univariate and bivariate local Moran's I statistic have been computed in addition to measure of spatial autocorrelation and auto regression using spatial error and spatial lag models. RESULTS: Results highlight that women's education was an important marker to the prevalence of Asthma. Smoking tobacco in any form among women were significantly more likely to suffer from Asthma. The prevalence of Asthma was further aggravated among women from the households without a separate room for kitchen, as well as those using unclean fuel for cooking. The poor-rich ratio in the prevalence of Asthma across various States/UTs in India depict inherent inequality. An analysis of spatial clustering in the prevalence of Asthma based on spatial autocorrelation portrays that Moran's I values were significant for improved source of drinking water, clean fuel used for cooking, and household environment. When spatial weights are taken into consideration, the autoregression model noticeably becomes stronger in predicting the prevalence of Asthma. CONCLUSIONS: Any programmatic effort to curb the prevalence of Asthma through vertical interventions may hinge around the use of clean fuel, poverty, and lifestyle of subjects, irrespective of urban-rural place of their residence, environmental and ecological factors.

Management and outcomes of patients hospitalized with severe COVID-19 at a tertiary care center in midwestern United States.

Knowledge of treatment regimens and outcomes for novel coronavirus disease 2019 (COVID-19) is evolving. Recent studies have reported mortality rates ranging from 39-50% among hospitalized patients with COVID-19. We report our experience ofmanagement and outcomes of hospitalized patients with COVID-19 at a large tertiary-care center in Midwestern United States. Of 658 patients presenting to our tertiary care center, 217 needed hospitalization, majority (77%) of whom were severely sick requiring admission to the intensive care unit (ICU). All received corticosteroids, and 78% of the patients received tocilizumab. More than two-thirds of the patients received anticoagulation and 80% of patients in the ICU had prone-positioning. The median duration of hospitalization was 12 days (interquartile range, 8 to16), median duration of intensive care unit stay was 7 days (interquartile range, 5 to 9) and requirement of mechanical ventilation was 6 days (interquartile range, 5 to 8) in our cohort. Of the 217 patients, 27 died (12% mortality). The majority of our patients received corticosteroids, tocilizumab, anticoagulation and prone positioning. While higher mortality rates of >30% have been reported in various studies among hospitalized patients with COVID-19, the majority of hospitalized patients in our cohort survived with a low mortality rate. The majority of our patients received corticosteroids, tocilizumab, anticoagulation and prone positioning. While higher mortality rates of >30% have been reported in various studies among hospitalized patients with COVID-19, the majority of hospitalized patients in our cohort survived with a low mortality rate.

Renewable poly(δ-decalactone) based block copolymer micelles as drug delivery vehicle: in vitro and in vivo evaluation.

Polymers from natural resources are attracting much attention in various fields including drug delivery as green alternatives to fossil fuel based polymers. In this quest, novel block copolymers based on renewable poly(δ-decalactone) (PDL) were evaluated for their drug delivery capabilities and compared with a fossil fuel based polymer i.e. methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL). Using curcumin as a hydrophobic drug model, micelles of PDL block copolymers with different orientation i.e. AB (mPEG-b-PDL), ABA (PDL-b-PEG-b-PDL), ABC (mPEG-b-PDL-b-poly(pentadecalactone) and (mPEG-b-PCL) were prepared by nanoprecipitation method. The size, drug loading and curcumin stability studies results indicated that mPEG-b-PDL micelles was comparable to its counterpart mPEG-b-PCL micelles towards improved delivery of curcumin. Therefore, mixed micelles using these two copolymers were also evaluated to see any change in size, loading and drug release. Drug release studies proposed that sustained release can be obtained using poly(pentadecalactone) as crystalline core whereas rapid release can be achieved using amorphous PDL core. Further, mPEG-b-PDL micelles were found to be non-haemolytic, up to the concentration of 40 mg/mL. In vivo toxicity studies on rats advised low-toxic behaviour of these micelles up to 400 mg/kg dose, as evident by histopathological and biochemical analysis. In summary, it is anticipated that mPEG-b-PDL block copolymer micelles could serve as a renewable alternative for mPEG-b-PCL copolymers in drug delivery applications.

Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review.

Glaucoma, an irreversible optic neuropathy, primarily affects retinal ganglion cells (RGC) and causes vision loss and blindness. The damage to RGCs in glaucoma occurs by various mechanisms, including elevated intraocular pressure, oxidative stress, inflammation, and other neurodegenerative processes. As the disease progresses, the loss of RGCs leads to vision loss. Therefore, protecting RGCs from damage and promoting their survival are important goals in managing glaucoma. In this regard, resveratrol (RES), a polyphenolic phytoalexin, exerts antioxidant effects and slows down the evolution and progression of glaucoma. The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina. Additionally, RES plays protective roles in RGCs by promoting cell growth, reducing apoptosis, and decreasing oxidative stress in H2O2-exposed RGCs. RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways. RES could alleviate retinal function impairment by suppressing the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway. Therefore, RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.

A Lagrange multiplier approach for excited state properties through intermediate Hamiltonian formulation of Fock space multireference coupled-cluster theory.

In this paper, we present a formulation based on Lagrange multiplier approach for efficient evaluation of excited state energy derivatives in Fock space coupled cluster theory within the intermediate Hamiltonian framework. The formulation is applied to derive the explicit generic expressions up to second order energy derivatives for [1, 1] sector of Fock space with singles and doubles approximation. Its advantage, efficiency, and interconnection in comparison to the Lagrange multiplier approach in traditional formulation of Fock space, which is built on the concept of Bloch equation based effective Hamiltonian, has been discussed. Computational strategy for their implementation has also been discussed in some detail.

A Scoping New Revolution for Tinnitus Management: A Neuromonics Narrative Review.

With a prevalence ranging from 16-21%, tinnitus is an irking neurological disorder, manifesting as the perception of a roar of cacophony without an external acoustic stimulus. Although tinnitus is a non-life-threatening symptom, tinnitus's negative repercussions, such as personality disturbances and social withdrawal, are daunting concerns despite a gamut of conventional and emerging treatment options. Tinnitus management is still a critical challenge that provides opportunities for clinicians, ENT (Ear/eye, nose and throat) physicians, and other specialists such as audiologists, psychiatrists, and psychologists. Among the new treatment modalities, Neuromonics tinnitus treatment (NTT) draws special attention in tinnitus management due to its mounting success rate. Nonetheless, unlike in developed countries like Australia, the United States, and the United Kingdom, the scanty awareness of NTT among Indian ENT specialists is a titanic setback for care providers. Because of this backdrop, this review emphasized the current perspectives on tinnitus management and the underlying principles and clinical efficacy of NTT. The challenges for tinnitus management can be met and reduced by suppressing tinnitus through motivation, counseling, cochlear implant, and psychotherapy.

PCSK9 Biomarker and Key Modulator for Cardiovascular Disorders: Heralding a New Therapeutic Era and Their Future Perspectives.

Cardiovascular disorders (CVDs) are the leading cause of death worldwide and are accelerated via the low level of low-density lipoprotein-cholesterol (LDL-C). The proprotein convertase subtilis/kexin type9 (PCSK9), a vital regulator and a biomarker, circulates for the LDL-C and has the degradation capability of the low-density lipoprotein receptor (LDLR). PCSK9 has modulated the overall mechanism by transcription, secretion, clearance, or extracellular inactivation in the past few years.PCSK9 has specific pathophysiological roles in many cardiovascular cells. The initial data on the PCSK9 inhibitor, Evolocumab, has a specific reduction in the composite end-point, such as cardiovascular, myocardial, and stroke, while the rest of the data release is still under wait. Furthermore, it is witnessed that the U.S. and the European authorities have approved two humanized antibodies against the LDL-R binding site of PCSK9. This review highlighted the recent data findings on the PCSK9 and its regulation, focusing on cardiovascular disorders, and summarized the current clinical studies. Thus it provides a ray of hope to overcome statin intolerance and alternative approaches for PSCK9 inhibition and significantly reduce cardiovascular complications. This review plays a pivotal role for the researchers and scientists working on PCSK9 inhibitors to treat cardiovascular disorders.

Immunoliposomes: A Targeted Drug Delivery System for Cancer Therapeutics and Vaccination.

Cancer has become one of the world's most lethal and life-threatening disorders, resulting in many deaths. Drug targeting and managing drug delivery are concepts that are implemented to increase a drug's therapeutic index by enhancing its specificity to particular cells, tissues, or organs and reducing its action and harmful side effects. Liposomes have proven to be one of the most innovative drug delivery systems in medicine. Immunoliposomes, also known as antibody-coupled liposomes, have gained a lot of attention as a homing device for targeted therapies. Monoclonal antibodies or antibody fragments that combine with liposomes to create immunoliposomes have been considered a leading technique for targeted delivery. Various functionalization strategies are adopted for the non-covalent and covalent binding of monoclonal antibodies and their components to liposomal surfaces, such as thiolation, amide bonds, hydrazone bonds, and electrostatic interactions, hydrophobic interactions, hydrogen bonding, etc. for cancer-specific targeting. This provides an overview of various stimulus-responsive immunoliposomes capable of regulating drug release in response to an exogenous magnetic field, changes in temperature or pH, enzyme concentration, endogenous stimuli, and applications of immunoliposomes in vaccination and cancer therapeutics and endogenous immune response stimulation.

Intra-cluster correlations in socio-demographic variables and their implications: An analysis based on large-scale surveys in India.

Individuals who share similar socio-economic and cultural characteristics also share similar health outcomes. Consequently, they have a propensity to cluster together, which results in positive intra-class correlation coefficients (ICCs) in their socio-demographic and behavioural characteristics. In this study, using data from four rounds of the National Family Health Survey (NFHS), we estimated the ICC for selected socio-demographic and behavioural characteristics in rural and urban areas of six states namely Assam, Gujarat, Kerala, Punjab, Uttar Pradesh, and West Bengal. The socio-demographic and behavioural characteristics included religion & caste of the household head, use of contraception & prevalence of anaemia among currently married women and coverage of full immunization services among children aged 12-23 months. ICC was computed at the level ofPrimary Sampling Units (PSUs), that is, villages in rural areas and census enumeration blocks in urban areas. Our research highlights high clustering in terms of religion and caste within PSUs in India. In NFHS-4, the ICCs for religion ranged from the lowest of 0.19 in rural areas of Kerala to the highest of 0.67 in urban areas of West Bengal. For the caste of the household head, the ICCs ranged from the lowest of 0.12 in the urban areas of Punjab to the highest of 0.46 in the rural areas of Assam. In most of the states selected for the study, the values of ICC were higher for the use of family planning methods than for full immunization. The value of ICC for use of contraception was highest for rural areas of Assam (0.15) followed by rural areas of Gujarat (0.13). A higher value of ICC has considerable implications for determining an effective sample size for large-scale surveys. Our findings agree with the fact that for a given cluster size, the higher the value of ICC, the higher is the loss in precision of the estimate. Knowing and taking into account ICCs can be extremely helpful in determining an effective sample size when designing a large-scale demographic and health survey to arrive at estimates of parameters with the desired precision.

Double-edged sword role of miRNA-633 and miRNA-181 in human cancers.

Understanding the function and mode of operation of microRNAs (miRNAs) in cancer is of growing interest. The short non-coding RNAs known as miRNAs, which target mRNA in multicellular organisms, are described as controlling essential cellular processes. The miR-181 family and miR-633 are well-known miRNAs that play a key role in the development and metastasis of tumor cells. They may facilitate either tumor-suppressive or oncogenic function in malignant cells, according to mounting evidence. Metastatic cells that are closely linked to cancer cell migration, invasion, and angiogenesis can be identified by abnormal levels of miR-181 and miR-633. Numerous studies have demonstrated their capacity to control drug resistance, cell growth, apoptosis, and the epithelial-mesenchymal transition (EMT) and metastasis process. Interestingly, the levels of miR-181 and miR-633 and their potential target genes in the basic cellular process can vary depending on the type of cancer cells and their gene expression profile. Such miRNAs' interactions with other non-coding RNAs such as long non-coding RNAs and circular RNAs can influence tumor behaviors. Herein, we concentrated on the multifaceted roles of miR-181 and miR-633 and potential targets in human tumorigenesis, ranging from cell growth and metastasis to drug resistance.

A state-of-art of underlying molecular mechanisms and pharmacological interventions/nanotherapeutics for cisplatin resistance in gastric cancer.

The fourth common reason of death among patients is gastric cancer (GC) and it is a dominant tumor type in Ease Asia. One of the problems in GC therapy is chemoresistance. Cisplatin (CP) is a platinum compound that causes DNA damage in reducing tumor progression and viability of cancer cells. However, due to hyperactivation of drug efflux pumps, dysregulation of genes and interactions in tumor microenvironment, tumor cells can develop resistance to CP chemotherapy. The current review focuses on the CP resistance emergence in GC cells with emphasizing on molecular pathways, pharmacological compounds for reversing chemoresistance and the role of nanostructures. Changes in cell death mechanisms such as upregulation of pro-survival autophagy can prevent CP-mediated apoptosis that results in drug resistance. Moreover, increase in metastasis via EMT induction induces CP resistance. Dysregulation of molecular pathways such as PTEN, PI3K/Akt, Nrf2 and others result in changes in CP response of GC cells. Non-coding RNAs determine CP response of GC cells and application of pharmacological compounds with activity distinct of CP can result in sensitivity in tumor cells. Due to efficacy of exosomes in transferring bioactive molecules such as RNA and DNA molecules among GC cells, exosomes can also result in CP resistance. One of the newest progresses in overcoming CP resistance in GC is application of nanoplatforms for delivery of CP in GC therapy that they can increase accumulation of CP at tumor site and by suppressing carcinogenic factors and overcoming biological barriers, they increase CP toxicity on cancer cells.

The metformin immunoregulatory actions in tumor suppression and normal tissues protection.

The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.

Approach to Cystic Lesions of the Pancreas: Review of Literature.

Pancreatic cystic lesions (PCL) have a wide range of demographical, clinical, morphological and histological characteristics. The distinction between these lesions is of paramount importance due to the risk of malignancy in specific categories of PCL. Considering the malignant potential for pancreatic cystic neoplasm (PCN) lesions, guidelines have been made to balance unnecessary treatment and manage the progression to malignancy. Various surgical procedures can be done for PCN depending on the location and size of the cyst; pancreatoduodenectomy is done for PCN located in the head of the uncinate process, whereas distal pancreatectomy is done for PCN in the body or tail. In the neck and proximal body of the pancreas, less extensive resections such as central pancreatectomy can be performed. Active surveillance of PCN is typically offered to asymptomatic PCNs of subtype intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) without any concerning features. In recent years, numerous guidelines have been created to augment PCN diagnosis, classification and management. Despite this, the management of PCNs remains complex. Thus, discussions with multidisciplinary teams involving surgeons, gastroenterologists, pathologists, and radiologists are required to ensure optimum care for the patient.