A PRAGMATIC APPROACH TO TREAT LUNG CANCER THROUGH LOADING THEAFLAVIN -3,3’-DIGALLATE AND EPIGALLOCATECHIN GALLATE IN SPANLASTIC

Lung cancer has the highest mortality rate as compared to other cancers. The anti-proliferative and antioxidant potential of epigallocatechin gallate (EGCG) and Theaflavin -3,3’-digallate (TF3) can play a major role in treatment if delivered efficiently. To improve the chemical stability and medicinal potential of EGCG and TF3 in the respiratory tract, a spanlastic is developed which is composed of Tween-80, Span-60, and cholesterol which encapsulate EGCG and TF3 inside its vesicular structure and deliver it specifically to the target cancer cells. The cholesterol layer will produce efficient penetration while tween-80 and span-60 will help in easily deformability and lowers the interfacial tension hence, produces a small Z-average diameter which facilitates efficient penetration between layers of cells. The nano-vesicular structure ensures the APIs stability at alkaline pH (7.6) and also increases cellular antioxidant activity and Ferric reducing antioxidant powers values of APIs. Better encapsulation efficiency and safe consideration by MTT assay are major advantages of Spanlastic. The lung cancer cell loses the ability of apoptosis, which can revived with the help of a nano-vesicular system of EGCG and TF3 and in addition, there will be activation of several other properties such as cell arrest, activation of miR-210, suppression of cyclin D1, inhibition of MAPK, ERK, and JAK-STAT at their maximum potential. Furthermore, a special type of spacer and pMDI canister are developed in order to maximize the drug stability and efficiency of its delivery

AN EXPEDIENT APPROACH TO TREAT ASTHMA THROUGH NON-STEROIDAL, NATURAL TRANSFEROSOMES AEROSOL SYSTEM

Asthma is the most common respiratory disease, affecting an estimated 262 million people and resulting in 461,000 fatalities in 2019. The treatment is available on the market, but it is quite expensive, and it also has serious adverse effects due to the high concentration of steroids in the medicine. If given effectively, curcumin, formononetin, and matrine’s anti-inflammatory properties can play a significant role in treatment. To improve the chemical stability and therapeutic potential of these active pharmaceutical ingredients (APIs) in the respiratory tract, a transferosomes system was designed, which encapsulates the APIs inside its vesicular structure and delivers them selectively to the inflamed cells. The DPPC layer will allow for efficient penetration, whereas Tween-80 will aid in deformability and lower interfacial tension, resulting in a small Z-average diameter, allowing for efficient penetration between layers of cells. The APIs’ stability at alkaline pH (7.6) is ensured by the nano-vesicular structure, which significantly increases cellular antioxidant activity and ferric reducing antioxidant power values. On the RAW264.7 cell line, the formulation will be tested for anti-inflammatory activity. Nuclear factor kappa B, tumor necrosis factor, interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, nitric oxide, and cyclooxygenase-2 are all reduced by curcumin, formononetin, and matrine. They also have an inhibitory effect on the MAPK signaling pathway, preventing extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 from causing inflammation. This formulation can effectively treat asthma without the use of steroids, has no adverse effects, and is inexpensive

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

NANOPARTICLES: THE FUTURE OF DRUG DELIVERY

Material in the nanometric size are used as diagnostic instruments or even to administer therapeutic compounds to particular target regions in a controlled way in nanoparticles and nano delivery systems, which is a relatively young but fast-emerging discipline. By delivering accurate medications to specified locations and targets, nanotechnology provides numerous advantages in the treatment of chronic human diseases. The use of nanomedicine (including chemotherapy medicines, biological agents, immunotherapeutic agents, etc.) in the treatment of various illnesses has recently seen a number of notable uses. Through careful examination of the discovering and use of nanomaterials in enhancing the effectiveness of both new and old drugs (such as organic products) and preferential diagnosis through disease marker substances, the review article offers a comprehensive overview of recent developments in the field of nanoparticles and nano-based drug delivery. The advantages and disadvantages of using nanoparticles for the therapeutic delivery of drugs from natural or synthetic origins are also covered. Additionally, we have provided details on the developments and prospects in the field of nanotechnology

TOPICAL FORMULATION CONSTITUTED WITH TRANSFEROSOMES FOR THE TREATMENT OF NON-MELANOMA SKIN CANCER

Overexposure to UV-B radiation causes an evolution in the strands of DNA of skin membrane cells, resulting in non-melanoma skin cancer. With the addition of excipients and nano-vesicular structures such as transferosomes that boost the permeability rate and pharmacological activity, a formulation containing Curcumin, Kaempferol, Trans-Resveratrol, and Apigenin have been developed which possess strong anti-inflammatory and anti-proliferative potential. The formulation quickly penetrates the stratum corneum and acts on cancer cells, inhibiting metastasis and angiogenesis by interfering with signalling molecules in the three primary MAPK pathways: ERK, JNK, and p38. It blocks pro-inflammatory cytokines such as LPS, TNF-α, IL1, IL6, COX-2, LOX, oxidative stress, and lowers the levels of (MMP)-3, MMP-9, and VEGF. The yield value, sensory testing, spreadibility, dynamic viscosity, water content, pH, specific gravity, anti-microbial preservative concentration, microbiological limit, sterility testing, contaminants, uniformity of dosage, and assay on RAW264.7 cell line will all be used to evaluate the formulation. The O/W cream that has been produced will be significantly more successful than traditional cancer treatments, and it will have no side effects, protects the patient from recurrence of cancer and inexpensive treatment

INTERACTION BETWEEN ACE 2 AND SARS-COV2, AND USE OF EGCG AND THEAFLAVIN TO TREAT COVID 19 IN INITIAL PHASES

Covid Virus particles engage with host cells via the ACE-2 and GRP78 receptors, transferring the genome particle to the host cell and transforming it into a replicating machine. RdRP is a key protein in the replication mechanism of all RNA viruses. 3CLpro is a cleavage enzyme that breaks down polyproteins into non-structural polyproteins. All four elements of the Covid viral particle are required for its propagation and action, and blocking any one of them can shut down the entire system. EGCG and Theaflavins are flavonoids that block virus particles from attaching to the host cell's ACE-2 and GRP78 receptors, preventing the genome from being transferred into the cell. EGCG binds to 3CLpro with a molecular docking value of 11.7, while TF3 has a docking score of 10.574, indicating that it prevents host cell contact. TF binds to RdRP with a binding energy of 9.11 kcal/mol, implying that RdRP activities are interfered with. Furthermore, these flavonoids have anti-inflammatory properties and reduce the action of cytokines, which can cause serious respiratory difficulties. Except these two there are many others flavonoids which possess anti-inflammatory and anti-viral properties. All of these data suggest that flavonoids could be a useful treatment for SARS-CoV19; however, the issue of stability and bioavailability arises because it is unstable at lungs pH

LUNG CANCER THERAPY USING NATURALLY OCCURRING PRODUCTS AND NANOTECHNOLOGY

Lung cancer is a severe type of cancer with highest mortality rate among all cancers. Natural products such as theaflavins, quercetin, arctigenin, EGCG, curcumin, and cinnamaldehyde are quite capable anti-inflammatory and anti-cancerous agents which are able to suppress ERK-MAPK, JAK-STAT, p38, AMPK, PI3K/Akt, MAPK, mTOR, STAT3, and Wnt/β-catenin signal transduction pathways. These APIs inhibit the inflammatory and proliferator enzymes such as COX-2, caspase-3, MMP-9, MMP-2, NF-κB, p53, Bcl-xL, Bcl-2,Mcl-1, miR-210, cyclin D1, iNOS, IL-1β, TNF-α, IFN-γ, IL-6, and IL-1α. All the above properties clearly show the anti-cancerous potential, but the problems arise because of their instability at gastrointestinal tract pH. All the compounds either degrade at gastric pH or loss their cancerous potential. New generation nanoparticles such as transferosomes are quite stable at 7.4 pH and its efficacy and drug entrapment potential are better than other conventional nanoparticle systems. If these APIs are added inside the nanovesicular structure of transferosomes and then loaded in pMDI canisters such as fluorocarbon polymerization (FCP), plasma-coated canisters with a better propellant such as HFA-134a and delivered with the help of spacers can cure lungs cancer economically, efficiently with minimal side effects and it also ensures that the cancer will not reoccur

Students' participation in collaborative research should be recognised

Letter to the editor