Javad Sharifi-Rad | Universidad de Especialidades Espíritu Santo (original) (raw)

Papers by Javad Sharifi-Rad

Long non-coding RNAs (lncRNAs) have been in the spotlight for the past two decades due to their e... more Long non-coding RNAs (lncRNAs) have been in the spotlight for the past two decades due to their extensive role in regulating
a wide range of cellular processes. Development, differentiation, regulation, and modulation are some of the vital cellular
cascades coordinated by these molecules. Despite their importance, there has been limited literature on their practical implications
in cancer prevention. Advancements in lncRNA biology have enabled the characterization of numerous secondary
structures and sequence motifs, which could serve as potential targets for cellular therapies. Several studies have highlighted
the involvement of lncRNAs in human pathologies, where they can be targeted by small molecules or antisense oligonucleotides
to prevent diseases. However, progress has been hindered by the challenge of developing specific delivery vehicles for
targeted delivery. Recent improvements in sequence optimization and nucleotide modification have enhanced drug stability
and reduced the immunogenicity of lncRNA-based therapies, yet further advances are needed to fully realize their potential
in treating complex diseases like cancer. This review aims to explore current lncRNA biology, their mechanisms of action,
nanoformulation strategies, and the clinical trials focused on lncRNA delivery systems.

Glypican-3 (GPC-3) is predominantly found in the placenta and fetal liver, with limited expressio... more Glypican-3 (GPC-3) is predominantly found in the placenta and fetal liver, with limited expression in adult tissues. Its
re-expression in hepatocellular carcinoma (HCC) and secretion into the serum highlights its potential as a diagnostic
marker. GPC-3 is involved in important cellular processes such as proliferation, metastasis, apoptosis, and epithelial–
mesenchymal transition through various signaling pathways including Wnt, IGF, YAP, and Hedgehog. To review
the structure, biosynthesis, and post-translational modifications of GPC-3, and to elucidate its signaling mechanisms
and role as a pro-proliferative protein in HCC, emphasizing its diagnostic and therapeutic potential. A comprehensive
literature review was conducted, focusing on the expression of GPC-3 in various tumors, with a special emphasis
on HCC. The review synthesized findings from experimental studies and clinical trials, analyzing the overexpression
of GPC-3 in HCC, its differentiation from other liver diseases, and its potential as a diagnostic and therapeutic target.
GPC-3 overexpression in HCC is linked to aggressive tumor behavior and poor prognosis, including shorter overall
and disease-free survival. Additionally, GPC-3 has emerged as a promising therapeutic target. Ongoing investigations,
including immunotherapies such as monoclonal antibodies and CAR-T cell therapies, demonstrate potential in inhibiting
tumor growth and improving clinical outcomes. The review details the multifaceted roles of GPC-3 in tumorigenesis,
including its impact on tumor-associated macrophages, glucose metabolism, and epithelial–mesenchymal
transition, all contributing to HCC progression. GPC-3’s re-expression in HCC and its involvement in key tumorigenic
processes underscore its value as a biomarker for early diagnosis and a target for therapeutic intervention. Further
research is warranted to fully exploit GPC-3’s diagnostic and therapeutic potential in HCC management.

Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcino... more Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcinoma (HCC) exhibits
distinct molecular and immune characteristics. These traits are influenced by multiple factors, including the gut
microbiome, which interacts with the liver through the "gut–liver axis". This bidirectional relationship between the gut
and its microbiota and the liver plays a key role in driving various liver diseases, with microbial metabolites
and immune responses being central to these processes. Our review consolidates the latest research on how gut
microbiota contributes to MASH development and its progression to HCC, emphasizing new diagnostic and therapeutic
possibilities. We performed a comprehensive literature review across PubMed/MedLine, Scopus, and Web
of Science from January 2000 to August 2024, focusing on both preclinical and clinical studies that investigate the gut
microbiota’s roles in MASH and HCC. This includes research on pathogenesis, as well as diagnostic and therapeutic
advancements related to the gut microbiota. This evidence emphasizes the critical role of the gut microbiome
in the pathogenesis of MASH and HCC, highlighting the need for further clinical studies and trials. This is to refine
diagnostic techniques and develop targeted therapies that exploit the microbiome’s capabilities, aiming to enhance
patient care in liver diseases.

Chronic kidney disease (CKD) is a critical global health issue, marked by a progressive decline i... more Chronic kidney disease (CKD) is a critical global health issue, marked by a progressive decline in kidney function and significant associated morbidity and mortality. Central to the pathogenesis of CKD is oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS ) and the body’s antioxidant defenses. This review provides an integrative insight into the roles of oxidative stress and antioxidants in CKD progression. It synthesizes current research, highlighting the pathogenic mechanisms through which oxidative stress exacerbates kidney damage – principally through inducing apoptosis and inflammation – and discusses the therapeutic potential of natural antioxidants. Our comprehensive literature search covered key databases including PubMed/MedLine, Science Direct, and Google Scholar, focusing on studies that elucidate the interplay between oxidative stress and antioxidants in CKD pathophysiology. While emerging evidence from preclinical studies suggests that antioxidants can play a protective role by neutralizing ROS, clinical trials remain insufficient to justify widespread adoption of antioxidant therapy in CKD treatment protocols. The review underscores the urgent need for more rigorous clinical studies to establish the efficacy and safety of antioxidant interventions in CKD patients. Future research should prioritize identifying effective antioxidant therapies and elucidating their mechanisms of action within the CKD context.

Lancet, 2024

Background Understanding the health consequences associated with exposure to risk factors is nece... more 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.

Cancer remains a major global health challenge, prompting the search for effective and less toxic... more Cancer remains a major global health challenge, prompting the search for effective and less toxic treatments.
Anethole, a bioactive compound found in essential oils of anise and fennel, commonly used as a food preservative,
has recently garnered attention for its potential anti-cancer properties. This comprehensive review aims
to systematically assess the anti-cancer effects of anethole, elucidating its mechanisms of action, pharmacokinetics,
bioavailability, and synergistic potential with conventional cancer therapies. A detailed literature search
was conducted across databases including PubMed, Embase, Scopus, Science Direct, Web of Science, and Google
Scholar. Criteria for inclusion were experimental studies in peer-reviewed journals focusing on the anti-cancer
properties of anethole. Extracted data included study design, intervention specifics, measured outcomes, and
mechanistic insights. Anethole demonstrates multiple anti-cancer mechanisms, such as inducing apoptosis,
causing cell cycle arrest, exhibiting anti-proliferative and anti-angiogenic effects, and modulating critical
signaling pathways including NF-κB, PI3K/Akt/mTOR, and caspases. It enhances the efficacy of chemotherapeutic
agents like cisplatin and doxorubicin while reducing their toxicity. In vitro and in vivo studies have shown
its effectiveness against various cancers, including breast, prostate, lung, and colorectal cancers. Anethole shows
significant potential as an anti-cancer agent, with its multi-faceted mechanisms of action and ability to synergize
with existing chemotherapy. Further clinical research is essential to fully understand its therapeutic potential and
application in oncology.

Hydroxycinnamic acids (HCAs) are plant compounds with anticancer potential due to their antioxida... more Hydroxycinnamic acids (HCAs) are plant compounds with anticancer potential due to their antioxidant, anti-inflammatory,
apoptosis-inducing, and proliferation-inhibiting effects. This review aims to consolidate and analyze current knowledge on
the anticancer effects of HCAs, exploring their mechanisms of action, bioavailability challenges, and potential therapeutic
applications. A comprehensive literature search on PubMed/MedLine, Scopus, Web of Science, and Google Scholar focused
on the anticancer properties, mechanisms, bioavailability, and safety profiles of HCAs. Studies have shown that HCAs, such
as caffeic acid, ferulic acid, and sinapic acid, inhibit the growth of cancer cells in vitro and in vivo and sensitize cancer cells
to chemotherapy and radiation therapy. These effects are mediated by mechanisms including the inhibition of cell survival
pathways, modulation of gene expression, and induction of oxidative stress and DNA damage. Additionally, several studies have
demonstrated that HCAs exhibit selective toxicity, with a higher propensity to induce cell death in cancerous cells compared to
normal cells. However, the toxicity profile of HCAs can vary depending on the specific compound, dosage, and experimental
conditions. The anticancer properties of HCAs suggest potential applications in cancer prevention and treatment. However, it
is essential to distinguish between their use as dietary supplements and therapeutic agents, as the dosage and formulation suitable
for dietary supplements may be insufficient for therapeutic purposes. The regulatory and practical implications of using
HCAs in these different contexts require careful consideration. Further research is needed to determine appropriate dosages,
formulations, long-term effects, and regulatory frameworks for HCAs as both dietary supplements and therapeutic agents.

Cancer remains a critical global health challenge, with limited progress in reducing mortality de... more Cancer remains a critical global health challenge, with limited progress in reducing mortality despite advancements in diagnosis and treatment. The growing resistance of tumors to existing chemotherapy exacerbates this burden. In response, the search for new anticancer compounds from plants has intensified, given their historical success in yielding effective treatments. This review focuses on α-solanine, a glycoalkaloid primarily derived from potato tubers and nightshade family plants, recognized for its diverse biological activities, including anti-allergic, antipyretic, anti-inflammatory, anti-diabetic, and antibiotic properties. Recently, α-solanine has gained attention as a potential anticancer agent. Utilizing resources like PubMed/MedLine, ScienceDirect, Web of Science, Scopus, the American Chemical Society, Google Scholar, Springer Link, Wiley, and various commercial websites, this review consolidates two decades of research on α-solanine's anticancer effects and mechanisms against nine different cancers, highlighting its role in modulating various signaling pathways. It also discusses α-solanine's potential as a lead compound in cancer therapy. The abundant availability of potato peel, often discarded as waste or sold cheaply, is suggested as a sustainable source for large-scale α-solanine extraction. The study concludes that α-solanine holds promise as a standalone or adjunctive cancer treatment. However, further research is necessary to optimize this lead compound and mitigate its toxicity through various strategies.

Angiogenesis, vital for tumor growth and metastasis, is a promising target in cancer therapy. Nat... more Angiogenesis, vital for tumor growth and metastasis, is a promising target in cancer therapy. Natural compounds offer potential as antiangiogenic agents with reduced toxicity. This review provides a comprehensive overview of natural product-based antiangiogenic therapies, focusing on molecular mechanisms and therapeutic potential. A systematic search identified relevant articles from 2019 to 2023. Various natural compounds, including polyphenols, terpenes, alkaloids, cannabinoids, omega-3 fatty acids, polysaccharides, proteins, and carotenoids, were investigated for their antiangiogenic properties. Challenges such as dose standardization, routes of administration, and potential side effects remain. Further studies, including in-depth animal models and human epidemiological studies, must elucidate clinical efficacy and safety. Synergistic effects with current antiangiogenic therapies, such as bevacizumab and tyrosine kinase inhibitors, should be explored. Additionally, the potential hormone-dependent effects of compounds like genistein highlight the need for safety evaluation. In conclusion, natural products hold promise as adjunctive therapies to conventional antineoplastic drugs in modulating angiogenesis in cancer. However, robust clinical trials are needed to validate preclinical findings and ensure safety and efficacy.

Raspberries (RBs) (Rubus idaeus) are rich in bioactive compounds with promising anticancer proper... more Raspberries (RBs) (Rubus idaeus) are rich in bioactive compounds with promising anticancer properties. This review provides a comprehensive analysis of the anticancer effects of RBs, highlighting their potential as natural agents in cancer prevention and therapy. Bioactive compounds in RBs induce apoptosis, arrest the cell cycle, inhibit angiogenesis, and suppress metastasis. Preclinical studies demonstrate significant
anticancer effects against colon, breast, lung, prostate, and cervical cancers, with clinical studies also supporting their therapeutic potential.Although preclinical findings are encouraging, further large-scale clinical trials are needed to confirm their efficacy and safety in humans. Optimizing formulations to enhance bioavailability and therapeutic effectiveness is crucial. This review emphasizes the potential of dietary interventions
involving RBs as a complementary approach to conventional cancer therapies, paving the way for future research and clinical innovations.

Moscatilin, a bibenzyl derivative from the Dendrobium genus, has been traditionally used in Chine... more Moscatilin, a bibenzyl derivative from the Dendrobium genus, has been traditionally used in Chinese medicine. Recent studies suggest its potential as a powerful anticancer agent due to its diverse pharmacological properties.This review aims to consolidate current research on moscatilin’s anticancer mechanisms, structure–activity relationships, and therapeutic potential to assess its viability for clinical use. A literature search was performed in PubMed/MedLine, Scopus, and Web of Science.The search focused on “cancer,” “moscatilin,” “anticancer,” “bioactivity,” “dendrobium,” and “pharmacological properties.” Relevant studies on molecular mechanisms, preclinical and clinical efficacy, and bioavailability were reviewed. Moscatilin exhibits significant anticancer effects in lung, breast, colorectal, and pancreatic cancers. It induces apoptosis via the JNK/SAPK pathway, inhibits cell proliferation, and suppresses metastasis. Structure–activity relationship studies reveal that phenolic groups and a two-carbon bridge are crucial for its efficacy. Additionally, moscatilin shows good bioavailability and a favorable safety profile, with low toxicity to healthy cells. Moscatilin demonstrates considerable potential as an anticancer agent, targeting multiple cancer progression pathways. Further clinical trials are essential to confirm its therapeutic efficacy and safety in humans.

The Lancet, 2024

Pyracantha is a plant with edible and medicinal value and widely distributed from eastern Asia to... more Pyracantha is a plant with edible and medicinal value and widely distributed from eastern Asia to southern Europe but is underutilized and has great potential. As scientists gradually study its properties, it was found that Pyracantha contains various phytochemical components such as pigments and phospholipids. Meanwhile, Pyracantha is also rich in phenolic substances, such as flavonoids. The extract of Pyracantha shows strong biological properties, such as inhibition of tyrosinase activity, anti-oxidative, and tumor-preventive effects. Pyracantha bioavailability releases quantities of compounds in the food matrix from the digestive process that are important for its health-promoting properties. The extraction of biologically active substances in Pyracantha would be applied in various aspects. Their extracts can also be used as health food, food additives, and cosmetics. As the interaction of phytochemicals, proteins, and phenolic compounds can affect the pharmacological activity and bioavailability of Pyracantha, it is important to understand the mechanism of effect, which can further allow consumers to choose a healthier Pyracantha dietary culture. This review aims to prove the nutritional components and pharmacological activities of Pyracantha and to make consumers better aware of the benefits of Pyracantha in connection with their bioavailability and application, in order to provide a reference for further research and development of Pyracantha resources.

Cancer is one of the leading causes of death worldwide. Serious side effects, drug resistance and... more Cancer is one of the leading causes of death worldwide. Serious side effects, drug resistance and a narrow therapeutic window of chemotherapy drugs have led to the exploration and discovery of new natural anticancer agents. Alvaradoins are the secondary metabolites of the Alvaradoa Liebm. plant species, from the Picramniaceae family, belonging to the class of anthracenone C-glycosides. Among them, alvaradoin E, isolated from A. haitiensis Urb., is characterized by the most powerful anticancer properties as demonstrated by in-vitro and in-vivo assays. This updated review aims to provide new insights into the anticancer efficacy of alvaradoin E and analyses molecular pharmacological evidence to contribute to researchers' efforts to discover new adjunctive therapies in the pharmacotherapeutic management of cancer. To achieve this goal, relevant recent data on the anticancer pharmacological mechanisms of alvaradoin E were searched in specialized databases such as PubMed/ MedLine, Scopus, TRIP database, Web of Science, and Google Scholar. Most of the studies investigated the cytotoxic effects of alvaradoins and the extracts of the Alvaradoa species. Alvaradoin E excelled in its tumor-modulating activity in vitro in several human carcinomas (epidermoid, prostate, colon, lung), promyelocytic leukemia, and cells expressing telomerase reverse transcriptase. The cytotoxic effects of alvaradoin E were associated with its capacity to induce cell apoptosis. Further detailed studies are necessary to explain the precise mechanisms of actions, the effects on living organisms and possible adverse effects. Although data on its anticancer activity in vivo are scarce, Alvaradoin E can develop into a promising agent in fighting carcinoma.

The article focuses on the pivotal role of plastin 1 (PLS1) in pancreatic cancer, as revealed by ... more The article focuses on the pivotal role of plastin 1 (PLS1) in pancreatic cancer, as revealed by Sun et al. in a recent study published in Minerva Biotechnology and Biomolecular Research. Topics discussed include the significance of actin-binding proteins (ABPs) in cancer progression, the potential of ABPs as biomarkers for early diagnosis and intervention, and the urgent need for personalized and precise treatments for pancreatic carcinoma.

Gossypol, a polyphenolic aldehyde derived from cottonseed plants, has seen a transformation in it... more Gossypol, a polyphenolic aldehyde derived from cottonseed plants, has seen a transformation in its pharmaceutical application from a male contraceptive to a candidate for cancer therapy. This shift is supported by its recognized antitumor properties, which have prompted its investigation in the treatment of various cancers and related inflammatory conditions. This review synthesizes the current understanding of gossypol as an anticancer agent, focusing on its pharmacological mechanisms, strategies to enhance its clinical efficacy, and the status of ongoing clinical evaluations.

The methodological approach to this review involved a systematic search across several scientific databases including the National Center for Biotechnology Information (NCBI), PubMed/MedLine, Google Scholar, Scopus, and TRIP. Studies were meticulously chosen to cover various aspects of gossypol, from its chemical structure and natural sources to its pharmacokinetics and confirmed anticancer efficacy. Specific MeSH terms and keywords related to gossypol’s antineoplastic applications guided the search strategy.

Results from selected pharmacological studies indicate that gossypol inhibits the Bcl-2 family of anti-apoptotic proteins, promoting apoptosis in tumor cells. Clinical trials, particularly phase I and II, reveal gossypol’s promise as an anticancer agent, demonstrating efficacy and manageable toxicity profiles. The review identifies the development of gossypol derivatives and novel carriers as avenues to enhance therapeutic outcomes and mitigate adverse effects.

Conclusively, gossypol represents a promising anticancer agent with considerable therapeutic potential. However, further research is needed to refine gossypol-based therapies, explore combination treatments, and verify their effectiveness across cancer types. The ongoing clinical trials continue to support its potential, suggesting a future where gossypol could play a significant role in cancer treatment protocols.

Background: Cancer, characterized by the rapid and abnormal growth of cells affecting any part of... more Background: Cancer, characterized by the rapid and abnormal growth of cells affecting any part of the body, stands as the leading
cause of death worldwide. Cell-free DNA (cfDNA) has garnered significant attention as a non-invasive liquid biopsy approach
for disease detection, therapy evaluation, and prognosis. This review aims to provide a comprehensive exploration of cfDNA
within the realm of oncology. It encompasses its diagnostic and therapeutic applications while identifying areas necessitating
standardization and optimization.
Methods: We reviewed existing literature to delve into the biological properties of cfDNA, exploring genetic and epigenetic
aberrations found in various bodily fluids. Additionally, we explored its correlation with circulating tumor DNA (ctDNA). The
review also encompasses preanalytical procedures and emerging technologies geared towards maximizing the complete potential
of cfDNA.
Results: Genetic and epigenetic markers have been identified in cfDNA across plasma, serum, and urine, presenting promising
diagnostic and prognostic applications. Furthermore, ctDNA preserves genomic profiles akin to those found in corresponding
tumor tissues, enabling a nuanced evaluation of tumor heterogeneity and mutation burdens. However, despite its potential,
current methodologies suffer from a lack of standardization and optimization, thereby restraining the complete clinical utility of
cfDNA.
Conclusions: Although cfDNA stands as a compelling avenue for non-invasive early cancer diagnosis and therapy evaluation,
unlocking its maximum potential requires methodological refinement and a deeper understanding of its biological characteristics.
This review advocates for targeted research to standardize and optimize cfDNA analytical techniques, thereby enhancing its role
in oncology.

Background Accurate assessments of current and future fertility—including overall trends and cha... more Background
Accurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios.

Methods
To estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline.

Findings
During the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction.

Interpretation
Fertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world.

Diosmin, a potent bioflavonoid derived from citrus fruits, has gained significant attention for i... more Diosmin, a potent bioflavonoid derived from citrus fruits, has gained significant attention for its anticancer potential, reflecting a critical need in the ongoing battle against cancer. Amidst increasing cancer incidence, the quest for safer and more effective treatments has brought diosmin to the forefront, given its unique pharmacological profile distinct from other flavonoids. Diosmin's anticancer mechanisms are multifaceted, involving apoptosis induction, angiogenesis inhibition, and metastasis prevention. Extensive research encompassing cellular studies, animal models, and limited clinical trials underscores its efficacy not only against cancer but also in managing chronic venous insufficiency and hemorrhoids, attributing to its anti-inflammatory properties. Furthermore, diosmin exhibits low toxicity and complements conventional chemotherapy, proposing its utility as an adjunct therapy in cancer treatment protocols. The review delves into the specific anticancer advantages of diosmin, distinguishing it from the broader flavonoid category. It provides a detailed analysis of its implications in preclinical and clinical settings, advocating for its consideration in the oncological therapeutic arsenal. By juxtaposing diosmin with other herbal medicines, the review offers a nuanced perspective on its role within the wider context of natural anticancer agents, emphasizing the need for further clinical research to substantiate its efficacy and safety in oncology.

The escalating global cancer burden underscores the urgent need for more effective therapeutic st... more The escalating global cancer burden underscores the urgent need for more effective therapeutic strategies. Phytochemicals, naturally occurring compounds in plants, have garnered attention for their potential in cancer chemoprevention and chemotherapy. Their ability to modulate molecular mechanisms and influence cell signaling pathways offers a promising avenue for cancer management. This review aims to synthesize current knowledge on phytochemicals’ chemopreventive and chemotherapeutic potential, focusing on their molecular mechanisms of action and impacts on cell signaling pathways involved in cancer. A systematic literature search was conducted across major databases, including PubMed/Medline, Web of Science, Scopus, and Google Scholar. The search strategy uses Medical Subject Headings (MeSH) and free-text terms using Boolean operators to capture relevant studies. Inclusion criteria targeted original research and reviews on the effects of phytochemicals in cancer, with a specific focus on molecular mechanisms. Phytochemicals, including flavonoids, polyphenols, and terpenoids, demonstrated significant anticancer properties by inducing cell cycle arrest, apoptosis, and autophagy. They modulate critical cell signaling pathways, such as cyclooxygenase-2, nuclear factor kappa B, and various growth factor-related pathways, and rectify epigenetic alterations, contributing to their chemopreventive and therapeutic effects. Phytochemicals represent a valuable resource for developing novel cancer prevention and treatment strategies; their actions on molecular mechanisms and cell signaling pathways underscore their potential in cancer prevention and combat. Further research is warranted to translate these findings into clinical applications, optimizing phytochemical-based interventions for cancer management.

Lancet, 2024

The Lancet, 2024