Khosrow Kashfi

Introduction: Research is a purpose-directed activity. Although aims, goals, objectives, and targets are interrelated statements of purpose, they differ in hierarchy, scope, measurability, timeframe, and significance. This brief review clarifies these terms and describes the characteristics of a good research objective. Methods: Relevant papers were analyzed to delineate the definitions, interrelations, and distinctions among aims, goals, objectives, and targets in research projects. Results: The apparent purpose of a study (objectives and goals) addresses specific research questions, whereas its deeper purpose (aim) represents the underlying reason for conducting the study. Aims express ideals and long-term direction; goals outline the primary intent and problem to be addressed; objectives link intention to action by specifying how the research question will be answered; and targets indicate desired values of outcome indicators. A strong objective should be SMART (specific, measurable, achievable, relevant, and time-bound). Conclusion: Clear articulation of research purpose facilitates translation of findings into practice and enhances the overall quality of research.

Nitric oxide (NO) is a small, bioactive molecule with diverse physiological functions. It is generated both enzymatically by NO synthases (NOS) and non-enzymatically through the nitrate-nitrite-NO reduction pathway. Recent studies have renewed interest in nitrate-based regulation of NO, highlighting a compartmentalization model of nitrate homeostasis. In this model, excess NO is rapidly oxidized to nitrite, which is then oxidized to nitrate, a more stable species that limits oxidative damage. Nitrate is differentially distributed across tissues, allowing both storage and rapid mobilization to maintain NO availability. Human and animal studies show that nitrate concentrations in skeletal muscle, plasma, and liver are approximately 100, 35, and 10 nmol/g, respectively, corresponding to a skeletal muscle-to-plasma-to-liver ratio of ~3:1:0.3. The large skeletal muscle reservoir and its higher muscle-to-plasma gradient support the release of nitrate into the circulation when needed. In contrast, the liver-to-plasma ratio < 1 suggests active hepatic uptake of circulating nitrate. Together, these findings support a compartmentalized system in which nitrate storage and flux contribute to whole-body NO homeostasis. Understanding this model may have implications for exercise physiology, metabolic regulation, and liver pathophysiology – all conditions in which NO biology plays a critical role.

Cancer metabolism underwent a conceptual revolution over the past decade. Research has long focused on aerobic glycolysis, but recently a more nuanced view is emerging. Tumors dynamically switch among different metabolic pathways, from oxidative phosphorylation to glutaminolysis and β-oxidation. Those metabolic alterations lead to increased growth and therapy resistance.Nevertheless, these alterations are not solely cell-autonomous. The tumor microenvironment (TME) acts as an active metabolic ecosystem, in which immune, stromal, and endothelial cells influence and respond to tumor metabolic demands.The cross-talk between immunity and metabolism, referred to as immunometabolism, determines how tumors evade immune surveillance or how immune activation reshapes cancer metabolism. This Special Issue in Frontiers in Immunology brings together five papers (three reviews and two original research articles) exploring these interconnections across diverse malignancies, from squamous and lymphoid cancers to lung and laryngeal carcinomas. These studies provide insight into how metabolism cues within the TME-sculpt immune function and influence cancer fate.In their review, Qinyi Dong and Lili Liang analyze cutaneous squamous cell carcinoma (cSCC) as a paradigm of immune dysregulation within a metabolically altered TME. They highlight how UV-induced mutagenesis and chronic inflammation generate a immunosuppressive niche dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Mechanistic insight into the PD-L1/PD-1 and TGF-β/Smad pathways reveals how these axes integrate metabolic stress with immune escape. The review also summarizes clinical data on immune checkpoint inhibitors, including the monoclonal antibodies cemiplimab and pembrolizumab. The authors propose future strategies, including combinatorial and vaccine-based immunotherapy, tailored to the metabolic and immune profile of cSCC.Chengqian Chen and colleagues provide a review on the metabolic-immune axis in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). They emphasize that enhanced glycolysis and amino acid metabolism fuel tumor growth, but concurrently shape an immunosuppressive milieu via lactate accumulation, nutrient competition, and checkpoint evasion, with a molecular network involving PD-L1, LAG-3, and TIM-3. Their synthesis of PET-based metabolic imaging and immune profiling data demonstrates that integrating metabolic and immune biomarkers refines prognostic stratification and supports the rational combination of metabolic inhibitors with immunotherapy. This represents an important step toward precision lymphoma management.Jiayi Dong et al. propose a review focusing on drug functional remapping as a strategic approach to accelerate the development of cancer immunotherapy. By reanalyzing clinically approved drugs, the authors reveal how these agents may reprogram immune metabolism or counteract checkpoint inhibitor resistance. This review also surveys computational and high-throughput screening tools enabling systematic repurposing. The result is a compelling case for expanding therapeutic discovery beyond de novo drug development, using immunometabolic principles to reposition well-characterized compounds for cancer treatment.Gen Li and colleagues identify fibrinogen alpha chain (FGA) as a suppressor of lung adenocarcinoma (LUAD) progression by modulating of SLC7A11/xCT-mediated disulfidptosis.Using transcriptomic analyses and functional assays, they demonstrate that FGA restrains malignant proliferation and invasion while influencing immune infiltration patterns in the LUAD TME. The study highlights disulfidptosis (a recently described disulfide-stress-induced cell death pathway) as a therapeutic vulnerability that links redox homeostasis to tumor immunity.Dan Zheng and colleagues have combined integrative multi-omics and machine learning to delineate two metabolic subtypes of laryngeal cancer (LCA), with distinct prognoses and immune features. The LCA1 subtype exhibits enhanced metabolic pathway enrichment and NSD1 mutations, both of which are associated with improved outcomes. On the other hand, the LCA2 subtype shows higher immune infiltration and checkpoint expression but poorer survival. The diagnostic and prognostic models developed by the authors demonstrate strong predictive performance, reinforcing the clinical potential of metabolic profiling for patient stratification.Across these studies, several unifying themes that reshape our understanding of cancer immunometabolism can be identified. First, the reciprocal regulation between tumor and immune cells, which are metabolically interdependent. Tumor-derived metabolites (lactate, kynurenine, adenosine) modulate immune effector function, while activated immune cells impose metabolic pressure on tumor survival pathways.Moreover, distinct metabolic states coexist within the same tumor, creating spatially and temporally heterogeneous niches that complicate therapy. Integrative -omics and spatial transcriptomic tools are beginning to unravel this complexity, but this will represent an important field of future research.From a therapeutic standpoint, metabolic reprogramming can be leveraged to potentiate immunotherapy. From repurposed metabolic drugs to redox-targeted interventions and metabolic subtype-based treatment design, these strategies promise to overcome resistance and enhance immune efficacy. Analyzing metabolic, immune, and clinical datasets enables predictive modeling of patient outcomes, advancing immunometabolism toward actionable clinical translation.The next frontier in this field lies in dissecting the spatial and temporal organization of metabolic networks within the TME. High-resolution single-cell and spatial metabolomic technologies can now map nutrient fluxes and redox gradients at the cellular level, offering unprecedented insight into local metabolic competition and...

Background: Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system. The use of high-fat diet is a modifiable risk factor for a variety of inflammatory diseases. Thus, the aim of this study was to investigate the effects of a high-fat diet on the progression of MS in a validated animal model. Methods: Adult Wistar rats (N = 10/group) were randomly divided into four groups: (1) standard diet, (2) high-fat diet, (3) and (4) standard and high-fat diet for 45 days, followed by induction of experimental encephalomyelitis. Animals were evaluated for clinical symptoms of MS and biochemical tests, including total cholesterol (TC), triglyceride (TG), low- and high-density lipoprotein-cholesterol (LDL-C and HDL-C), fibrinogen, interferon-gamma (IFN-γ), and interleukin-17 (IL-17). Tissue samples were subjected to neuropathological evaluation. The analysis was performed by one-way analysis of variance (ANOVA). Results: The high-fat diet increased the progression of experimental autoimmune encephalomyelitis (EAE) disease, INF-γ (approximately 1.5 folds), IL-17 levels (approximately 3 folds), lymphocyte proliferation, TG (approximately 40 folds), TC (approximately 80 folds), LDL-C (approximately 14 folds), and fibrinogen levels (approximately 100 folds), but HDL-C (approximately 40 folds) was decreased ( P < 0.05) in the affected MS group compared to standard diet. Conclusions: This study demonstrates that a high-fat diet significantly worsens clinical and immunological outcomes in an animal model of MS. The elevation of pro-inflammatory cytokines, particularly IFN-γ and IL-17, suggests that dietary fat may promote an inflammatory environment that accelerates disease progression. These findings highlight the need for further research to elucidate the underlying mechanisms.

Background: A well-constructed hypothesis is central to scientific knowledge, guiding the research process from a problem to its potential solution. This paper aims to provide a brief history of the scientific hypothesis, emphasize its central role in hypothesis-driven research, and outline the characteristics of a well-formulated scientific hypothesis. Methods: We conducted a narrative review of philosophical and scientific literature to examine the evolution of hypothesis formulation within the hypothetico-deductive (HD) framework, with emphasis on Karl Popper’s principles of falsifiability and deduction. Findings: The HD method remains the cornerstone of scientific inquiry, with hypothesis formulation serving as a critical link between theory and empirical testing. The 5E rule, which is a framework that defines an effective research hypothesis as Explicit, Evidence-based, Ex-ante, Explanatory, and Empirically testable, ensures that hypotheses are clear, relevant, and actionable within scientific investigation. Conclusion: Despite its importance, hypothesis formulation is often underemphasized in modern biomedical research, where many struggle to construct well-defined, testable hypotheses.

This study aims to evaluate the long-term dose-dependent effects of sodium nitrate on serum ALT, AST, and ALP in healthy female and male rats. A total of 120 rats (60 females and 60 males) were divided into 6 subgroups (n = 10). In each sex, a control group received regular tap water, while five treatment groups received sodium nitrate in tap water (50, 100, 150, 250, and 500 mg/L). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and nitric oxide (NO) metabolites (NOx) were measured at baseline (month 0) and after 6 mo. Hormetic zones for sodium nitrate in female rats were 10–230 mg/L for ALT, 20–180 mg/L for AST, and 8–270 mg/L for ALP. In males, the zones were 5–190 mg/L for ALT, 7–180 mg/L for AST, and 7–265 mg/L for ALP. Serum NOx levels were negatively correlated with ALT (r = −0.498) and AST (r = −0.320) at moderate doses (100–150 mg/dL) but positively correlated with ALT (r = 0.500) and AST (r = 0.300) at higher doses (250–500 mg/dL (all P < 0.05). Sodium nitrate exhibited a J-shaped dose–response relationship with liver function tests (LFTs) in both female and male rats. Protective effects were observed at moderate doses (100 mg/L for ALT and AST; 150 mg/L for ALP), while low doses (200 mg/L for ALT/AST; >250 mg/L for ALP) were toxic. These findings highlight the dual potential of sodium nitrate as both beneficial and harmful, depending on the dosage in healthy state.