MOLECULAR AND CELLULAR INFLAMMATORY MODULATORS GOVERNING WOUND HEALING AND TISSUE REPAIR

MOLECULAR AND CELLULAR INFLAMMATORY MODULATORS GOVERNING WOUND HEALING AND TISSUE REPAIR

Shweta Aher, Nisha Prasad, Pallavi Pujari, Komal Salunke and Malati Salunke *

Department of Pharmacognosy, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India.

ABSTRACT: Inflammation is a critical protective response that involves a complex network of inflammatory modulators, which coordinate the body's detection, reaction to, and repair of tissue damage or infection. These modulators include cytokines, chemokines, adhesion molecules, lipid mediators, neuroimmune signals, and emerging regulators such as A3 adenosine receptors, formyl peptide receptors, CCN (cellular communication network) proteins, microRNAs, and the Nrf2 (Nuclear factor erythroid 2-related factor 2) pathway. These components work together to initiate and guide immune responses, ensuring effective tissue communication and resolution of inflammation. When functioning properly, inflammation supports healing, but when imbalanced or overactive, it can lead to chronic inflammatory diseases such as arthritis, cardiovascular disorders, autoimmune conditions, and metabolic dysfunction. Understand operate and interact has enabled the development of targeted therapies, including cytokine inhibitors and receptor specific drugs, to restore immune balance. Inflammatory modulators form an interconnected system that determines the intensity, duration, and outcome of inflammation, making them essential targets for improving treatments of chronic inflammatory conditions.

Keywords: Wound Healing, Receptor, Pathways, Anti- inflammatory Mediator

INTRODUCTION: Inflammation is one of the most complex and essential biological processes, acting as the body's immediate defence mechanism against harmful stimuli such as microbial invasion, physical injury, chemical exposure, and cellular stress ¹. It is deeply embedded in human physiology, orchestrated through a sophisticated communication system of molecular messengers known as inflammatory modulators ².

These modulators include classical agents such as pro-inflammatory and anti-inflammatory cytokines, chemokines, adhesion molecules, and lipid mediators, as well as emerging regulators that add depth and complexity to the inflammatory network ^{3, 4}.

When a harmful event occurs, the body detects it through pattern recognition receptors, triggering a cascade in which pro-inflammatory cytokines like T N F-IL-1 and IL-6 rapidly activate immune pathways, increase vascular permeability, and initiate the recruitment of leukocytes to the affected site ^5–7. Chemokines act as directional signals, ensuring these immune cells migrate accurately toward the site of inflammation, while adhesion molecules allow their controlled exit from the bloodstream into tissues. Lipid mediators such as prostaglandins and leukotrienes coordinate the early inflammatory response but also contribute to preventing excessive inflammation through specialized pro-resolving mediators ^{8, 9}. Beyond these well-established players, scientific advancements have uncovered newer modulators that shape inflammation at genetic, cellular, and systemic levels. For example, the A3 adenosine receptor fine-tunes inflammation by regulating cell survival and cytokine release under stress, while the formyl peptide receptor responds directly to infection-associated signals and promotes phagocytic activity ¹⁰. CCN family proteins influence cell migration, adhesion, and tissue remodelling during inflammatory episodes, contributing to wound healing and fibrosis. MicroRNAs add a post-transcriptional layer of control by turning genes on or off depending on the inflammatory environment, and the Nrf2 signalling pathway helps limit oxidative stress and enhance cellular resilience ¹¹.

These components function in a precise yet delicate balance, allowing inflammation to protect and repair tissues while preventing unnecessary damage ¹². However, when this balance is disrupted, acute inflammation may transition into a chronic state that silently damages organs over time. Prolonged cytokine elevation, continuous immune cell recruitment, and persistent oxidative stress are all factors that contribute to conditions such as rheumatoid arthritis, atherosclerosis, Type 2 diabetes, inflammatory bowel disease, Alzheimer’s disease, and several autoimmune disorders ¹³. Such chronic conditions often arise when regulatory mechanisms fail to resolve inflammation effectively, allowing harmful signalling to dominate. Understanding this shift from protective to pathological inflammation is essential for developing more effective therapeutic strategies. Modern treatments, including T N F inhibitors, IL-6 blockers, integrin-blocking drugs, and agents that activate Nrf2 pathways, demonstrate how targeting specific inflammatory modulators can significantly improve clinical outcomes ^{14, 15}. As research continues to uncover how these modulators interact and influence one another, the possibility of personalized anti-inflammatory therapies grows stronger. Studying inflammatory modulators is therefore not only essential for understanding the biology of healing and disease but also for developing next-generation interventions that can precisely regulate the immune response without compromising the body's natural defence mechanisms ^16–18. This introduction aims to provide a comprehensive foundation for understanding the vast landscape of inflammatory modulators, their mechanisms, and their profound impact on both health and disease, ultimately highlighting why they stand at the centre of modern anti-inflammation ¹⁹.

Some natural anti-inflammatory mediators helps to reduce the oxidative stress such as diosgenin has qualities that help fight oxidative stress and lessen inflammation. Numerous disorders, including diabetes, obesity, irregularities in blood and brain function, and allergy diseases, may benefit from it ²⁰. Poor wound healing in diabetic patients is associated with several diseases, including neuropathy, vascular disease, and deformities of the feet. At the cellular level, epidermal migration, an increase in acute inflammatory cells, and a decrease in cellular proliferation have all been observed. These biological changes might make people more vulnerable to wound infection. Improving and planning for the care of chronic wounds has been increasingly important in recent decades in an effort to extend life and improve human quality of life ²¹.

Cellular Receptors Modulating Wound Healing: Upon an injury, the coagulation cascade is activated and endothelial cells and platelets engage immediately, causing clotting. Neutrophils and macrophages are drawn from the bloodstream as a result of an inflammatory response driven by mediators secreted during this early period. These cells then release growth factors and proinflammatory cytokines, which attract stromal cells and cause them to undergo division into myofibroblasts, which are in charge of wound healing and extracellular matrix deposition. These cells have a tendency to promote the proliferation of endothelial and epithelial cells in the wound site, resulting in neoangiogenesis and re-epithelialization, respectively. Tissue repair proceeds toward and concludes with scarring following the removal of clots and tissue debris by macrophages and extracellular hydrolases (matrix metalloproteases, elastase, and plasmin) ^{22, 23}.

FIG. 1: INTERPLAY OF IMMUNE CELLS, RECEPTORS, AND SIGNALLING PATHWAYS DURING WOUND REPAIR

Toli-like Receptors: Toll-like receptors (TLRs) occupy a central position in both the initiation and fine-tuning of the innate immune response. They are expressed across a broad range of skin-resident immune and non-immune ²⁴. Cells and their importance in host defence stems from their ability to modulate both innate and adaptive immunity. TLRs are found on diverse cell populations, including macrophages, neutrophils, dendritic cells, Langerhans cells, mast cells, lymphocytes, endothelial cells, keratinocytes, and fibroblasts. As prototypical pattern recognition receptors (PRRs), they are capable of detecting pathogen-associated molecular patterns (PAMPs) and other foreign ligands, making them indispensable sentinels at the interface of the host and the external environment ²⁵.

Chemokine Receptors: Chemokines are a family of small secreted proteins, typically ranging from 7 to 13 kDa in molecular weight, that have been shown to regulate a wide spectrum of biological processes beyond immune cell trafficking including angiogenesis, chemotaxis, and homeostasis. They are crucial in guiding the healing and closure of wounds. Based on the structural features they possess, the chemokine family is divided into four subfamilies ^26–28. Chemokines exert critical immunostimulatory effects during wound healing: platelet activation and the subsequent release of chemokines such as CXCL2 and CXCL8 stimulate neutrophils and monocytes, which in turn secrete additional chemokines including CCL2, CCL3, CCL4, and CCL5. This secondary release further activates lymphocytes, keratinocytes, and endothelial cells, amplifying and sustaining the reparative response ²⁹.

Formyl Peptide Receptors: Gi-protein-coupled receptors (GPCRs) comprise the family of seven transmembrane domains known as formyl-peptide receptors (FPRs). FPR1, FPR2, and FPR3 are the three FPRs found in humans. Several chemoattractants regulate the neutrophil accumulation ³⁰, such as IL-8 (CXCL8), CXCL7, and CXCL1, which rely on neutrophil-expressed CXCR2. However, in both humans and mice, neutrophils also express FPR1 (Fpr1) and FPR2 (Fpr2). Fpr1/Fpr2 are the first to detect chemotaxis signals in a mouse skin-wound healing model, which leads to rapid neutrophil infiltration. When agonists generated at the site of injury activate FPR1/FPR2 (Fpr1/Fpr2), a signaling cascade is triggered, leading to neutrophil migration, enhanced phagocytosis, and superoxide production ³¹.

Integrin Receptors: Integrins represent the principal molecular mediators of cell attachment to the extracellular matrix (ECM) ³². Based on their ligand specificity and/or phylogenetic comparison of the α subunits, integrins can be categorized into four subfamilies ⁶⁶. Integrin heterodimers exist in all multicellular organisms and are able to recognize the arginine-glycine-aspartic acid (RGD) pattern in extracellular ligands. The integrins α3β1, α6β1, α7β1, and α6β4 that belong to the laminin receptor subfamily can mediate cellular attachment to basement membranes in a variety of tissues. Integrins α4β1, α4β7, and α9β1 constitute a distinct subfamily. They are able to identify RGD-independent ECM ligands like fibronectin. Various kinds of wound cells interact actively with one another. Integrins and ECM proteins are important components of these interactions ³³. For instance, eliminating monocytes and neutrophils. For instance, in mice, skin wound re-epithelialization is delayed when neutrophil and monocyte integrin αMβ2 is eliminated, but it is accelerated when αvβ3 integrin, which is expressed in wounds by platelets, endothelial cells, macrophages, and fibroblasts, is eliminated ³⁴.

Pathways Involved in Healing:

The Signalling Pathway MAPK: The MAPK (Mitogen-Activated Protein Kinase) pathway is organized as a three-tiered kinase module comprising the MAPK itself, a MAPK kinase (MEK or MKK), and a MAPK kinase kinase (MEKK or MKKK). Sequential and coordinated activation of these three enzymatic layers enables the pathway to regulate a diverse array of physiological and pathological outcomes, including cell growth, differentiation, stress responses, and inflammatory cascades. The MAPK framework branches into four primary signalling arms: ERK, JNK, p38/MAPK, and ERK5. In the context of wound repair, activation of the MAPK signalling pathway has been shown to accelerate healing by promoting cell migration and proliferation at the wound site ³⁵.

PI3K/AKT Signalling Pathway: PI3K is a cytosolic lipid kinase that participates in cellular membrane metabolism, intracellular transport, and signal transduction. Structurally, it exists as a heterodimer composed of a regulatory subunit (p85) and a catalytic subunit (p110). Upon binding to growth factor receptors such as EGFR, PI3K induces conformational changes in AKT, thereby activating it. Activated AKT subsequently phosphorylates a range of downstream substrates including the apoptosis-regulating proteins Bad and Caspase-9 to govern cell proliferation, differentiation, survival, and migration. Additionally, protein kinase B (AKT) can initiate crosstalk with the NF-κB pathway through IKK activation. The downstream targets of PI3K/AKT include the mammalian target of rapamycin (mTOR) and transcription factors such as FoxO (Forkhead Box O), HIF-1α, and c-MYC. Wound healing has a particularly close functional relationship with PI3K/AKT signalling ³⁶.

TGF - β Signalling Pathway: The TGF-β (Transforming Growth Factor-beta) family comprises secreted polypeptide signalling proteins that govern cell proliferation, differentiation, apoptosis, and wound repair. Within this pathway, the primary signal sources are TGF-β1, TGF-β2, TGF-β3, and BMPs (bone morphogenetic proteins), while Smad proteins serve as the canonical downstream transcriptional effectors. Evidence suggests that inhibiting TGF-β signal transduction may facilitate faster and potentially scarless wound closure ³⁷. TGF-β1 in particular is a master regulator of scar formation and wound healing: it promotes fibroblast proliferation and the conversion of stromal cells into fibroblasts. Furthermore, TGF-β1 drives the differentiation of fibroblasts into myofibroblasts, a process that is instrumental in wound contraction and closure ^38-40.

NF-kB Signalling Pathway: The NF-κB signalling network is a master regulatory system that underpins the body's inflammatory response and is involved in the initiation and progression of numerous inflammatory diseases. Once translocated to the nucleus, activated NF-κB binds to promoter and enhancer elements of target genes, driving adhesion molecule production in endothelial cells and stimulating leukocyte and fibroblast proliferation alongside the broader inflammatory response ^{41, 42}. This pathway also exerts considerable influence over wound healing through its regulation of vascular regeneration. Studies have demonstrated that NF-κB signalling controls VEGF (Vascular Endothelial Growth Factor) transcription, such that pharmacological blockade of NF-κB activation leads to a marked reduction in VEGF expression and capillary network formation ⁴³.

New Paths and Targets:

Cytokine Signalling: Cytokines are the chemical communication molecules that cells employ to convey signals to one another. While this term was historically associated primarily with immune function, its scope is considerably broader ⁴⁴. Structurally, cytokines are classified into two major categories: Type I and Type II. Type I cytokines share a characteristic four-alpha-helix bundle architecture ⁴⁵ and perform critical regulatory functions throughout the immune system. Type II cytokines, a category that includes interferons, participate in distinct biological processes. Importantly, cytokine classification does not restrict their functional reach — these molecules exert regulatory influence across a wide variety of cell types and physiological systems ⁴⁶.

JAK/STAT Pathway: The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signalling pathway is vital for conveying messages from cytokines to the cell’s interior. Initially linked to interferons, this pathway helps regulate immune responses ⁴⁷. When conditions are right, specific kinases (called JAKs) become active and begin a cascade of reactions that lead to gene expression changes in the nucleus ^{48, 49}. There are different JAK types, and they play specific roles in signalling pathways that affect immune cell functions. Once activated, STAT proteins are crucial for transmitting these signals and can even influence gene activity by binding to specific DNA regions. This pathway not only supports immune function but also impacts various bodily processes, highlighting the intricate ways our cells communicate and operate ⁵⁰.

NLRP3 Inflammasomes and Inflammation: NLRP3 (NLR family pyrin domain containing 3) inflammasomes area part of our innate immune system that can respond to various stimuli. Unlike other inflammasomes that react to specific triggers, NLRP3 is quite versatile and can engage with numerous different signals related to danger or infection. It works through a two-step process: a priming phase that gets it ready and an activation phase where it responds to signals like cell damage or pathogens. This activation influences inflammatory responses, which is essential for fighting infections but can also lead to issues if not controlled. Learning about how NLRP3 works helps us understand the complexities of our immune reactions and how they can sometimes go awry, leading to diseases ⁵¹. In summary, the advances in personalized healthcare, nanotechnology, epigenetics, microbiome studies, and understanding immune signalling pathways, among others, are paving the way for innovative treatments and better health outcomes.

Natural Anti-Inflammatory Modulators: Numerous disorders, including as allergies, cardiovascular dysfunction, metabolic syndrome, cancer, and autoimmune diseases, which have a substantial financial impact on both people and society at large, are primarily caused by an unregulated inflammatory response. This is true despite the fact that inflammation is a protective process our body performs in reaction to damaging stimuli such as allergens and/or tissue damage ⁵². Numerous medications are available to regulate and suppress inflammatory crises; immuno-suppressants, steroids, and nonsteroid anti-inflammatory drugs are practical examples of these drugs that have side effects. In practice, however, we aim to apply the lowest effective dose with the most effectiveness and the fewest side effects. Therefore, to maximize pharmaceutical efficacy and minimize undesirable side effects, we must incorporate natural anti-inflammatory agents into prescription therapy. Prescription medication must include natural anti-inflammatory ingredients to optimize drug effectiveness and reduce unwanted side effects. Naturally, since herbal remedies are increasing medical research, we need to learn more about them. Complementary, alternative, and traditional medicine are the main sources of recommendations for herbal drugs; nevertheless, modern medicine must first validate these suggestions through scientific methods before putting them into practice. Many inflammatory mediators are generated and released during different types of inflammatory reactions ^{53, 54}.

Turmeric: Curcumin, also known as 1,7-bis(4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5-dione, is a chemical compound with anti-inflammatory, anti-oxidant, and anti-tumour properties. Curcumin's anti-inflammatory qualities are thought to be the foundation of its many biological actions and are crucial in the management of illnesses ⁵⁵.

Curcumin is mostly obtained from the rhizome of Curcuma longa L. (Turmeric) of the Zingiberaceae family and the root tuber of Curcuma aromatica Salisb. In China, these traditional Chinese remedies have long been used to treat pain, inflammation, and other illnesses by increasing blood flow and removing blood stasis. In India, turmeric is a popular spice that has been used in Ayurveda to treat inflammatory conditions ^{56, 57}.

Inducers, sensors, mediators, and effectors are the four parts of the inflammatory process. Different inflammatory triggers cause different physiological and pathological mechanisms of inflammation, which are currently unknown. Generally speaking, the main methods that drugs reduce inflammation include: controlling how target tissues react to inflammatory mediators; generating anti-inflammatory mediators; reversing the medium's effect on the target tissue; and influencing receptors and signaling cascades. By regulating inflammatory signaling pathways and inhibiting the production of inflammatory mediators, curcumin has anti-inflammatory properties ⁵⁸.

Curcumin binds to Toll-like receptors (TLRs) and modifies downstream nuclear factor kappa-B (NF-κB), mitogen-activated protein kinases (MAPK), activator protein 1 (AP-1), and other signaling pathways to regulate inflammatory mediators and cure inflammatory diseases. Curcumin inhibits NF-κB via acting on Peroxisome proliferator-activated receptor gamma (PPARγ) ^{59, 60}.

By controlling the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) inflammatory signalling pathway, curcumin can also have anti-inflammatory effects ^{61, 62}.

Furthermore, a number of inflammatory illnesses are influenced by the cytosolic multiprotein complexes known as the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. The NLRP3 complex is composed of a protease known as caspase-1, an apoptosis-associated speck-like protein with a caspase recruitment domain, and a sensor protein. One of curcumin's potential mechanisms for treating inflammatory illnesses is its ability to either directly reduce NLRP3 inflammasome assembly or inhibit NLRP3 inflammasome activation by inhibiting the NF-κB pathway ⁶³.

Ginger: It has been shown that both fresh ginger, which is mostly made up of gingerols, and dried ginger extracts, which are a major source of shogaols, can prevent the synthesis of prostaglandin E2 (PGE2) when lipopolysaccharide (LPS) is present ⁶⁴. Depending on the length of the side chains, 10-gingerol showed the highest inhibitory impact. This activity was ascribed to the inhibitory effects of 6-, 8-, and 10-gingerols on COX-2(Cyclooxygenase-2) mRNA expression and the corresponding COX-2 enzyme. However, it was discovered that the The 6-, 9-, and 10-shogaols had a less noticeable inhibitory effect on the expression of COX-2 mRNA. In a rat paw edema model caused by carrageenan, the anti-inflammatory properties of ginger extract were evaluated at different dosages. The findings showed that in a dose-dependent manner (25-200 mg/kg), the extract decreased the levels of inflammatory mediators PGE2, TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), and myeloperoxidase (MPO) by 32% to 60%. 6-SG was more effective than other shogaols, and ginger extract's anti-inflammatory properties were shown to be noticeably stronger than diclofenac's at the same concentration. Ginger extract enhanced overall antioxidant capacity and inhibited carrageenan-induced histopathological damage at a dose of 200 mg/kg ⁶⁵. According to the scientists, the primary mechanisms underlying ginger extract's anti-inflammatory properties are the stimulation of inflammatory cells and the inhibition of cell migration ^66–69.

6-GN was found to  inhibit the expression of TNF-α and inducible nitric oxide synthase (iNOS) in mouse macrophages stimulated by LPS, lower the levels of IL-6, IL-8, and ROS in hepatic HuH7 cells stimulated by IL-1β, lower the levels of IL-8, IL-6, IL-1β protein, and mRNA in intestinal epithelial cell inflammation caused by Vibrio cholerae, and (iv) decrease the secretion and expression of TNF-α, IL-1β, IL-6, PGE2, COX-2, and iNOS in murine RAW 264.7 monocyte/macrophage-like cells exposed to LPS, and (v) decreased the expression of iNOS and COX-2 protein in murine skin cells exposed to 12-O-tetradecanoylphorbol 13-acetate (TPA) either by changing or blocking a signalling pathway mediated by NF-θB (nuclear factor kappa-light-chain-enhancer of activated B cells) or by interacting with different endogenous mediators like PI3K/Akt/I kappaB kinases (IKK) and MAPK. Furthermore, it has been observed that 6-GN's anti- inflammatory properties are facilitated by its inhibitory action on the COX-2 enzyme ⁷⁰.

Ashawagandha: Withaferin's presence results in anti-inflammatory activity. The compounds 3-b-hydroxy-2,3-dihydrowithanolide F and withaferin A, which were extracted from Withania somnifera, exhibit encouraging antibacterial, antitumoral, immunomodulatory, and anti-inflammatory qualities.

Numerous conditions linked to inflammation in the body, including diabetes, cancer, neuro-degenerative illnesses, pulmonary, cardiovascular, and autoimmune disorders, are being researched in relation to Withania somnifera. Preclinical research has shown that this plant can control apoptosis and mitochondrial function while lowering inflammation by blocking inflammatory indicators such reactive oxygen species, nitric oxide, and cytokines like TNF-a and IL-6 ⁷¹.

In a mouse model of lupus, ashwagandha root powder was demonstrated to have a potential inhibitory effect in conditions such as proteinuria and nephritis. In a study using the HaCaT (human keratinocyte cell line), an aqueous solution from ashwagandha root was found to inhibit the NF-κB and MAPK (mitogen-activated protein kinase) pathways by increasing the expression of anti-inflammatory cytokines and decreasing the expression of pro-inflammatory cytokines like interleukin (IL)-8, IL-6, tumor necrosis factor (TNF-α), IL-1β, and IL-12. These results suggest that ashwagandha's anti-inflammatory qualities may be used to reduce skin irritation 72.

Animals administered Ashwagandha water extract (ASH-WEX) showed decreased reactive gliosis, inflammatory cytokine production (TNF-α, IL-1β, and IL-6), and nitro-oxidative stress enzyme expression in a preclinical study of the anti-neuroinflammatory properties of ASH-WEX against lipopolysaccharide-induced systemic neuroinflammation. Lipopolysaccharide (LPS)-induced regulation of the NFκB, P38, and JNK/SAPK MAPK pathways seems to be the molecular mechanism behind ASH-WEX's anti-inflammatory effects. According to the study's findings, Withania somnifera may be used to reduce inflammation in the nervous system linked to a number of neurological conditions ⁷³.

Green Tea: According to recent research, polyphenols have anti-inflammatory and antioxidant qualities that improve health and help treat disorders linked to inflammation ⁷⁴. A variety of actions are produced by the absorption, metabolism, and delivery of polyphenolic chemicals to specific tissues or organs ^{75, 76}. By interacting with receptors on the surfaces of immune cells and enterocytes, the unabsorbed polyphenols can prevent pro-inflammatory signals. The gut microbes can metabolize the unabsorbed polyphenols ⁷⁷. Unabsorbed polyphenols and their metabolites can either reduce local inflammation or serve as prebiotics to encourage the growth of good bacteria, which will improve gut health. By directly functioning as antioxidants, triggering cytoprotective mechanisms, and blocking proinflammatory signaling transduction, dietary tea polyphenols have been shown to lower inflammation ⁷⁸.

Resveratrol: Enzymes and pathways that generate inflammatory mediators and trigger the death of activated immune cells are regulated in part by RV. In this way, RV serves as a powerful anti-inflammatory and potential source of cancer treatment ⁷⁹. RV treatment has significantly reduced brain damage and decreased important inflammatory markers at the mRNA and proteomic levels. It has also been observed that the expression of Bcl-2(B-cell lymphoma 2), caspase3, and Bax-linked genes has changed. In rats with polycystic kidney disease, RV reduced blood urea nitrogen and creatine levels while lowering "two kidney/total body weight and density of cyst volume." Additionally, the investigation revealed decreased monocytic chemoattractant protein-1 (MCP-1) levels. Pro-inflammatory factors include complement factor B (CFB) and TNF-α. By disrupting the pathway of the NF-κB signal, NF-κB (p50/p65) function was reduced 80.

Pro-inflammatory mediator triggering is lessened as a result of increased short-term expression of MyD88 (Myeloid Differentiation primary response 88). In mouse animal models, NTHi (Haemophilus influenza) did not activate the component MyD8 by inhibiting ERK1/2 expression. According to some experts, there is a non-steroidal activity that can be used therapeutically to treat a variety of illnesses that have a direct or indirect relationship to inflammatory diseases, either alone or in combination ^{81, 82}.

Frankincense: The anti-inflammatory and anti-cancer properties of Boswellia species and their chemical compounds include 3-O-acetyl-11keto-β boswellic acid, α- and β-boswellic acids, 11-keto-β-boswellic acid and other boswellic acids, lupeolic acids, incensole, cembrenes, triterpenediol, tirucallic acids, and olibanumols. Frankincense operates by inhibiting a variety of processes, including oxidative stress, cyclooxygenase 1/2 and 5-lipoxygenase, leukotriene synthesis, and immune cell regulation from the innate and acquired immune systems. Frankincense also suppresses angiogenesis, invasion, metastasis, and proliferation via altering the transmission of signals that result in stoppage of the cell cycle Clinical research has discovered that le and its phytochemicals are useful against a variety of conditions, including osteoarthritis, multiple sclerosis, asthma, psoriasis, erythematous dermatitis, plaque-induced gingivitis, and irritation. While it had a beneficial effect on oedema related to brain tumors, frankincense did not reduce the size of gliomas. It has been demonstrated that the immune system benefits from decreased neutrophilic granulocyte invasion, mast cell stabilization, dropped T-effector cell differentiation and increased T-regulatory cell differentiation, decreased platelet Ca2+ mobilization, decreased immune cell and platelet infiltration in inflammatory tissues, and decreased leukocyte and its cell adhesive reaction ⁸³.

Capsaicin: Capsaicin, the active ingredient in chilli peppers produced from plants in the genus Capsicum, is the most frequently eaten chilli in the world. A naturally occurring chemical group consisting of capsaicin and related compounds is called capsaicinoids. Primarily having anti-pain, anti-inflammatory effects. Dura mast cells are activated and vascular permeability is increased by trigeminal nerve stimulation; capsaicin inhibits these effects. Vasodilation, catecholamines, and sensory neuropeptides are released when capsaicin is taken. According to numerous studies, capsaicin effectively reduces blood pressure and cholesterol, enhances digestion, helps prevent cardiovascular illness, and relieves and prevents migraine headaches. The pathophysiology and potential treatment of neuroinflammatory diseases may be affected by the results of these investigations ⁸⁴.

Quercetine: Green tea, onions, and apples are among the plants and vegetables that contain quercetin, a flavonoid component. For example, quercetin, quercetin-3-O-βglucoside (Q3G), quercetin-4ʹ-O-β-glucoside (Q4ʹG), and quercetin-3,4ʹ-di-O-β-glucoside (Q3,4ʹG) have been identified as the predominant onion flavonoids 5. It's interesting to note that cooking techniques have an impact on the final flavonoid content; boiling lowers the levels of Q4ʹG, whereas microwave heating for oneminute increases the overall quercetin abundance by 1.5 times. atherosclerosis: Quercetin reduces cellular lipid buildup, enhances autophagy, and inhibits mammalian Ste20-like kinase 1 (MST1) during the course of atherosclerosis by suppressing the generation of ox-LDL-induced RAW264.7 macrophage foam cells, a model for foam cells. In human umbilical vein endothelial cells (HUVECs), a model of vascular endothelial damage in the early stages of atherosclerosis, quercetin ameliorates glucosamine-induced apoptosis and inflammation. Quercetin and docosahexaenoic acid (DHA) together inhibit the phosphorylation of ERK1/2 and JNK1/2, as well as the mRNA expression of NF-κB subunits p50 and p65, in LPS-stimulated ⁸⁵.

Pycnogenol: According to some, pycnogenol has beneficial pharmacological properties since it contains procyanidins, phenolic acids, bioflavonoids, and catechins. These qualities include antioxidant and anti-inflammatory properties. Flavonoids, mainly procyanidins and phenolic chemicals, make up the well-known strong antioxidant pycnogenol. Several procyanidins from the bark of French maritime pines (Pinus pinaster) are found in pycnogenol, a standardized extract. The ability of pycnogenol to reduce oxidized ascorbate is probably going to boost the vitamin's activity in the vicinity of the wound, encouraging the production of collagen. The high binding of pycnogenol components to collagen and their potent inhibitory effect on matrix metalloproteinases (MMPs) likely play a significant role in wound healing. Pycnogenol will also aid in the inflammatory, or early, stage of the wound-healing process ⁸⁶.

Cannabidiol: Hemp, or Cannabis sativa L., is a perennial herbaceous plant that belongs to the Cannabaceae family. The flowery tops contain the largest concentration of cannabinoids, such as delta-9 tetrahydrocannabinol and cannabidiol (CBD), a cannabinoid that does not produce a psychoactive effect. CBD did not influence IL-8 release, in contrast to VEGF release, which solely shown an inhibitory trend. A concentration-dependent decrease of MMP-9 was observed with 50% inhibition at 5 μM, suggesting that CBD inhibited the extract's ability to stimulate the release of MMP-9 (Matrix Metallopeptidase 9) ⁸⁷. CBD usually suppresses the immune system and lowers inflammation, but it can also increase cytokine production in certain conditions. THC and CBD both reduced or boosted the production of IFN-γ and IL-2 by mouse splenocytes under optimal or suboptimal stimulation.

It has been established that these two cannabinoids either increase or decrease HIVgp120-specific T cell responses. A recent study found that ajulemic acid was synthesized with great care, resulting in a molecule that exhibited anti-inflammatory qualities but was essentially devoid of CB1 action. HU-320 and HU-239 showed anti-inflammatory therapeutic effects in a mouse model of collagen-induced arthritis, but none of them showed a cannabimetic profile in-vivo. It stopped the in vitro production of TNF-a by RAW 264.7 cell ROIs and murine macrophages. Additionally, it stopped serum TNF-a levels from rising following an LPS attack ⁸⁸.

Devil's Claw: The mother tuber, the main tuber of the perennial tuberous plant Devil's claw, has a taproot that can reach a depth of two meters, and creeping annual stems originate from it. Devil's claw extract successfully lowered a number of oxidative stress and inflammatory indicators, including prostanoid, cytokine, and serotonin colon levels, demonstrating that the extract can potentially be used to treat ulcerative colitis ⁸⁹. Pure harpagoside's mode of action demonstrated that it moderately reduced the arachidonic acid pathway's cyclooxygenases 1 and 2 (COX-1/2) and nitric oxide production in human blood. In accordance with the concentration of each component, devil's claw can have a range of medicinal effects, although harpagoside is the main ⁹⁰.

TABLE 1: NATURAL ANTI-INFLAMMATORY MODULATORS

TABLE 2: NATURAL ANTI-INFLAMMATORY MODULATORS

TABLE 3: NATURAL ANTI-INFLAMMATORY MODULATORS

Inflammatory Modulators Risk and Side Effects: The gastrointestinal mucosa, cardiovascular system, hepatic system, renal system, and hematologic system are all known to be harmed by NSAIDs.

The suppression of COX-1, which stops the synthesis of prostaglandins that shield the gastric mucosa, might be the cause of the negative consequences in the stomach. Patients with a history of peptic ulcers are more prone to sustain harm. The usage of COX-2 selective NSAIDs is a less hazardous alternative because it is COX-1 specific ⁹⁸.

Because COX-1 and COX-2 promote prostaglandin synthesis, which affects renal hemodynamics, there are unfavorable effects on the kidneys. In patients with normal renal function, lowering prostaglandin synthesis does not pose any significant concerns; however, in patients with renal failure, prostaglandins become very important and can create problems when suppressed with NSAIDs. Among the potential consequences include renal papillary necrosis, nephrotic syndrome/interstitial nephritis, acute renal failure, and fluid and electrolyte deficits ⁹⁹.

NSAID use might increase the chance of cardiovascular side effects, such as atrial fibrillation, thromboembolic events, and MI. The NSAID with the most documented increase in adverse cardiovascular events appears to be diclofenac ¹⁰⁰.

Hepatic side effects are less likely; hospitalization for liver-related reasons is extremely rare, as is the risk of hepatotoxicity (higher aminotransferase levels) linked with NSAIDs.

New Trends in Healthcare:

Personalized Healthcare: You might have heard about the buzz around personalized healthcare, which is all about tailoring medical treatments to each individual’s specific needs and traits. It’s often confused with precision medicine, but they aren’t exactly the same ¹⁰¹. The term personalized medicine first popped up in an article by a Canadian doctor back in 1971, where he stressed treating patients as unique individuals rather than just focusing on their diseases. Fast forward to the late ‘90s, when the Human Genome Project made significant strides, and suddenly, personalized medicine was the talk of the town.

The Wall Street Journal even featured a piece titled New Era of Personalized Medicine: Targeting Drugs for Each Unique Genetic Profile back in April 1999, putting this fresh concept on the map ¹⁰². Nowadays, personalized medicine involves making key decisions regarding disease prevention, diagnosis, and treatment based on a person’s genetic makeup. It’s revolutionary in how we view and handle healthcare today ¹⁰³.

Nanotechnology in Medicine: Let’s talk about nanotechnology, which uses tiny materials like nanoparticles and nanorobots in medicine. This field, known as nanomedicine, plays a significant role in diagnosing and treating diseases. Often, drugs don’t perform well in the body because they don’t dissolve or circulate effectively. Nanotechnology can help solve these issues. By designing drugs at a nanoscale, scientists can tackle challenges such as poor drug absorption, unwanted side effects, and the need for higher doses ¹⁰⁴. The beauty of nanotechnology lies in its ability to make drug delivery easier, less toxic, and more effective. It essentially helps in delivering medications directly to the right parts of the body, letting them do their job without affecting other areas. Some advanced drug systems are crafted to release their contents in response to specific triggers, making treatment much more efficient ¹⁰⁵.

Epigenetic Controls: Now, let’s dive into epigenetics. This fascinating area focuses on how certain chemical changes can impact gene expression without altering the underlying DNA sequence. Researchers have proposed that the various chemical modifications, known as epigenetic changes, create a sort of code that finely tunes the structure of our DNA ¹⁰⁶.

For example, when specific proteins stick to DNA or histones, they can either promote or suppress gene activity. It’s been found that DNA methylation, which often occurs in gene promoter regions, is particularly important active genes usually have less methylation, while silenced genes tend to be hyper-methylated. This whole process can dictate a cell’s behavior and identity, which helps explain why different cell types, like skin or nerve cells, function so differently despite sharing the same DNA ¹⁰⁷.

The Microbiome’s Role: Did you know that the bacteria living in our gut play a vital role in our immune system? Research shows that mice without these gut bacteria (known as germ-free mice) face a variety of immune issues ¹⁰⁸. For example, they lack certain types of immune cells like Th17 and have a reduced ability to fight off infections. Interestingly, certain types of beneficial gut bacteria, like Clostridium, can help boost these immune cells ¹⁰⁹. They trigger the production of critical signalling molecules that promote the development of immune cells capable of defending against diseases like cancer. In fact, some studies have shown that the right mix of gut bacteria can even enhance the effectiveness of cancer treatments. As we learn more about these tiny allies, understanding their role in our health becomes increasingly important ¹¹⁰.

Stem Cell Therapy: Stem cells hold huge promise for treating a wide range of diseases. The ability of mesenchymal stem cells (MSCs), often referred to as mesenchymal stromal cells, to differentiate into many cell types, including fat, bone, and cartilage, makes them special ¹¹¹. They’re easy to find gathered from various tissues and are known for being pretty safe to use without serious ethical concerns. These cells don’t just sit around; they actively help heal the body through their ability to send important signals to other cells, reduce inflammation, and support new blood vessel growth. They’re currently investigation for treating conditions ranging from diabetes to heart disease and autoimmune illnesses. Even though we still have many questions about how best to use MSCs, their potential as a tool for cell therapy is undeniable ¹¹².

Patents:

TABLE 4: RECENT PATENTS ON INFLAMMATORY MODULATORS

Measuring Wound Healing: Wound contraction and macroscopic appearance were the two factors evaluated for excision wound healing. In order to assess the macroscopic appearance and wound contraction, the skin wound area was measured and photographed on days 0, 7, 14, and 21 after the damage ^{113, 114}. A digital camera (Sony Cybershot, Japan) was used to take pictures, and a digital calliper was used to measure the wounds ¹¹⁵.

CONCLUSION: Inflammation is a critical and tightly regulated process in wound healing, governed by cytokines, chemokines, cellular receptors, and key signalling pathways such as MAPK, PI3K/AKT, TGF-β, NF-κB, and JAK/STAT. Balanced inflammatory responses promote effective tissue repair, whereas dysregulation leads to delayed healing and chronic inflammatory conditions. Natural anti-inflammatory agents, including curcumin, ginger, resveratrol, and quercetin, demonstrate multi-targeted therapeutic potential with fewer adverse effects compared to conventional drugs. Advances in molecular targeting, nanotechnology, and personalized medicine offer promising strategies to enhance wound healing outcomes. A deeper understanding of inflammatory modulators is essential for developing safer and more effective therapeutic interventions.

ACKNOWLEDGMENTS: We would like to thank Dr. S.S. Kadam, Chancellor, Bharati Vidyapeeth (Deemed to be University), Dr. A. P. Pawar, Principal, BVDU Poona College of Pharmacy for providing the necessary facilities and support.

Data Availability: Not applicable.

Declarations:

Consent for Publication: Not applicable

CONFLICT OF INTEREST: The authors declare that they have no competing interests.

REFRENCES:

1. Abdulkhaleq LA, Assi MA and Abdullah R: The crucial roles of inflammatory mediators in inflammation: A review. Vet World 2018; 11: 627–635.
2. Brandt SJ, Götz A and Tschöp MH: Gut hormone polyagonists for the treatment of type 2 diabetes. Peptides (NY) 2018; 100: 190–201.
3. Ahmed SMU, Luo L and Namani A: Nrf2 signaling pathway: Pivotal roles in inflammation. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2017; 1863: 585–597.
4. Li B, Wang Y and Jiang X: Natural products targeting Nrf2/ARE signaling pathway in the treatment of inflammatory bowel disease. Biomedicine & Pharmacotherapy 2023; 164: 114950.
5. Brennan E, Kantharidis P, Cooper ME, et al. Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function. Nat Rev Nephrol 2021; 17: 725–739.
6. Sidibé H, Vande Velde C. RNA Granules and Their Role in Neurodegenerative Diseases 2019; 195–245.
7. Tan YF, Lao LL and Xiong GM: Controlled-release nanotherapeutics: State of translation. Journal of Controlled Release 2018; 284: 39–48.
8. Chen L, Yan G and Ohwada T: Building on endogenous lipid mediators to design synthetic receptor ligands. Eur J Med Chem 2022; 231: 114154.
9. Yang S, Li F and Lu S: Ginseng root extract attenuates inflammation by inhibiting the MAPK/NF-κBsignaling pathway and activating autophagy and p62-Nrf2-Keap1 signaling in-vitro and in-vivo. J Ethnopharmacol 2022; 283: 114739.
10. Pasquini S, Contri C and Borea PA: Adenosine and Inflammation: Here, There and Everywhere. Int J Mol Sci 2021; 22: 7685.
11. Xu S, Chen Y and Miao J: Esculin inhibits hepatic stellate cell activation and CCl4-induced liver fibrosis by activating the Nrf2/GPX4 signaling pathway. Phytomedicine 2024; 128: 155465.
12. Rasquel-Oliveira FS, Silva MDV da and Martelossi-Cebinelli G: Specialized Pro-Resolving Lipid Mediators: Endogenous Roles and Pharmacological Activities in Infections. Molecules 2023; 28: 5032.
13. Leuti A, Fazio D and Fava M: Bioactive lipids, inflammation and chronic diseases. Adv Drug Deliv Rev 2020; 159: 133–169.
14. Freire MO and Van Dyke TE: Natural resolution of inflammation. Periodontol 2000 2013; 63: 149–164.
15. Kilaru A and Chapman KD: The endocannabinoid system. Essays Biochem 2020; 64: 485–499.
16. Halade GV and Lee DH: Inflammation and resolution signaling in cardiac repair and heart failure. Ebio Medicine 2022; 79: 103992.
17. Loy CJ, Sotomayor-Gonzalez A and Servellita V: Nucleic acid biomarkers of immune response and cell and tissue damage in children with COVID-19 and MIS-C. Cell Rep Med 2023; 4: 101034.
18. Xia J, Wang D and Guo W: Exposure to micron-grade silica particles triggers pulmonary fibrosis through cell-to-cell delivery of exosomal miR-107. Int J Biol Macromol 2024; 266: 131058.
19. Cavalli R, Soster M and Argenziano M: Nanobubbles: A Promising Efficient Tool for Therapeutic Delivery. Ther Deliv 2016; 7: 117–138.
20. Lanjekar D, Salunke M and Mali A: Formulation and Evaluation of Topical Delivery Diosgenin Emulgel for Diabetic Wounds. Toxicol Int 2024; 111–119.
21. Salunke MR and Shinde V: Development and Characterization of Psoralen-Loaded PVP/PCL Electrospun Nanofibers for Wound Healing Applications. Bionanoscience 2025; 15: 509.
22. Cañedo-Dorantes L and Cañedo-Ayala M: Skin Acute Wound Healing: A Comprehensive Review. Int J Inflam 2019; 2019: 1–15.
23. Tottoli EM, Dorati R and Genta I: Skin Wound Healing Process and New Emerging Technologies for Skin Wound Care and Regeneration. Pharmaceutics 2020; 12: 735.
24. Miller LS and Modlin RL: Toll-like receptors in the skin. Semin Immunopathol 2007; 29: 15–26.
25. Sabroe I, Dower SK and Whyte MKB: The Role of Toll-Like Receptors in the Regulation of Neutrophil Migration, Activation, and Apoptosis. Clinical Infectious Diseases 2005; 41: 421–426.
26. Engelhardt E, Toksoy A and Goebeler M: Chemokines IL-8, GROα, MCP-1, IP-10, and Mig Are Sequentially and Differentially Expressed During Phase-Specific Infiltration of Leukocyte Subsets in Human Wound Healing. Am J Pathol 1998; 153: 1849–1860.
27. Rosenkilde MM and Schwartz TW: The chemokine system – a major regulator of angiogenesis in health and disease. APMIS 2004; 112: 481–495.
28. Brandt E, Petersen F and Ludwig A: The β-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation. J Leukoc Biol 2000; 67: 471–478.
29. Goebeler M, Yoshimura T and Toksoy A: The Chemokine Repertoire of Human Dermal Microvascular Endothelial Cells and Its Regulation by Inflammatory Cytokines. Journal of Investigative Dermatology 1997; 108: 445–451.
30. Foxman EF, Campbell JJ and Butcher EC: Multistep Navigation and the Combinatorial Control of Leukocyte Chemotaxis. J Cell Biol 1997; 139: 1349–1360.
31. Liu M, Chen K and Yoshimura T: Formylpeptide Receptors Mediate Rapid Neutrophil Mobilization to Accelerate Wound Healing. PLoS One 2014; 9: 90613.
32. Barczyk M, Carracedo S and Gullberg D: Integrins. Cell Tissue Res 2010; 339: 269–280.
33. Werner S, Krieg T and Smola H: Keratinocyte–Fibroblast Interactions in Wound Healing. Journal of Investigative Dermatology 2007; 127: 998–1008.
34. Johnson MS, Lu N and Denessiouk K: Integrins during evolution: Evolutionary trees and model organisms. Biochimica et Biophysica Acta (BBA) - Biomembranes 2009; 1788: 779–789.
35. Liu Z and Fang Y: Wound healing and signaling pathways. Open Life Sci; 20. Epub ahead of print 1 September 2025. DOI: 10.1515/biol-2025-1166.
36. Gan D, Su Q and Su H: Burn Ointment Promotes Cutaneous Wound Healing by Modulating the PI3K/AKT/mTOR Signaling Pathway. Front Pharmacol; 12. Epub ahead of print 8 March 2021. DOI: 10.3389/fphar.2021.631102.
37. Zhang J, Zheng Y and Lee J: A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing. Nat Commun 2021; 12: 1670.
38. Basu S, Kumar M and Chansuria JPN: Effect of Cytomodulin-10 (TGF-ß1 analogue) on wound healing by primary intention in a murine model. International Journal of Surgery 2009; 7: 460–465.
39. Hou-Dong L, Bin S and Ying-Bin X: Differentiation of Rat Dermal Papilla Cells into Fibroblast-Like Cells Induced by Transforming Growth Factor β 1. J Cutan Med Surg 2012; 16: 400–406.
40. Liu J, Wang Y and Pan Q: Wnt/β-catenin pathway forms a negative feedback loop during TGF-β1 induced human normal skin fibroblast-to-myofibroblast transition. J Dermatol Sci 2012; 65: 38–49.
41. Gordon JW, Shaw JA and Kirshenbaum LA: Multiple Facets of NF-κB in the Heart. Circ Res 2011; 108: 1122–1132.
42. Park YR, Sultan MdT and Park HJ: NF-κBsignaling is key in the wound healing processes of silk fibroin. Acta Biomater 2018; 67: 183–195.
43. Shibata A, Nagaya T and Imai T: Inhibition of NF-κB Activity Decreases the VEGF mRNA Expression in MDA-MB-231 Breast Cancer Cells. Breast Cancer Res Treat 2002; 73: 237–243.
44. Gaboriau-Routhiau V, Rakotobe S and Lécuyer E: The Key Role of Segmented Filamentous Bacteria in the Coordinated Maturation of Gut Helper T Cell Responses. Immunity 2009; 31: 677–689.
45. Greenlund AC, Morales MO and Viviano BL: Stat recruitment by tyrosine-phosphorylated cytokine receptors: An ordered reversible affinity-driven process. Immunity 1995; 2: 677–687.
46. Ivanov II, Frutos R de L and Manel N: Specific Microbiota Direct the Differentiation of IL-17-Producing T-Helper Cells in the Mucosa of the Small Intestine. Cell Host Microbe 2008; 4: 337–349.
47. Darnell JE. STATs and Gene Regulation. Science 1997; 277: 1630–1635.
48. Horvath CM and Darnell JE: The state of the STATs: recent developments in the study of signal transduction to the nucleus. Curr Opin Cell Biol 1997; 9: 233–239.
49. Darnell JE, Kerr lan M and Stark GR: Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins. Science (1979) 1994; 264: 1415–1421.
50. Miyazaki T, Kawahara A and Fujii H: Functional Activation of Jak1 and Jak3 by Selective Association with IL-2 Receptor Subunits. Science 1994; 266: 1045–1047.
51. Viaud S, Saccheri F and Mignot G: The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide. Science (1979) 2013; 342: 971–976.
52. Sorg H, Tilkorn DJ and Hager S: Skin Wound Healing: An Update on the Current Knowledge and Concepts. European Surgical Research 2017; 58: 81–94.
53. Medzhitov R: Origin and physiological roles of inflammation. Nature 2008; 454: 428–435.
54. Medzhitov R: Inflammation 2010: New Adventures of an Old Flame. Cell 2010; 140: 771–776.
55. Bagad AS, Joseph JA and Bhaskaran N: Comparative evaluation of anti-inflammatory activity of curcuminoids, turmerones, and aqueous extract of Curcuma longa. Adv Pharmacol Sci 2013; 2013: 1–7.
56. Ammon H and Wahl M: Pharmacology of Curcuma longa. Planta Med 1991; 57: 1–7.
57. Gao Y, Zhuang Z and Lu Y: Curcumin Mitigates Neuro-Inflammation by Modulating Microglia Polarization Through Inhibiting TLR4 Axis Signaling Pathway Following Experimental Subarachnoid Hemorrhage. Front Neurosci; 13. Epub ahead of print 15 November 2019. DOI: 10.3389/fnins.2019.01223.
58. Li Q, Sun J and Mohammadtursun N: Curcumin inhibits cigarette smoke-induced inflammation via modulating the PPARγ-NF-κBsignaling pathway. Food Funct 2019; 10: 7983–7994.
59. Rahimifard M, Maqbool F and Moeini-Nodeh S: Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation. Ageing Res Rev 2017; 36: 11–19.
60. Zhu T, Chen Z and Chen G: Curcumin attenuates asthmatic airway inflammation and mucus hypersecretion involving a PPAR γ -Dependent NF- κ B Signaling Pathway in-vivo and in-vitro. Mediators Inflamm 2019; 2019: 1–15.
61. Ashrafizadeh M, Rafiei H and Mohammadinejad R: Potential therapeutic effects of curcumin mediated by JAK/STAT signaling pathway: A review. Phytotherapy Research 2020; 34: 1745–1760.
62. Kahkhaie KR, Mirhosseini A and Aliabadi A: Curcumin: a modulator of inflammatory signaling pathways in the immune system. Inflammopharmaco 2019; 27: 885–900.
63. Hasanzadeh S, Read MI and Bland AR: Curcumin: an inflammasome silencer. Pharmacol Res 2020; 159: 104921.
64. Jolad SD, Lantz RC and Chen GJ: Commercially processed dry ginger (Zingiber officinale): Composition and effects on LPS-stimulated PGE2 production. Phytochemistry 2005; 66: 1614–1635.
65. Calder PC, Yaqoob P and Harvey DJ: Incorporation of fatty acids by concanavalin A-stimulated lymphocytes and the effect on fatty acid composition and membrane fluidity. Biochemical Journal 1994; 300: 509–518.
66. Yaqoob P, Newsholme EA and Calder PC: Influence of cell culture conditions on diet-induced changes in lymphocyte fatty acid composition. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1995; 1255: 333–340.
67. Li X-H, McGrath KCY and Tran VH: Attenuation of Proinflammatory Responses by S-[6]-Gingerol via Inhibition of ROS/NF-Kappa B/COX2 Activation in HuH7 Cells. Evidence-Based Complementary and Alternative Medicine 2013; 2013: 1–8.
68. Brouard C and Pascaud M: Effects of moderate dietary supplementations with n — 3 fatty acids on macrophage and lymphocyte phospholipids and macrophage eicosanoid synthesis in the rat. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1990; 1047: 19–28.
69. Chapkin RS, Akoh CC and Lewis RE: Dietary fish oil modulation of in-vivo peritoneal macrophage leukotriene production and phagocytosis. J Nutr B 1992; 3: 599–604.
70. Palombo JD, Demichele SJ and Lydon E: Cyclic vs Continuous Enteral Feeding With ω‐3 and γ‐Linolenic Fatty Acids: Effects on Modulation of Phospholipid Fatty Acids in Rat Lung and Liver Immune Cells. Journal of Parenteral and Enteral Nutrition 1997; 21: 123–132.
71. Dar NJ, Hamid A and Ahmad M: Pharmacologic overview of Withania somnifera, the Indian Ginseng. Cellular and Molecular Life Sciences 2015; 72: 4445–4460.
72. Sikandan A, Shinomiya T and Nagahara Y: Ashwagandha root extract exerts anti inflammatory effects in HaCaT cells by inhibiting the MAPK/NF κB pathways and by regulating cytokines. Int J Mol Med. Epub ahead of print 2 April 2018. DOI: 10.3892/ijmm.2018.3608.
73. Gupta M and Kaur G: Withania somnifera as a potential anxiolytic and anti-inflammatory candidate against systemic lipopolysaccharide-induced neuroinflammation. Neuromolecular Med 2018; 20: 343–362.
74. Yan Z, Zhong Y and Duan Y: Antioxidant mechanism of tea polyphenols and its impact on health benefits. Animal Nutrition 2020; 6: 115–123.
75. Scalbert A, Manach C and Morand C: Dietary Polyphenols and the Prevention of Diseases. Crit Rev Food Sci Nutr 2005; 45: 287–306.
76. Zhang H and Tsao R: Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects. Curr Opin Food Sci 2016; 8: 33–42.
77. Rahman SU, Li Y and Huang Y: Treatment of inflammatory bowel disease via green tea polyphenols: possible application and protective approaches. Inflammopharmacology 2018; 26: 319–330.
78. Nicholson JK, Holmes E and Kinross J: Host-Gut Microbiota Metabolic Interactions. Science (1979) 2012; 336: 1262–1267.
79. Balamurugan J and Lakshmanan M: Non-Steroidal anti-inflammatory medicines. in: introduction to basics of pharmacology and toxicology. Singapore: Springer Nature Singapore 2021; 335–352.
80. Mebratu Y and Tesfaigzi Y: How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle 2009; 8: 1168–1175.
81. Caughey G, Mantzioris E and Gibson R: The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nut 1996; 63: 116–122.
82. Sperling RI: The effects of dietary n -3 polyunsaturated fatty acids on neutrophils. Proceedings of the Nutrition Society 1998; 57: 527–534.
83. Efferth T and Oesch F: Anti-inflammatory and anti-cancer activities of frankincense: Targets, treatments and toxicities. Semin Cancer Biol 2022; 80: 39–57.
84. Sharma SK, Vij AS and Sharma M: Mechanisms and clinical uses of capsaicin. Eur J Pharmacol 2013; 720: 55–62.
85. Sato S and Mukai Y: <p> Modulation of chronic inflammation by quercetin: the beneficial effects on obesity</p>. J Inflamm Res 2020; 13: 421–431.
86. Blazsó G, Gábor M and Schönlau F: Pycnogenol ® accelerates wound healing and reduces scar formation. Phytotherapy Research 2004; 18: 579–581.
87. Burstein S: Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorg Med Chem 2015; 23: 1377–1385.
88. Sangiovanni E, Fumagalli M and Pacchetti B: <scp>Cannabis sativa</scp> L. extract and cannabidiol inhibit in-vitro mediators of skin inflammation and wound injury. Phytotherapy Research 2019; 33: 2083–2093.
89. Menghini L, Recinella L and Leone S: Devil’s claw (<scp>Harpagophytum procumbens</scp>) and chronic inflammatory diseases: A concise overview on preclinical and clinical data. Phytotherapy Research 2019; 33: 2152–2162.
90. Chrubasik S, Conradt C and Black A: The quality of clinical trials with Harpagophytum procumbens. Phytomedicine 2003; 10: 613–623.
91. Curcumin 2014; 113–204.
92. Medzhitov R: Inflammation 2010: New Adventures of an Old Flame. Cell 2010; 140: 771–776.
93. Jolad SD, Lantz RC and Solyom AM: Fresh organically grown ginger (Zingiber officinale): composition and effects on LPS-induced PGE2 production. Phytochemistry 2004; 65: 1937–1954.
94. Yan Z, Zhong Y and Duan Y: Antioxidant mechanism of tea polyphenols and its impact on health benefits. Animal Nutrition 2020; 6: 115–123.
95. Singh R, Akhtar N and Haqqi TM: Green tea polyphenol epigallocatechi3-gallate: Inflammation and arthritis. Life Sci 2010; 86: 907–918.
96. Varoni EM, Lo Faro AF and Sharifi-Rad J: Anticancer Molecular Mechanisms of Resveratrol. Front Nutr; 3. Epub ahead of print 12 April 2016. DOI: 10.3389/fnut.2016.00008.
97. Zhang Q, Luo P and Xia F: Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis. Cell Chem Biol 2022; 29: 1248-1259.e6.
98. Wallace JL: Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn’t the Stomach Digest Itself? Physiol Rev 2008; 88: 1547–1565.
99. Whelton A: Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 1999; 106: 13S-24S.
100. McGettigan P and Henry D: Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011; 8: 1001098.
101. Hood L and Friend SH: Predictive, personalized, preventive, participatory (P4) cancer medicine. Nat Rev Clin Oncol 2011; 8: 184–187.
102. Ginsburg GS and Willard HF: Genomic and personalized medicine: foundations and applications. Translational Research 2009; 154: 277–287.
103. Offit K: Personalized medicine: new genomics, old lessons. Hum Genet 2011; 130: 3–14.
104. Farokhzad OC and Langer R: Impact of Nanotechnology on Drug Delivery. ACS Nano 2009; 3: 16–20.
105. Wang AZ, Langer R and Farokhzad OC: Nanoparticle Delivery of Cancer Drugs. Annu Rev Med 2012; 63: 185–198.
106. Jones PA and Baylin SB: The Epigenomics of Cancer. Cell 2007; 128: 683–692.
107. Berger SL, Kouzarides T and Shiekhattar R: An operational definition of epigenetics: Figure 1. Genes Dev 2009; 23: 781–783.
108. Round JL and Mazmanian SK: The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009; 9: 313–323.
109. Honda K and Littman DR: The microbiota in adaptive immune homeostasis and disease. Nature 2016; 535: 75–84.
110. Hooper LV, Littman DR and Macpherson AJ: Interactions between the microbiota and the immune system. Science (1979) 2012; 336: 1268–1273.
111. Pittenger MF, Mackay AM and Beck SC: Multilineage potential of adult human mesenchymal stem cells. Science (1979) 1999; 284: 143–147.
112. Squillaro T, Peluso G and Galderisi U: Clinical trials with mesenchymal stem cells: an update. Cell Transplant 2016; 25: 829–848.
113. Phadtare P, Viswapriya V and Shinde V: Hybrid bionanocomposites as the advancements in biomedical utility. Hybrid Advances 2025; 8: 100365.
114. Chaudhari D, Muthal A and Mali A: Phytochemical and pharmacological activities of Tagetes erecta L: An updated review. Int J Herb Med 2024; 12: 10–15.
115. Salunke MR and Shinde V: Molecular insights and efficacy of guava leaf oil emulgel in managing non diabetic as well as diabetic wound healing by reducing inflammation and oxidative stress. Inflammopharmacology 2025; 33: 1491–1503.
     

     ---

     How to cite this article:

     Aher S, Prasad N, Pujari P, Salunke K and Salunke M: Molecular and cellular inflammatory modulators governing wound healing and tissue repair. Int J Pharmacognosy 2026; 13(6): 529-43. doi link: http://dx.doi.org/10.13040/IJPSR.0975-8232.IJP.13(6).529-43.

     ---

     This Journal licensed under a Creative Commons Attribution-Non-commercial-Share Alike 3.0 Unported License.