From traditional remedies to modern immunotherapy: A comparative review of selected Herbal immunomodulators

Introduction

The COVID-19 pandemic, which resulted in over 7.9 million deaths and 212 million disability adjusted life years (DALYs), was the main cause of the historic high in the worldwide burden of viral diseases in 2021. Beyond the pandemic, viral "disease of poverty" continues to pose a concern, causing 259.2 million DALYs and 8.7 million deaths annually. While HIV/AIDS remains a major cause of long-term morbidity with 40 million DALYs, other viruses exhibit different patterns. Since 1990, the death rate from acute hepatitis and rabies has decreased by more than 50% as a result of improved therapies. Geographically and economically, these burdens are highly stratified. A disproportionate amount of the health losses caused by HIV, Ebola, and rabies occur in nations with low sociodemographic indices (SDIs), especially in South Asia and Sub-Saharan Africa. A significant "prevention gap" makes this discrepancy worse because there is now no effective vaccine for about 75% of the most dangerous diseases. Additionally, the frequency of outbreaks more than 3,000 occurrences have been documented since 1996 highlights the increasing risks of zoonotic spillover brought on by urbanization and climate change. Global health security is seriously threatened by newly emerging and reemerging viral infections. New pathogens like SARS-CoV-2, MERS-CoV, and Nipah virus are examples of emerging illness, whereas formerly controlled infections like polio, yellow fever, and measles are examples of re-emerging diseases. Viral evolution, ecological upheavel, and human activity all contribute to their spread. Rapid urbanization and globalization make it possible for diseases to spread across continents more quickly than their incubation times, raising the possibility of global outbreaks.

Global Burden of Viral Infections

Global health security is seriously threatened by newly emerging and reemerging viral infections. New pathogens like SARS-CoV-2, MERS-CoV, and Nipah virus are examples of emerging illness, whereas formerly controlled infections like polio, yellow fever, and measles are examples of re-emerging diseases. Viral evolution, ecological upheavel, and human activity all contribute to their spread. Rapid urbanization and globalization make it possible for diseases to spread across continents more quickly than their incubation times, raising the possibility of global outbreaks. Zootnotics spillover events, in which viruses spread from animals to humans, have increased as a result of envioronmental changes like deforestation and climate change that have changed the distribution of vectors like Aedes mosquitoes and displaced species. Additionally, viruses have a high degree of genomic flexibility, which enables quick recombination, mutation, and reassortment. Additionally, viruses have a high degree of genomic flexibility, which enables quick recombination, mutation, and reassortment. As demonstrated by novel influenza strains and COVID-19 variations, this allows them to adapt to new hosts, become resistant to antiviral medications, and avoid vaccine-induced immunity. The comeback of vaccine-preventable diseases has also been exacerbated by gaps in vaccination coverage and a decline in public trust, which has led to localized outbreaks turning into regional disasters. In addition to their negative effects on health, these illnesses put a burden on healthcare systems, cause economic disruption, and necessitate stringent public health measures. Current immunomodulatory and antiviral treatments have a number of drawbacks. The quick emergence of drugresistant viruses frequently undermines direct-acting antivirals, which target certain stages of viral reproduction. Additionally, a lot of antivirals have low bioavailability and poor solubility, necessitating greater dosages that may be harmful to the kidneys and liver. The limited treatment window is another drawback because many antivirals cannot eradicate latent viral reservoirs and must be taken within 48-72 hours of the onset of symptoms. Immunomodulatory treatments may reduce immunity, making patients more vulnerable to recurrent bacterial or fungal infections, even if their goal is to manage overactive immunological responses. Additionally, biologic medications may cause anti-drug antibodies, which lessen the efficacy of treatment. Resistance, toxicity, and accessibility problems further complicate the management of viral infections. While offtarget toxicity can harm host tissues like the kidneys and bone marrow, high mutation rates encourage medication resistance. Many people are unable to receive treatment because to accessibility difficulties, such as high pricing, patent restrictions, inadequate diagnostic facilities, and supply-chain constraints. These interrelated issues show that better antiviral tactics, combination treatments, and tailored medicine are required to improve treatment outcomes and strengthen global health preparedness.

Rationale for Exploring Herbal Immunomodulators

Traditional medicine has traditionally relied on medicinal plants, but current biomedical research aims to confirm their processes and therapeutic efficacy. Since traditional antiviral and immune-targeting treatments frequently have drawbacks such high prices, adverse effects, and uneven performance during acute inflammatory reactions, this interest has grown in response to the growth of emerging and re-emerging viral infections. Herbal remedies contain a variety of phytochemicals that can affect several immune system components, in contrast to synthetic medications that usually work on a single molecular target. According to studies, some botanical substances can improve immune activities such T-cell responses, cytokine modulation, natural killer (NK) cell activity, and macrophage activation. This supports a hostdirected approach that supports pathogen-specific antiviral therapies. However, there is still a large translational gap that prevents the use of herbal remedies in contemporary clinical practice. There are comparatively few large-scale human clinical trials, and the majority of the evidence that is now available is based on in vitro investigations or animal studies. The lack of regulated herbal formulations, irregular dosage schedules, and variations in phytochemical makeup are further difficulties. It is challenging to convert encouraging test results into trustworthy treatment outcomes for patients because of these constraints. Therefore, to ascertain the true therapeutic potential of herbal immunomodulators, thorough examination and more robust clinical data are crucial. The increasing incidence of chronic lifestyle diseases and the need for safer therapies have also raised scientific interest in herbal medicines. The compounds found in plants and their biological interconnections are increasingly studied using cutting-edge technologies including metabolomics, big data, genomics, and artificial intelligence. Delivery methods based on nanotechnology have also increased the bioavailability of substances like artemisinin and curcumin. Modern research increasingly focuses on multi-target immune modulation involving pathways like the MAPK and NF-κB signaling pathways, providing a comprehensive approach to illness management, with support from the World Health Organization's standardization initiatives.

Objective and Scope of the Review

With a focus on translational potential and research gaps, this structured narrative review objectively assesses the molecular and clinical data supporting particular herbal immunomodulators in viral infections.

Methodological Approach 2.1 Literature Search Strategy

 Databases searched (e.g., PubMed, Scopus, Web of Science)  Keywords used (e.g., "herbal immunomodulators," "viral infections," "cytokines," specific plant names)  Time frame (e.g., 2000-2025) [1]

Inclusion and Exclusion Criteria Inclusion

Immunological Basis of Host Defense against Viral

Infections: A multi-tiered system that combines innate and adaptive immunity protects the host from viral infections. Natural Killer (NK) cells lyse infected cells and Toll-Like Receptors (TLRs) and Type I Interferons (IFN-α/β) impede replication. Adaptive immunity uses CD8+ Cytotoxic T cells to destroy infected cells and B cells to produce antibodies.

Innate Immune Responses

The body's immediate, non-specific first line of defense is the innate immune response, which is active from birth and neutralizes pathogens like bacteria and viruses without the need for prior exposure. In addition to a specialized cellular network of phagocytes (neutrophils and macrophages) and Natural Killer (NK) cells that engulf and eliminate invaders, this system uses chemical and physical barriers such as the skin and antimicrobial enzymes in saliva to prevent entry. Pattern Recognition Receptors (PRRs) control detection by recognizing common microbial signatures (PAMPs), which set off a series of cytokines and the complement system to cause inflammation. The innate response signals the adaptive immune system to create a more focused, longterm defense while simultaneously offering vital protection by quickly attracting white blood cells and limiting infections.

Adaptive Immune Responses

Long-term immunological memory is provided by the adaptive immune response, a particular defense mechanism powered by B and T cells. It has two primary branches: cell-mediated immunity, in which T cells eliminate malignant or infected cells, and humoral immunity, in which B cells generate antibodies against external infections. The technique guarantees a quick reaction to upcoming illnesses by producing memory cells through clonal growth, a concept used by vaccines.

Immune Dysregulation in Severe Viral Infections

Immune dysregulation in severe viral infections makes the body's defenses a major source of illness instead of clearing the virus. Tissue damage and organ failure result from a cytokine storm, which is defined by an overabundance of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β. At the same time, the adaptive immune system exhibits deficiencies such T-cell fatigue and lymphopenia. The impaired interferon response, which facilitates high initial viral replication, is a crucial determinant. Through processes like NET formation, dysfunctional neutrophils and monocytes also contribute to thrombosis and inflammation. Immunomodulators, JAK inhibitors, and supportive care are examples of management techniques. A cytokine storm, which is an uncontrollably high level of inflammatory proteins that harm organs, can be brought on by severe viral infections. Immune exhaustion, in which immune cells like T-cells lose their capacity to effectively fight the pathogen, might eventually result from this acute phase of inflammation turning into chronic inflammation with continuous immunological activation and tissue damage. When taken as a whole, these mechanisms allow the immune response to become the primary source of disease pathology rather than a preventive one.

Selected Herbal Immunomodulators: Mechanistic and Experimental Evidence 4.1 Withania somnifera

Native to India, the Middle East, and some regions of Africa, Withania somnifera is a tiny shrub in the Solanaceae family. Often referred to as ashwagandha, the plant has been used extensively in ancient medical systems, especially Ayurveda, where its leaves and roots are employed for therapeutic purposes. The plant's pharmacological qualities are thought to be caused by a number of bioactive components, such as alkaloids, flavonoids, saponins, and withanolides (steroidal lactones). According to experimental research, Withania somnifera extracts have immunomodulatory effects via a variety of mechanisms. The improvement of innate immune responses, especially through increased activity and proliferation of natural killer (NK) cells, is one of the most commonly reported benefits. NK cells are crucial for the host's defense against tumor cells and viral infections. In experimental settings, Withania somnifera has been demonstrated to boost white blood cell counts and macrophage phagocytic activity. Modulation of the hypothalamic-pituitary-adrenal (HPA) axis is another significant mechanism. It is well recognized that prolonged stress raises cortisol levels, which can weaken host defense systems and inhibit immunological function. According to research, Withania somnifera has adaptogenic qualities that may prevent immunological suppression brought on by stress by controlling cortisol levels and boosting immune cell activity. These results are corroborated by animal research, which shows that administering Withania somnifera can improve NK cell and macrophage function, boost leukocyte numbers, and reverse stress-induced myelosuppression. These immunomodulatory effects point to a possible function for the plant in promoting host immunological responses. Withania somnifera's adaptogenic and stress-reducing qualities have been the main focus of human clinical research; multiple studies have shown improvements in stress-related measures and decreases in serum cortisol levels. Additionally, several research show that supplementation increases immune cell function. However, since many studies have relatively small sample sizes and brief intervention periods, it is important to evaluate these results carefully. Despite encouraging experimental results, there are still a number of methodological issues. Direct comparisons between studies are made more difficult by variations in plant extracts, variations in dosage schedules, and the absence of standardized preparations. Furthermore, judgments about long-term efficacy and safety are limited because the majority of clinical trials have been carried out with small sample numbers and brief follow-up periods.Overall, by modifying innate immune responses and stress-related immunological pathways, Withania somnifera has possible immunomodulatory action. However, to determine its decisive significance in immune support and viral infection treatment, more extensive, carefully planned clinical trials utilizing standardized formulations are needed.

Tinospora cordifolia

The perennial vine Tinospora cordifolia (Giloy) has heartshaped leaves, aerial roots, succulent stems, and corky bark. It has red-orange drupes and greenish-yellow blooms. Its stem is highly valued in Ayurveda, where it is used to cure skin conditions, rheumatism, gout, jaundice, fever, and diabetes. While generally safe in the short term, excessive use might aggravate autoimmune diseases, damage the liver, and interfere with pregnancy or surgery. Guduchi/Giloy, or Tinospora cordifolia, is a potent immunomodulator that balances cytokine levels and increases macrophage function. Alkaloids and polysaccharides activate macrophages, increasing phagocytosis and nitric oxide and ROS generation through TLR4/TLR6-NF-κB pathways. In infections, it increases IL-1β, IL-6, and TNF-α; in chronic inflammation, it suppresses IL-6, TNF-α, and IL-17, supporting Th1/Th2 balance.

Effectiveness in leukocytosis, arthritis, and infections is confirmed by experimental models. Clinically, it helps treat diabetic wounds, dengue, HIV, allergic rhinitis, and childhood immunity. Lack of standardization, few human studies, and safety issues including hepatotoxicity from contaminated formulations are some of the drawbacks, though.

Panax ginseng

For thousands of years, traditional medicine has utilized Panax ginseng, also known as Asian or Korean ginseng, a perennial herb native to East Asia, as an adaptogen to strengthen the body's tolerance to exhaustion and stress. Its medicinal effects on the immune system, cognitive function, and energy levels are attributed to its active constituents, called ginsenosides. Due mostly to ginsenosides and polysaccharides, Panax ginseng, also known as Asian/Korean ginseng, is a well-researched adaptogen with potent immunomodulatory effects. These substances enhance macrophage phagocytosis, modulate cytokines, and promote T/B cell proliferation via controlling the NF-κB, MAPK, and PI3K/Akt pathways. Ginseng increases vaccine responses; in influenza investigations, it doubles NK cell activity and antibody levels; in COVID-19 models, it strengthens IgG/IgA responses. HIV/AIDS patients have better CD4+ counts, more NK cytotoxicity, and fewer respiratory infections, according to clinical research. Consistent quality control is crucial for therapeutic usage because of issues like adulteration, isomer complexity, ginsenoside potency inconsistency, and a lack of worldwide standardization.

Curcuma longa

Turmeric is a perennial herbaceous plant that belongs to the ginger family (Zingiberaceae) and is indigenous to Southeast Asia and the Indian subcontinent. Its botanical name is Curcuma longa. The main reason it is grown is for its rhizomes, which are underground stems that are processed into the vivid yellow-orange spice known as "Indian Saffron" or "Golden Spice". Curcumin, a polyphenol with potent anti-inflammatory and antiviral properties, is responsible for the medicinal properties of Curcuma longa, or turmeric. It suppresses cytokines (TNFα, IL-1β, and IL-6), inhibits enzymes like COX-2, iNOS, and LOX, and controls the NF-κB, MAPK, JAK-STAT, and NLRP3 pathways. Curcumin reduces the expression of inflammatory genes by inhibiting IKK activation, which stops NF-κB nuclear translocation and DNA binding. It suppresses influenza replication, reduces cytokine storms, and obstructs SARS-CoV-2 entry and protease activity in viral models. Clinical research reveal reduced levels of MCP-1 and IL-6 in COVID-19 survivors. Piperine coadministration and nano formulations greatly improve absorption and therapeutic potential despite low bioavailability.

Comparative Evaluation of Evidence Strength

The therapeutic potential of Curcuma longa, Panax ginseng, Tinospora cordifolia, and Withania somnifera is supported by a large body of traditional knowledge, but the transition to modern clinical validation remains uneven across these species.

Discussion of Evidence Challenges

The comparative analysis reveals that the majority of the mechanistic evidence supporting herbal immunomodulators comes from in vitro and animal research, where notable immuneregulatory effects have been noted. However, due to inconsistent extract standardization and rather few human studies, the use of these findings in therapeutic practice is still restricted. These drawbacks highlight the necessity of more extensive, carefully planned randomized controlled trials to confirm the therapeutic efficacy of herbal immunomodulators.

Predominance of Preclinical Data

The majority of the scientific literature for all four plants is found in preclinical research. While studies in mice for Withania somnifera show notable improvements in physical endurance and Tinospora cordifolia demonstrates high antiinflammatory potential, these models frequently use doses (mg/kg) that are difficult to replicate in human safety profiles.

Limited Large-Scale Randomized Trials

Curcuma longa and Withania somnifera have progressed into more human trials, but Tinospora cordifolia research is often limited to small-scale safety pilots (e.g., n=30). Phase III multicenter trials for these botanicals are conspicuated by high costs and the difficulty of obtaining patents for naturally occurring compounds.

Variability in Formulations

Depending on the extraction technique and the plant portion used (e.g., W. somnifera root vs. stem), these plants' chemical profiles vary significantly. The amounts of active markers in commercial products, like ginsenosides in Panax ginseng, vary greatly, ranging from less than 1% to more than 6%. Because of this discrepancy, conclusions drawn from one clinical research might not apply to another formulation of the same plant.

Clinical Translation Challenges

The transition of Curcuma longa, Panax ginseng, Tinospora cordifolia, and Withania somnifera from traditional use to mainstream clinical applications is hindered by several structural and biological hurdles.

Standardization and Quality Control Variability in Phytochemical Composition

Environmental conditions have a significant impact on the concentration of secondary metabolites, such as curcuminoids in turmeric, ginsenosides in ginseng, and withanolides in ashwagandha. The chemical composition of the raw plant material might vary significantly depending on soil quality, altitude, and harvesting time. For instance, research has revealed that the amount of withaferin A in various commercial preparations of Withania somnifera varies by up to 70 times.

Dose Inconsistencies

Different producers employ different solvents and ratios in the absence of a worldwide standard for extraction, producing "extracts" that are not biologically similar. Only 58% of products had the levels of active curcuminoids stated on the label, according to a study on curcuma supplements. Clinicians find it challenging to establish a precise, repeatable therapeutic dose because of this lack of consistency.

Safety and Herb-Drug Interactions

Pharmacokinetic interactions mainly occur through the modulation of the Cytochrome P450 enzyme system, which is responsible for metabolizing approximately 70-80% of clinically used drugs. Following are the CYP enzymes modulation of the herbs -Withania somnifera Panax ginseng, Tinospora cordifolia and curcumin:

Turmeric (Curcumin): Exhibits notable in-vitro inhibition of CYP17A1 (a key enzyme in steroid biosynthesis) along with CYP1A2, CYP2C9, and CYP3A4. Although high oral doses in humans (up to about 8 g) are generally considered safe, such inhibition may alter the metabolism of medications processed by these enzymes, including some antidepressants and NSAIDs.

Panax ginseng: This herb is reported to inhibit CYP3A4 one of the most important drugmetabolizing enzymes as well as CYP1A2. In clinical practice, this inhibition may elevate the risk of toxicity for drugs with a narrow therapeutic range, such as the anticoagulant Warfarin. Tinospora cordifolia: It contains the bioactive compound Berberine, which has demonstrated inhibitory effects on CYP2C9, CYP2D6, and CYP3A4.

Withania somnifera: Aqueous extracts generally show minimal inhibitory activity toward CYP3A4 and CYP2D6, suggesting that it may present a lower risk of drug-enzyme interactions when co-administered with many commonly metabolized drugs compared to herbs like turmeric or ginseng.

Potential

Interactions with Antivirals or Immunosuppressants: Plants with immunomodulatory qualities, such as Tinospora cordifolia and Withania somnifera, may potentially interfere with the effectiveness of immunosuppressive drugs (like cyclosporine) or biological therapies used for autoimmune diseases or following transplants. Additionally, taking Panax ginseng with some antivirals, such as raltegravir, may raise the risk of liver damage.

Absence of lengthy-Term Safety Trials: Despite the lengthy history of traditional usage of these plants, current clinical evidence is frequently restricted to short-term research (e.g., 21 to 90 days). The safety of continued highdose supplementation with respect to possible cumulative toxicity cannot be conclusively established due to a lack of multi-year longitudinal evidence.

Regulatory Considerations

There is a dearth of worldwide harmonization in the regulatory environment for these botanicals. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the FDA in the US regulates these goods as dietary supplements. Within this framework: • Although manufacturers do not need pre-market FDA approval for efficacy, they are accountable for ensuring safety and truthful labeling before to commercialization. • No product may make a claim to "diagnose, treat, cure, or prevent" any illness. Globally, regulations differ greatly. For example, Canada and Australia regulate these items more like pharmaceuticals, requiring pre-market registration and evidence-based claims. Global clinical validation is hampered by this diversity since a supplement that is deemed safe in one area can be subject to more stringent regulations in another.

Limitations and Bias in Current Research

To ensure a rigorous and high-maturity evaluation of Curcuma longa, Panax ginseng, Tinospora cordifolia, and Withania somnifera, it is essential to acknowledge the systemic limitations that currently affect the quality of botanical research. Current research on medicinal plants including Withania somnifera, Tinospora cordifolia, Curcuma longa, and Panax ginseng has a number of limitations that limit their wider clinical acceptability and use. Small clinical sample sizes are a significant drawback. Pilot trials with small participant groups provide the majority of the clinical evidence currently available, particularly for Tinospora cordifolia and Withania somnifera. These studies are helpful in assessing initial safety and therapeutic potential, but they don't have the statistical power to identify uncommon side events or minute clinical advantages. Additionally, Type I errors in which random observations are mistakenly perceived as significant treatment effects are more likely to occur in small samples. A lack of multicenter and multinational trials is another significant problem. Many investigations are carried out in isolated research facilities, frequently in areas where these plants have long been used, like Korea for ginseng or India for Ayurveda. Because differences in genetic background, diet, and environmental factors may affect treatment outcomes in other groups, this regional concentration restricts the generalizability of the results. The overinterpretation of in vitro results is another issue. The issue known as the "bioavailability gap" occurs when botanical research frequently extrapolates laboratory (testtube) results directly to human clinical effects. Curcuma longa, for example, exhibits potent anticancer effect in cell culture tests; however, quick metabolism and limited intestinal absorption make it unlikely to reach comparable amounts in human plasma. As a result, drawing judgments about clinical efficacy based only on molecular docking or cellline research may be deceptive. Furthermore, a major factor in herbal research is publication bias. Studies showing neutral or negative results are less likely to be published than those showing positive results for herbs like Withania somnifera and Panax ginseng. This "file drawer effect" distorts the idea of effectiveness. Lastly, financial bias may be introduced by industry influence. Independent replication and objective clinical evaluation are more challenging when research supported by producers of standardized extracts (such as proprietary formulations) uses unique mixes and selectively emphasizes positive results.

Future Research Directions

Advanced study on medicinal herbs including Curcuma longa, Panax ginseng, Tinospora cordifolia, and Withania somnifera is necessary to bridge the gap between traditional herbal medicine and contemporary evidence-based healthcare. To increase therapeutic reliability and clinical acceptance, future research should move away from separate phytochemical studies and toward integrated clinical and technical approaches. Enhanced bioavailability and advanced standardization are two important study areas. The medicinal potential of many plant-derived chemicals, like the active ingredient in Curcuma longa, is limited by their poor solubility and quick metabolism. To increase absorption and stability, new approaches include delivery systems based on nanotechnology, such as liposomes and polymeric nanoparticles. Future quality-control procedures should also prioritize phytochemical fingerprinting, utilizing cuttingedge analytical methods like DNA fingerprinting with highperformance liquid chromatography. These techniques guarantee batch-to-batch uniformity in herbal formulations and enable thorough metabolomic analysis. Multi-target and synergistic research is another crucial area of study. Instead of using single plants, traditional medical systems usually use polyherbal mixtures. The combined immunomodulatory impact of Tinospora cordifolia and Withania somnifera is one example of a synergistic interaction of herbs that should be investigated. Furthermore, integrated "omics" technologies, such as transcriptomics, metabolomics, and genomics, can be used in a systems biology approach to assist researchers comprehend how complex herbal extracts interact with several biological pathways at once. Enhancing clinical research methods is also crucial. To verify effectiveness and identify uncommon side effects, extensive Phase III randomized controlled studies involving numerous sites and a variety of demographics are required. To assess the safety of long-term herbal usage, observational studies that last longer than a year are also necessary. Lastly, pharmacogenomics and customized therapy should be included in future studies. Individual responses to herbal compounds may be influenced by genetic polymorphisms in drug-metabolizing enzymes, such as the Cytochrome P450 enzyme system. Precision phytotherapy, dosage optimization, fewer herb-drug interactions, and the discovery of new therapeutic uses for conventional medicinal plants could all be made possible by combining pharmacogenomic data with artificial intelligence and bigdata analytics.

Conclusion

Curcuma longa, Panax ginseng, Tinospora cordifolia, and Withania somnifera are examples of medicinal plants that exhibit significant pharmacological characteristics, such as antiinflammatory, antioxidant, adaptogenic, and immunomodulatory actions, connecting traditional ethnobotanical knowledge with contemporary medicine. However, because they rely more on tiny pilot trials and preclinical research than on large-scale randomized clinical trials, their clinical integration is still restricted. Variability in herbal standards and possible interactions with the Cytochrome P450 enzyme system present further difficulties. Stronger multicenter clinical trials, better standardization, and cutting-edge strategies like systems biology and nanotechnology-based delivery are needed in the future to increase bioavailability and guarantee safe, evidence-based therapeutic use.

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